Formulations for di- or tri-halogenated methane generation and uses thereof

Abstract

The disclosure provides veterinary compositions, which comprise one or more compounds that can have a methane inhibiting effect when the composition is administered to an animal. Veterinary compositions can also be included in a bolus, a pellet or a feed supplement. Uses of the veterinary composition, the bolus, pellet or feed supplement are also provided.

Description

Formulations for di- or tri-halogenated methane generation and uses thereof

[0001] This application claims priority to European priority application no. EP23207055 (filed on 31 October 2024), the entire contents of which is incorporated by reference.Field of the disclosure

[0002] The present disclosure relates to veterinary compositions which may inhibit methane production in ruminant animals and administration forms and uses thereof.Background of the disclosure

[0003] In order to reduce the adverse effects of agriculture, substances may be administered to animals that can ameliorate these adverse effects. For instance, various methane and nitrification inhibiting agents are known to be administered to animals to reduce or mitigate the adverse effects of the methane and nitrate containing compounds produced by the animals.

[0004] However, despite current efforts, climate change is creating a wide range of environmental and social impacts globally. As a result, there has been a global push to reduce harmful greenhouse gas (GHG) emissions in an effort to reduce the effects of climate change.

[0005] The agricultural sector is considered to be a major source of GHG emissions.

[0006] The main GHGs released by agriculture are methane (CH4) and nitrous oxide (N2O), with the main source of methane emission attributed to livestock. Most methane is thought to be emitted by cattle during ructus, i.e. the oral regurgitation of air from the stomach.

[0007] A reduction of methane emissions is expected to be helpful in reducing the effects of global warming.

[0008] Release of GHGs by animals may also have adverse effects on animal productivity. Any feed that is converted to a compound which is subsequently expired or released by the animal is an energy source that has not been converted to a productive use.

[0009] In view of the need for a reduction of greenhouse gas emissions, and particularly methane emissions, from animals, and particularly from ruminant animals, there is a need for improved methane inhibiting compounds, compositions and dosage forms fordelivery to animals. An improvement may be particularly desirable if it improves one or more of ease of manufacture, ease or length of storage, dosage schedule, and safety.Summary of the disclosure

[0010] The present disclosure relates to veterinary compositions which may inhibit methane production in ruminant animals as well as to administration (ie dosage) forms and uses of such compositions. The present disclosure is exemplified with reference to embodiments, which however, are not to be seen as limiting on the scope of the disclosure. All documents cited herein are incorporated by reference. All embodiments disclosed herein can be combined as appropriate unless stated otherwise.

[0011] In an aspect the disclosure provides a veterinary composition, the veterinary composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically or veterinary acceptable excipient,formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br andCl; and at least two of Y1 , Y2 and Y3 are selected from the group consisting of I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), OH, H, optionally substituted Ci-is-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

[0012] In some embodiments, X is formula (li). In some embodiments, X is formula (lii).In some embodiments, X is formula (liii).

[0013] In some embodiments, L is absent.

[0014] In some embodiments, wherein R is selected from the group consisting of OH, N(Ra)2, and optionally substituted Ci -is-aliphatic.

[0015] In an aspect the disclosure provides a composition comprising a compound having the structure of formula (Hi) or formula (Ilii),formula (Hi) formula (Ilii) or a pharmaceutically acceptable salt thereof, wherein(1 ) each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl;(2) L is CH2, O, NH, or absent (preferably L is O or NH); and(3) R is an optionally substituted group selected from the group consisting of OH, Ci- -alkyl, Ci- -alkoxy and Ci-s-alkyl-COOH; wherein if R is substituted, then it is substituted by one or more groups independently selected from the group consisting of Ci -s-alkyl, -OH, halogen, NH2, -COOH, -CO-Ci-4-alkyl, -COO-Ci-4-alkyl, -NO2, and more particularly is substituted with one or more groups selected from the group consisting of Ci -2-alkyl, -OH, halogen, NH2, -COOH, -COMe, and -COOMe.

[0016] In an aspect the disclosure provides a veterinary composition comprising a compound having the structure of formula (la),Y1Y2- C - ZY I3formula (la)or a pharmaceutically acceptable salt thereof, wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from the group consisting of I, F, Br and Cl; and wherein Z is(1 ) a group that will be cleaved off the carbon atom shown in formula (la) when the composition is exposed to the environment inside the rumen of a ruminant animal; or(2) a group that will be cleaved off the carbon atom shown in formula (la) when formula (la) is contacted with a second activating agent, wherein the second activating compound will come into contact with the formula (la) only when the composition is exposed to the environment inside the rumen of a ruminant animal; wherein cleavage of Z from formula (la) generates a compound of formula (lb)YiY2- C - HY I3formula (lb) or a pharmaceutically acceptable salt thereof.

[0017] In an aspect the disclosure provides a composition comprising a compound having the structure of formula (la),Y1Y2- C - ZY I3formula (lb) or a pharmaceutically acceptable salt thereof, wherein each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl; and wherein Z is(1 ) a group that will be cleaved off the carbon atom shown in formula (la), such that Z is replaced by a hydrogen atom when the composition is exposed to the environment inside the rumen of a ruminant animal; or(2) a group that will be cleaved off the carbon atom shown in formula (la), such that Z is replaced by a hydrogen atom when formula (la) is contacted with a second activatingcompound that is comprised in said composition, wherein the second activating compound will come into contact with the formula (la) only when the composition is exposed to the environment inside the rumen of a ruminant animal.

[0018] In some embodiments, Z is selected from COOH, optionally substituted Ci-wester, optionally substituted Ci- -amide, an acid halide, and an acid anhydride.

[0019] In an aspect of the disclosure, there is provided a di- or tri-halogenated methane release system, the release system comprising: a compound of the disclosure, a housing, and a solid with a melting point from about 28 °C to about 45 °C, wherein the compound and the solid are within the housing, wherein the solid, or the combination of both the solid and the housing encapsulate or substantially encapsulate the compound.

[0020] In another aspect, the disclosure provides a bolus for administration to a ruminant animal that comprises a compound or a composition of the disclosure. In another aspect, the disclosure provides a pellet for administration to a ruminant animal that comprises a compound or a composition of the disclosure. In another aspect, the disclosure provides a feed supplement for a ruminant animal that comprises a compound or a composition of the disclosure.

[0021] In another aspect, the disclosure relates to the use of the compound, the composition, the bolus, the di- or tri-halogenated methane release system, the pellet or the feed supplement as described herein for use in reducing methane production in a ruminant animal. In another aspect, the disclosure relates to the use of the feed supplement described herein for admixing the feed supplement to drinking water of a ruminant animal, optionally wherein the feed supplement is dissolvable in water.

[0022] In another aspect, the disclosure relates to a method of treating a ruminant animal to reduce methane production in said animal, comprising administering to said animal the compound, the composition, the bolus, the di- or tri-halogenated methane release system, the pellet and / or the feed supplement as defined herein in an effective amount.

[0023] In another aspect, the disclosure relates to a method of improving production of a ruminant animal, comprising administering to said animal the compound, the composition, the bolus, the di- or tri-halogenated methane release system, the pellet and / or the feed supplement as defined herein in an effective amount.

[0024] In another aspect, the disclosure provides a method of preparing a compound, composition, bolus, pellet and / or feed supplement as defined herein.

[0025] In an aspect of the disclosure there is provided a method for producing a di- or tri-halogenated methane release system according to the disclosure, the method comprising: selecting a compound of the disclosure, a housing and a solid, wherein the solid has a melting point from about 28 °C to about 45 °C, inserting the compound into the housing, inserting the solid in the housing, either by a) melting the solid or obtaining the solid as a molten liquid, pouring the molten solid in the housing such that once it solidifies the combination of both the solid and the housing encapsulate or substantially encapsulate the compound, and allowing the molten solid to cool and solidify, or b) forming a matrix with the compound prior to insertion of the compound in the housing, optionally closing the housing to encapsulate or substantially encapsulate the compound and the solid or molten solid in the housing.

[0026] Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.

[0027] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

[0028] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0029] Further aspects of the present disclosure and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Detailed Description of the Disclosure

[0030] In some embodiments, the disclosure seeks to provide improved compositions, devices, systems and methods for administering to an animal for reducing methane production, where improvements can be for example in terms of one or more of volatility, control of release rate and versatility and safety of administration.

[0001] In an aspect, the disclosure provides a veterinary composition, the veterinary composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically or veterinary acceptable excipient,formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from the group consisting of I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci-w-heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1)(Y2)(Y3), OH, H, optionally substituted Ci-is-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

[0032] In an aspect, the disclosure provides a composition comprising a compound having the structure of formula (Hi) or formula (llii),formula (Hi) formula (llii) or a pharmaceutically acceptable salt thereof, wherein (1 ) each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl; (2) L is CH2, O, NH, or absent (preferably L is O or NH); and (3) R is an optionally substituted group selected from the group consisting of OH, Ci-is-alkyl, Ci- -alkoxy and Ci-s-alkyl-COOH; wherein if R is substituted, then it is substituted by one or more groups independently selected from the group consisting of C-i-s-alkyl, -OH, halogen, NH2, -COOH, -CO-C1-4- alkyl, -COO-Ci-4-alkyl, -NO2, and more particularly is substituted with one or more groups selected from the group consisting of C-i-2-alkyl, -OH, halogen, NH2, -COOH, - COMe, and -COOMe.

[0033] The following definitions are meant to further define certain terms used in the context of the present disclosure. If a particular term used herein is not specifically defined, the term should not be considered to be indefinite. Rather, such terms are to be construed in accordance with their meaning as regularly understood by the skilled artisan in the field of art to which the disclosure is directed, particularly in the field of organic chemistry, pharmaceutical sciences and medicine.

[0034] Some of the compounds and salts according to the disclosure may exist in different crystalline forms (polymorphs), all of which are within the scope of the disclosure. Some of the compounds according to the disclosure may be present as cocrystals, all of which are within the scope of the disclosure.

[0035] The term “pharmaceutically acceptable” means that the respective entity (for instance, a prodrug, a salt of a prodrug) which upon administration to a subject (for instance, a ruminant), is capable of providing (directly or indirectly) a di- and / or trihalogenated methane compound or an active metabolite or residue thereof, and is not unacceptably harmful to the subject (or animal). Similarly, term “veterinary acceptable” means that the respective entity (for instance, a prodrug, a salt of a prodrug) which upon administration to an animal subject (for instance, a ruminant), is capable of providing(directly or indirectly) a di- and / or tri-halogenated methane compound or an active metabolite or residue thereof, and is not unacceptably harmful to the animal.

[0036] Compositions according to the present disclosure, comprising a compound according to the present disclosure or a pharmaceutically acceptable salt thereof and a a pharmaceutically or veterinary acceptable excipient, such as a pharmaceutically acceptable excipient, include particularly compositions suitable for oral administration, for instance in the form of a controlled release systems (e.g. sustained release, pH- controlled release, delayed release, repeat action release, prolonged release, extended release). Suitable examples of controlled release systems include a bolus, pellets, semipermeable matrices of solid hydrophobic polymers enclosing the compound of the disclosure, which matrices may for instance be in form of films or microcapsules, or controlled release solid dosage forms, e.g. core tablets, coated tablets and multi-layer tablets.

[0037] The composition of the disclosure can take different forms including suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for re-constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0038] The “dispersing agent” as used herein is a substance added to a mixture or suspension of solid or liquid particles in a composition to improve separation of the particles and to prevent their settling or clumping. The dispersing agent may act to evenly disperse compound(s) as defined herein in the composition of the disclosure. Suitable dispersing agents include ionic (such as anionic) and non-ionic surfactants, poly ethylene glycol, sugars, dry inert powder materials and derivatives thereof, glucosides and others and the skilled person will be aware of suitable compounds and polymers to be used as dispersing agents.Chemical definitions

[0039] The term “C1-C18 aliphatic” refers to saturated and unsaturated, straight chain, and branched hydrocarbons having from 1 to 18 carbon atoms. Those skilled in the art will appreciate that aliphatic groups include, for example, alkyl, alkenyl, and alkynyl groups. In some embodiments, aliphatic groups comprise from 1 -12, 1 -10, 1 -8, 1 -6, 1 - 4, 1 -3, 1 -2, 2-4, 2-3 or 3-4 carbon atoms. In some embodiments C1-C18 aliphatic groups have any single integer of carbon atoms within 1 -18. In some embodiments, the aliphaticgroup is an alkyl group. In some embodiments, the aliphatic group is an alkenyl group. In some embodiments, the aliphatic group is an alkynyl group. In some embodiments, the aliphatic group is a haloalkyl group.

[0040] The term “C1-C18 heteroaliphatic” refers to aliphatic groups, wherein one or more chain atoms are independently replaced with a heteroatom selected from oxygen, nitrogen and sulfur, resulting in a chain having from 1 to 18 atoms inclusive of carbon and heteroatoms. In some embodiments, heteroaliphatic groups comprise from 1 -12, 1 - 10, 1 -8, 1 -6, 1 -4, 1 -3, 1 -2, 2-4, 2-3 or 3-4 atoms. In some embodiments heteroaliphatic groups have 1 , 2, 3 or 4 atoms. Typically the C1-C4 heteroaliphatic groups comprise 1 or 2 heteroatoms with the remaining chain atoms being carbon. In some embodiments, the heteroaliphatic group is saturated. Examples of heteroaliphatic groups include linear or branched, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, haloalkoxy, ester, substituted amino, substituted ketone, substituted amido, disubstituted amido, alkylthio, substituted sulfinyl, substituted sulfonyl, substituted sulfonamido, disubstituted sufonamido groups.

[0041] In some embodiments, the substituted or unsubstituted C1-18 heteroaliphatic is selected from substituted or unsubstituted C1-18 alkoxy, substituted or unsubstituted - OC2-18 alkenyl, substituted or unsubstituted -OC2-18 alkynyl, substituted or unsubstituted -NHC1-18 alkyl, substituted or unsubstituted -NHC2-18 alkenyl and substituted or unsubstituted -NHC2-18 alkynyl.

[0042] In some embodiments, the substituted or unsubstituted C1-18 heteroaliphatic is a substituted or unsubstituted C1-4 heteroaliphatic. In some embodiments, the substituted or unsubstituted C1-4 heteroaliphatic is selected from substituted or unsubstituted C1-3 alkoxy, substituted or unsubstituted -OC2-3 alkenyl, substituted or unsubstituted -OC2-3 alkynyl, substituted or unsubstituted -NHC1-3 alkyl, substituted or unsubstituted -NHC2-3 alkenyl and substituted or unsubstituted -NHC2-3 alkynyl.

[0043] As used herein, the terms “alkyl” and the prefix “alk” are inclusive of both straight chain and branched chain groups and include the respective alkane, alkene and alkyne groups. It is apparent, that alkene and alkyne groups cannot consist only of a single carbon unit and such nonexistent groups are not comprised by the present disclosure; accordingly, and logically, terms such as Ci-x-alkyl (wherein x is an integer as specified in the respective context) include the respective Ci-x-alkanyl, C2-x-alkenyl and C2-X- alkynyl. In some embodiments, alkyl groups have a total of up to 5, particularly up to 4, more particularly up to 3 carbon atoms. In particular embodiments the alkyl group isselected from the group consisting of -CH3, -C2H5, -C3H7, -C4H9, -C5H11, -CeH , each of which may be optionally substituted, and even more particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl (again each of which may be optionally substituted), and even more particularly methyl and ethyl. All of the aforementioned alkyl groups, unless specified otherwise, are optionally substituted as detailed further herein, i.e. one or more hydrogen atoms are optionally replaced by a substituent as specified in said respective embodiment.

[0044] As used herein, an “alkoxy” group denotes an O-alkyl group, wherein the alkyl group is as defined above. The alkoxy group is particularly selected from the group consisting of methoxy, ethoxy and propoxy, more particularly methoxy. Said aforementioned alkoxy groups can optionally be substituted with one or more other atoms or groups.

[0045] The term “Cx-yalkenyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and x to y carbon atoms. Examples include vinyl, 1 - propenyl, 1 - and 2-butenyl and 2-methyl-2-propenyl. Unless the context requires otherwise, the term “C2-4alkenyl” also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. In some embodiments, alkenyl is “C2-4alkenyl” including ethenyl, propenyl and butenyl. In some embodiments, alkenyl is “C2-3alkenyl” including ethenyl and propenyl. In some embodiments, alkenyl is ethenyl.

[0046] The term “Cx-yalkynyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and x to y carbon atoms. Examples include ethynyl, 1 -propynyl, 1 - and 2-butynyl, 2-methyl-2-propynyl, and the like. Unless the context indicates otherwise, the term “C2-4alkynyl” also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. In some embodiments, alkynyl is C2-3alkynyl.

[0047] The term “C3-i2cycloalkyl” is used interchangeably with “3-12 membered cycloaliphatic” and refers to non-aromatic cyclic groups having from 3 to 12 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cyclododecyl. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. In some embodiments, cycloalkyl is Cs ecycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. Cycloalkyl groups also include polycyclic carbocycles and include fused, bridged and spirocyclic systems.

[0048] The terms “hydroxy” and “hydroxyl” refer to the group -OH.

[0049] The term “oxo” refers to the group =0.

[0050] The term “Ci-ealkoxy” refers to an alkyl group as defined above covalently bound via an O linkage containing 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isoproxy, butoxy and tert-butoxy. In some embodiments, alkoxy is “Ci-3alkoxy” and “Ci- 2alkoxy” including methoxy, and ethoxy. In some embodiments alkoxy ismethoxy.

[0051] The terms “haloCi-ealkyl” and “Ci-ealkylhalo” refer to a Ci ealkyl which is substituted with one or more halogens. In some embodiments, haloalkyl is haloCi-2alkyl, such as for example, -CH2CF3, and -CF3.

[0052] The terms “haloCi-ealkoxy” and “Ci-ealkoxyhalo” refer to a Ci-ealkoxy which is substituted with one or more halogens. In some embodiments, alkoxyhalo is C1- 2alkoxyhalo, such as for example, -OCF3.

[0053] The term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH.

[0054] The term “ester” refers to a carboxyl group having the hydrogen replaced with, for example a Ci-4alkyl group (“carboxylCi-4alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. In some embodiments, ester is CO2Ci-2alkyl groups, such as for example, methylester (CO2Me), ethylester (CO2Et) and includes reverse esters thereof (e.g. -OC(O)Me, and -OC(O)Et.

[0055] The terms “cyano” and “nitrile” refer to the group -CN.

[0056] The term “nitro” refers to the group -NO2.

[0057] The term “amino” refers to the group -NH2.

[0058] The term “substituted amino” refers to an amino group having at least one hydrogen replaced with, for example a Ci-4alkyl group (“Ci-4alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on. Substituted amino groups include “monosubstituted amino” (or “secondary amino”) groups, which refer to an amino group having a single hydrogen replaced with, for example a Ci-4alkyl group, an aryl or aralkyl group and so on. In some embodiments, secondary amino groups are Ci salkylamino groups, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr). Substituted amino groups also include “disubstituted amino” (or “tertiary amino”) groups, which refer to amino groups having both hydrogens replaced with, for example Ci-4alkyl groups, which may be the same or different (“dialkylamino”), aryl and alkyl groups (“aryl(alkyl)amino”) and so on. In some embodiments, tertiary amino groups aredi(Ci-3alkyl)amino groups, such as for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variations thereof (e.g. N(Me)(Et) and so on).

[0059] The term “aldehyde” refers to the group -C(=O)H.

[0060] The terms “acyl” and “acetyl” refers to the group -C(O)CH3.

[0061] The term “ketone” refers to a carbonyl group which may be represented by - C(O)-.

[0062] The term “substituted ketone” refers to a ketone group covalently linked to at least one further group, for example, a Ci-4alkyl group (“Ci-4alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone) and so on. In some embodiments, substituted ketone is Ci-2alkylacyl.

[0063] The term “amido” or “amide” refers to the group -C(O)NH2.

[0064] The term “substituted amido” or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a Ci-4alkyl group (“Ci-4alkylamido” or “Ci-4alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on. In some embodiments, substituted amide is Ci-2alkylamide, such as for example, methylamide (-C(O)NHMe), and ethylamide (-C(O)NHEt) and includes reverse amides thereof (e.g. -NHMeC(O)-, -and NHEtC(O)-).

[0065] The term “disubstituted amido” or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a Ci-4alkyl group (“di(Ci- 4alkyl)amido” or “di(Ci-4alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on. In some embodiments, disubstituted amide is di(Ci-2alkyl)amide, such as for example, dimethylamide (-C(O)NMe2), and diethylamide (-C(O)NEt2) and includes reverse amides thereof (e.g. -N(Me)C(O)Me, -N(Et)C(O)Et, and -N(Me)C(O)Et).

[0066] The term “thiol” refers to the group -SH.

[0067] The term “Ci-4alkylthio” refers to a thiol group having the hydrogen replaced with a Ci-4alkyl group. In some embodiments, Ci-4alkylthio is Ci-2alkylthio, such as for example, thiolmethyl, and thiolethyl.

[0068] The term “thioxo” refers to the group =S.

[0069] The term “sulfinyl” refers to the group -S(=O)H.

[0070] The term “substituted sulfinyl” or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a Ci-4alkyl group (“Ci -4alkylsulfinyl” or “Ci-4alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on. In some embodiments, substituted sulfinyl is Ci-2alkylsulfinyl, such as for example, - SOmethyl, and -SOethyl.

[0071] The term “sulfonyl” refers to the group -SO2H.

[0072] The term “substituted sulfonyl” refers to a sulfonyl group having the hydrogen replaced with, for example a Ci-4alkyl group (“sulfonylCi-4alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on. In some embodiments, substituted sulfonyl is sulfonylCi-2alkyl, such as for example, -SC Me, and -SC Et.

[0073] The terms “sulfonylamido”, “sulfonamido”, “sulfonamide”, “sulphonylamido”, “sulphonamido”, “sulphonylamide” or “sulphonamide” refer to the group -SO2NH2.

[0074] The terms “substituted sulfonamido”, “substituted sulfonamide”, “substituted sulphonamido” or “substituted sulphonamide” refer to an sulfonylamido group having a hydrogen replaced with, for example a Ci-4alkyl group (e.g. “sulfonylamidoCi-4alkyl”), an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on. In some embodiments, substituted sulfonamido is sulfonylamidoCi-2alkyl, such as for example, -SC NHMe, and -SC NHEt and includes reverse sulfonamides thereof (e.g. -NHSC Me, and -NHSC Et). In some embodiments, the alkylsulfonamides may be optionally substituted, for example with a halo group.

[0075] The terms “disubstituted sulfonamido”, “disubstituted sulfonamide”, “disubstituted sulphonamido” or “disubstituted sulphonamide” refers to an sulfonylamido group having the two hydrogens replaced with, for example a Ci-4alkyl group, which may be the same or different (“sulfonylamidodi(Ci-4alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on. In some embodiments, disubstituted sulfonamido is sulfonylamidodi(Ci-2alkyl), such as for example, -SO2NMe2, and - SO2NEt2 and variations thereof (e.g. -SO2N(Me)Et and so on) and includes reserve sulfonamides thereof (e.g. -N(Me)SO2Me and so on).

[0076] The term “sulfate” refers to the group OS(O)2OH and includes groups having the hydrogen replaced with, for example a Ci-4alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on. In some embodiments, sulfate is Ci-asulfate, such as for example, OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.

[0077] The term “sulfonate” refers to the group SO3H and includes groups having the hydrogen replaced with, for example a Ci-salkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on. In some embodiments, sulfonate is Ci-2sulfonate, such as for example, SOsMe and SOsEt.

[0078] The term “aryl” refers to a carbocyclic (non-heterocyclic) aromatic ring or mono-, bi- or tri-cyclic ring system. Poly-cyclic ring systems may be referred to as “aryl” provided at least 1 of the rings within the system is aromatic. The aromatic ring or ring system isgenerally composed of 6 to 10 carbon atoms. Examples of aryl groups include but are not limited to phenyl, biphenyl, naphthyl and tetrahydronaphthyl. In some embodiments, aryl is 6-membered aryl such as phenyl. The term “alkylaryl” refers to Ci-4alkylaryl such as benzyl.

[0079] The term “alkoxyaryl” refers to Ci-4alkyloxyaryl such as benzyloxy.

[0080] The term “heterocyclyl” refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 8 ring atoms (unless otherwise specified), of which 1 , 2, 3 or 4 are ring heteroatoms with each heteroatom being independently selected from O, S and N. Heterocyclyl groups include monocyclic and polycyclic (such as bicyclic) ring systems, such as fused, bridged and spirocyclic systems, provided at least one of the rings of the ring system contains at least one heteroatom.

[0081] In this context, the prefixes 3-, 4-, 5-, 6-, 7-, 8- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms. For example, the term “3-8 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, or 8 ring atoms. Examples of heterocylyl groups include 5-6- membered monocyclic heterocyclyls and 7-8 membered fused bicyclic heterocyclyls.

[0082] Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3-membered ring), azetidine (4- membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5- dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5- membered rings) , piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7-membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5- membered rings), piperazine (6-membered ring); those containing one oxygen atom such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole (dihydrofuran) (5-membered rings), oxane (tetrahydropyran), dihydropyran, pyran (6-membered rings), oxepin (7-membered ring); those containing two oxygen atoms such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); those containing three oxygen atoms such as trioxane (6-membered ring); those containing one sulfur atom such as thiirane (3- membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5- membered ring), thiane (tetrahydrothiopyran) (6-membered ring), thiepane (7- membered ring); those containing one nitrogen and one oxygen atom such astetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5- membered rings), morpholine, tetrahydrooxazine, dihydrooxazine, oxazine (6- membered rings); those containing one nitrogen and one sulfur atom such as thiazoline, thiazolidine (5-membered rings), thiomorpholine (6-membered ring); those containing two nitrogen and one oxygen atom such as oxadiazine (6-membered ring); those containing one oxygen and one sulfur such as: oxathiole (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen, one oxygen and one sulfur atom such as oxathiazine (6-membered ring).

[0083] Heterocyclyls encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted. “Heterocycloaliphatic” may be used interchangeably with the term “non-aromatic heterocyclyl”.

[0084] The term “aromatic heterocyclyl” may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”. The heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O. The aromatic heterocyclyl groups may comprise 1 , 2, 3, 4 or more ring heteroatoms. In the case of fused aromatic heterocyclyl groups, only one of the rings must contain a heteroatom and not all rings must be aromatic.

[0085] “Heteroaryl” is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls. The term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. The term aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.

[0086] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. The heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0087] Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.

[0088] Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1 H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like). Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphtyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5- membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5- membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.

[0089] The term “non-aromatic heterocyclyl” encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O. The ring may contain 1 , 2 or 3 heteroatoms. The ring may be a monocyclic ring or part of a polycyclic ring system. Polycyclic ring systems include fused rings and spirocycles. Not every ring in a non-aromatic heterocyclic polycyclic ring system must contain a heteroatom, provided at least one ring contains one or more heteroatoms.

[0090] Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.

[0091] As used herein, a halo or halogen group particularly denotes fluorine, chlorine, bromine or iodine.

[0092] In some embodiments for optionally substituted “Ci-i2alkyl”, “C2-i2alkenyl” and “C2-i2alkynyl”, the optional substituent or substituents are selected from halo, aryl, heterocyclyl, Ca-scycloalkyl, Ci -ealkoxy, hydroxyl, oxo, aryloxy, haloCi -ealkyl, haloCi- ealkoxyl and carboxyl. Each of these optional substituents may also be optionally substituted with any of the optional substituents referred to above. In some embodiments, the optional substituents of the optional substituents are selected from nitro, amino, substituted amino, cyano, heterocyclyl (including non-aromatic heterocyclyl and heteroaryl), Ci ealkyl, C2-eakenyl, C2-ealkynyl, Ci-ealkoxyl, haloCi-ealkyl, haloCi- ealkoxy, halo, hydroxyl and carboxyl.

[0093] It will be understood that suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof.

[0094] In the case of hybrid naming of substituent radicals describing two moieties that may both form a bond attaching the radical to the rest of the compound, such as alkyl- heterocyclyoaliphatic and alkaryl, no direction in the order of groups is intended, so the point of attachment may be to any of the moieties included in the hybrid radical. For example, the terms “alkaryl” and “arylalkyl”, are intended to refer to the same group and the point of attachment may be via the alkyl or the aryl moiety (or both in the case of diradical species). The direction of attachment of such a hybrid radical may be denoted by inclusion of a bond, for example, “-alkaryl” or “arylalkyl-” denotes that the point of attachment of the radical to the rest of the compound is via the alkyl moiety, and “alkaryl- “ or “-arylalkyl” denotes that the point of attachment is via the aryl moiety.

[0095] As used herein the term “substituted with” or “substituted by” means that one or more hydrogen atoms connected to a carbon atom or heteroatom of a chemical group or entity are exchanged with a substituent group, respectively. Said hydrogen atom(s) to be replaced may be attached to a carbon atom or heteroatom, and may be expressly shown in a specific formula, such as for example in an -NH- group, or may not expressly be shown but intrinsically be present, such as for example in the typical “chain” notation which is commonly used to symbolize e.g. hydrocarbons. As used herein the term “substituted with one or more groups” also includes the possibility that R is substituted with multiple groups of the same type, for example substituted with two or more C1-18- alkyl residues. The skilled person will readily understand that particularly such substituents or substituent patterns are excluded, which lead to compounds which are not stable and / or not accessible via the synthesis methods known in the art. Particular substituent groups for R may be selected from the group consisting of C-i-s-alkyl, -OH, halogen, NH2, -COOH, -CO-Ci-4-alkyl, -COO-Ci-4-alkyl, -NO2, and more particularly from the group consisting of C-i-2-alkyl, -OH, halogen, NH2, -COOH, -COMe, and -COOMe.

[0096] Unless otherwise defined, the term “optionally substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1 , 2, 3, 4 or more groups, optionally 1 , 2 or 3, or optionally 1 or 2 groups selected from the group consisting of Ci ealkyl, C2-ealkenyl, C2-ealkynyl, Ca-scycloalkyl, hydroxyl, oxo, Ci ealkoxy, aryloxy, Ci ealkoxyaryl, halo, Ci ealkylhalo (such as CF3), Ci ealkoxyhalo (such as OCF3), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, substituted ketones, amides, aminoacyl, substituted amides,disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arCi ealkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case of heterocycles containing N may also include but are not limited to Ci ealkyl i.e. N-Ci-aalkyl. In embodiments, optional substituents in the case of heterocycles containing N also include but are not limited to methyl. In embodiments, optional substituents in the case of heterocycles containing N also include but are not limited to N-methyl.

[0097] As used herein, acid halide refers to a compound derived from an oxoacid by replacing a hydroxyl group with a halide. In some embodiments, the halide of the acid halide is a chloride.

[0098] As used herein, acid anhydride refers to a compound where two acyl groups are bound to the same oxygen (ie bearing the functional group -C(=O)-O-C(=O)-). Formula (li) defines acid anhydrides. In some embodiments, the two acyl groups are the same (ie both including C(Y1 )(Y2)(Y3)). In some embodiments, the two acyl groups are different (ie a mixed anhydride).

[0099] As used herein, the term “physiologically functional derivative” of a compound according to the present disclosure is for instance a prodrug of said compound, wherein at least one of the following groups are derivatized as specified in the following: A carboxylic acid (-COOH) group is derivatized into an ester, a hydroxyl (-OH) group is derivatized into an ester; a carboxylic acid is derivatized into an amide, an amine (-NH2) is derivatized into an amide and a hydroxyl group is derivatized into a phosphate ester. The compounds according to the present disclosure are to be understood to comprise all tautomeric forms thereof, even if not expressly shown in the formulae described herein.

[0100] The compounds represented by the structure formulae as defined herein are to be understood to encompass, where applicable, all stereoisomers of said compounds, unless specified otherwise. The term “stereoisomer” as used herein refers to a compound with at least one stereogenic center, which may be R- or S-configured, as defined by the according IUPAC rules, and encompasses enantiomers and diastereomers as commonly understood by the skilled person. It has to be understood, that in compounds with more than one stereogenic center, each of the individual stereogenic centers may independently from each other be R- or S-configured. The term“stereoisomer” as used herein also refers to salts of the compounds herein described with optically active acids or bases. The disclosure further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.Salts

[0101] In the present disclosure, the salts of the compounds according to the present disclosure are particularly pharmaceutically acceptable salts of the compounds according to the present disclosure. Pharmaceutically acceptable salts are such salts which are usually considered by the skilled person to be suitable for veterinary and / or medical applications, e.g. because they are not harmful to subjects which may be treated with said salts, or which give rise to side effects which are tolerable within the respective treatment. Usually, said pharmaceutically acceptable salts are such salts which are considered as acceptable by the regulatory authorities, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Japanese Ministry of Health, Labor and Welfare Pharmaceuticals and Medical Devices Agency (PMDA).

[0102] In some embodiments, the compounds according to the present disclosure are present as pharmaceutically acceptable salts.

[0103] However, the present disclosure in principle also encompasses salts of the compounds according to the present disclosure which are as such not pharmaceutically acceptable, e.g. as intermediates in the production of the compounds according to the present disclosure or physiologically functional derivatives thereof, or as intermediates in the production pharmaceutically acceptable salts of the compounds according to the present disclosure or physiologically functional derivatives thereof. Said salts include water-insoluble and, particularly, water-soluble salts.

[0104] In each case, the skilled person can readily determine whether a certain compound according to the present disclosure or physiologically functional derivative thereof can form a salt, i.e. whether said compound according to the present disclosure or physiologically functional derivative thereof has a group which may carry a charge, such as e.g. an amino group, a carboxylic acid group, etc.

[0105] Exemplary salts of the compounds of the present disclosure are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acids and bases customarily used in pharmacy, which are either water insoluble or, particularly, water-soluble acid addition salts. Salts with bases may - depending on the substituents of the compounds of the present disclosure - also be suitable. Acidaddition salts may, for example, be formed by mixing a solution of a compound of the present disclosure with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Likewise, pharmaceutically acceptable base addition salts may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate, and the like (see, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1 -19 (1977)).

[0106] Salts, which are not pharmaceutically acceptable and which can be obtained, for example, as process products during the preparation of the compounds according to the disclosure on an industrial scale, are also encompassed by the present disclosure and, if desired, may be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.Prodrugs

[0107] Compounds as described herein can be regarded as prodrug formulations of di- or tri-halogenated methane compounds, such as haloforms, including bromoform, or dihalogenated methane compounds. A prodrug as used herein is a biologically inactive compound or only partially active compound, which upon administration to asubject undergo chemical conversion under physiological conditions or are metabolized to provide a biologically active compound, i.e. a di- or tri-halogenated methane compound, such as a haloform, including bromoform, or a dihalogenated methane compound.

[0108] As used herein, “di- or tri-halogenated methane compound” refers to a haloform or a dihalogenated methane compound.

[0109] As used herein, “haloform” is CHX3 where X is a halogen and each X atom may be a different halogen. Thus, “haloform” includes CHCIBr2 and the like. As used herein, “mixed haloform” refers to haloforms where not every X attached to the carbon atom is the same. In some embodiments, each X atom is the same. In some embodiments, each X atom is Br. In some embodiments, the haloform is a mixed haloform.

[0110] As used herein, “dihalogenated methane compound” is CH2X2 where X is a halogen and each X atom may be a different halogen. Thus, “dihalogenated methane compound” includes CH2CIBr and the like. As used herein, “mixed dihalogenated methane compound” refers to dihalogenated methane compounds where each X attached to the carbon atom is different. In some embodiments, each X atom is the same. In some embodiments, each X atom is Br. In some embodiments, the dihalogenated methane compound is a mixed dihalogenated methane compound.

[0111] Compounds as described herein, which can be regarded as prodrug formulations of di- or tri-halogenated methane compounds, such as haloforms, including bromoform, or dihalogenated methane compounds generally possess reduced volatility relative to the active compound. This includes that the compound described herein - before administration - is generally less volatile compared to the di- or tri-halogenated methane compound, including a haloform such as bromoform, or a dihalogenated methane compound which is released from said compound after administration. Reduced volatility can ease handling and formulation, thus increasing efficiency and / or ease of the dosage process. In some embodiments, the prodrug may also be safer (to administrator and / or animal) than the resultant active compound. In some embodiments, administration of a prodrug (particularly in a suitable composition) can extend the release profile of active compound. This can lead to a less intensive dosage schedule. Less intensive dosage schedules are particularly desirable in less intensive farming (for instance, open grazing) contexts.

[0112] As used herein, the term “stable” specifies a compound in which the chemical structure is not altered when the compound is stored at a temperature from about -80 °C to about +40 °C, particularly from about -80 °C to +25 °C in the absence of light, moisture or other chemically reactive conditions for at least one week, particularly at least one month, more particularly at least six months, even more particularly, at least one year, and / or a compound which under IUPAC standard conditions and in the absence of light, moisture or other chemically reactive conditions maintains its structural integrity long enough to be useful for therapeutic or prophylactic administration to a patient, i.e. at least one week. The skilled person will readily recognize, based on his general knowledge in his field of expertise, which compounds and which substitution patterns result in stable compounds.

[0113] In some embodiments, the active ingredient generated from the prodrug is a methane inhibitor. A “methane inhibitor” as used herein is an active agent, such as a compound or compound mixture, which is capable of inhibiting or reducing the production of methane gas in the rumen of a ruminant animal. In some embodiments, the methane inhibitor is a haloform, including a mixed haloform. In some embodiments, the haloform is selected from chloroform, bromoform, iodoform, or combinations thereof. In some embodiments, the haloform is bromoform. In some embodiments, the methane inhibitor is a dihalogenated methane compound, including a mixed dihalogenated methane compound.

[0114] Optionally, the prodrug is about 20 to about 90%, about 30 to about 80%, about 40 to about 80%, about 50 to about 70% or about 60% w / w of the composition.General definitions

[0115] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a salt” may include a plurality of salts and a reference to “at least one carrier” may include one or more carriers, and so forth.

[0116] The term “and / or” can mean “and” or “or”.[001 17] The term “(s)” following a noun contemplates the singular or plural form, or both.

[0118] Various features of the disclosure are described with reference to a certain value, or range of values. These values are intended to relate to the results of the various appropriate measurement techniques, and therefore should be interpreted as includinga margin of error inherent in any particular measurement technique. Some of the values referred to herein are denoted by the term “about” to at least in part account for this variability. The term “about”, when used to describe a value, may mean an amount within ±10%, ±5%, ±1 % or ±0.1 % of that value.

[0119] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.Veterinary compositions

[0120] A veterinary composition as used herein is a composition suitable for administration to animals that treats, prevents, or ameliorates a condition in the animal subject on administration at a suitable level. In some embodiments, the composition ameliorates greenhouse gas emissions (particularly methane emissions) from the animal (particularly ruminant animals). The skilled person will appreciate that in general an excipient (including a carrier, filling agent etc) acceptable for a veterinary composition will include an excipient (including a carrier, filling agent etc) acceptable for pharmaceutical (ie acceptable for humans) compositions.

[0121] In some embodiments, the composition comprises a carrier. In some embodiments, the composition does not comprise a carrier.

[0122] In some embodiments, the composition comprises a filling agent. In some embodiments, the composition does not comprise a filling agent.

[0123] In some embodiments, the composition comprises an excipient other than a carrier or filling agent. In some embodiments, the composition does not comprise an excipient other than a carrier or filling agent.

[0124] In some embodiments, the composition comprises a carrier and a filling agent. In some embodiments, the composition comprises a carrier and a further excipient. In some embodiments, the composition comprises a filling agent and a further excipient.Y1 , Y2 and Y3

[0125] In some embodiments, Y1 , Y2 and Y3 are independently selected from the group consisting of I, F, Br and Cl. In some embodiments, Y1 , Y2 and Y3 are independently selected from the group consisting of Br and Cl. In some embodiments, each of Y1 , Y2 and Y3 are Br. In some embodiments, each of Y1 , Y2 and Y3 are Cl.

[0126] In some embodiments, each of Y1 , Y2 and Y3 are the same.

[0127] In some embodiments, Y1 , Y2 and Y3 are selected from the group consisting of H, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from the group consisting of Br and Cl.

[0128] In some embodiments, two of Y1 , Y2 and Y3 are Br. In some embodiments, two of Y1 , Y2 and Y3 are Br; and the remaining one of Y1 , Y2 and Y3 is H. In some embodiments, two of Y1 , Y2 and Y3 are Cl; and the remaining one of Y1 , Y2 and Y3 is H.X

[0129] In some embodiments, X is formula (li). In embodiments where X is formula (li), the compound of formula (I) may also be provided as a compound of formula (Hi)formula (Hi) wherein Y1 , Y2, Y3, L and R are as defined for formula (I) or any embodiment thereof.

[0130] In some embodiments, X is formula (lii). In embodiments where X is formula (lii), the compound of formula (I) may also be provided as a compound of formula (llii)formula (llii) wherein Y1 , Y2, Y3, L and R are as defined for formula (I) or any embodiment thereof.

[0131] In some embodiments, X is formula (liii). In embodiments where X is formula (liii), the compound of formula (I) may also be provided as a compound of formula (lliii)formula (lliii)wherein Y1 , Y2, Y3, Laand Raare as defined for formula (I) or any embodiment thereof.

[0132] In some embodiments, X is selected from formula (li) and formula (lii). In some embodiments, X is selected from formula (li) and formula (liii). In some embodiments, X is selected from formula (lii) and formula (liii).L

[0133] In some embodiments, L is CH2, O, NH, or absent. In some embodiments, L is CH2, O, or NRa. In some embodiments, L is O or NRa. In some embodiments, L is O or NH. In some embodiments, L is absent. In some embodiments, L is CH2. In some embodiments, L is O. In some embodiments, L is NRa. In some embodiments, L is NH. La

[0134] In some embodiments, Lais selected from CH2, O and NH. In some embodiments, Lais selected from CH2 and O. In some embodiments, Lais CH2. In some embodiments, Lais O.R

[0135] In some embodiments, R is selected from the group consisting of OH, halo, optionally substituted Ci-is-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

[0136] In some embodiments, R is selected from the group consisting of OH, H, halo, optionally substituted Ci-is-aliphatic, and optionally substituted C1-18- heteroaliphatic.

[0137] In some embodiments, R is selected from the group consisting of optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

[0138] In some embodiments, R is selected from the group consisting of OH, H, halo, optionally substituted Ci-is-alkyl, optionally substituted Ci- -alkoxy, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl. In some embodiments, R is selected from the group consisting of OH, H, halo, optionally substituted Ci -is-alkyl, and optionally substituted Ci- -alkoxy.

[0139] In some embodiments, the optionally substituted Ci -is-aliphatic at R is optionally substituted Ci-12-aliphatic, optionally substituted Ci-s-aliphatic, optionallysubstituted Ci-6-aliphatic, optionally substituted Ci-4-aliphatic, or optionally substituted Ci-2-aliphatic.

[0140] In some embodiments, R is an optionally substituted group selected from the group consisting of OH, Ci -is-alkyl, Ci- -alkoxy and Ci-s-alkyl-COOH; wherein if R is substituted, then it is substituted by one or more groups independently selected from the group consisting of Ci -s-alkyl, -OH, halogen, NH2, -COOH, -CO-Ci-4-alkyl, -COO-C1- 4-alkyl, -NO2, and more particularly is substituted with one or more groups selected from the group consisting of C-i-2-alkyl, -OH, halogen, NH2, -COOH, -COMe, and -COOMe. Ra

[0141] In some embodiments, Rais selected from the group consisting of C(Y1 )(Y2)(Y3), OH, optionally substituted Ci-is-aliphatic, optionally substituted C1-18- heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

[0142] In some embodiments, Rais selected from the group consisting of OH, H, C(Y1 )(Y2)(Y3), optionally substituted Ci -is-aliphatic, optionally substituted C1-18- heteroaliphatic.

[0143] In some embodiments, Rais selected from the group consisting of optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, optionally substituted 3-10 membered heteroaryl.

[0144] In some embodiments, Rais selected from the group consisting of H, C(Y1 )(Y2)(Y3), OH, optionally substituted Ci -is-alkyl, optionally substituted Ci- -alkoxy, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl. In some embodiments, Rais selected from the group consisting of H, optionally substituted Ci- -alkoxy, optionally substituted Ci-w- alkoxy.

[0145] In some embodiments, the optionally substituted Ci-is-aliphatic at Rais optionally substituted Ci-12-aliphatic, optionally substituted Ci-s-aliphatic, optionally substituted Ci-6-aliphatic, optionally substituted Ci-4-aliphatic, or optionally substituted Ci-2-aliphatic.

[0146] In some embodiments, Rais C(Y1 )(Y2)(Y3).

[0147] Advantages of the compounds of the disclosure, which can be regarded as prodrug formulations of active compound haloforms, such as bromoform, and dihalogenated methane compounds, further include a reduced volatility when compared to the haloform or dihalogenated methane compound that will be released from the compound. The reduction in volatility improves the ease of handling and manufacture and assists with reproducible dosing and delivery of the compound.

[0148] The release mechanism provided by a composition of the disclosure comprising compounds as described herein is useful when a delayed release is sought. Delayed as used in this context is to be understood as delaying onset of release of the haloform or dihalogenated methane compound to a subject until a certain point after administration to the subject, i.e. particularly until after the compound has reached an animal’s rumen and after coming into contact with the aqueous environment and / or pH conditions of the ruminal liquid. Furthermore, a compound of the disclosure may reduce the volatility of a methane inhibiting agent, such as a haloform (including bromoform) or a dihalogenated methane compound. This reduces the chances of the methane inhibiting agent spreading, being inhaled and being ingested by staff or farmers handling the compound. Advantages of provided compounds of the disclosure include protecting farmers or other staff handling the composition from haloforms, such as bromoform, or dihalogenated methane compounds, that may for instance have a health hazardous or irritating effect on humans when coming directly into contact with humans.Formula (la)

[0149] In a further aspect the disclosure provides a veterinary composition comprising a compound having the structure of formula (la),Y1Y2- C - Z Y I3formula (la) or a pharmaceutically acceptable salt thereof, wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from the group consisting of I, F, Br and Cl and wherein Z is(1 ) a group that will be cleaved off the carbon atom shown in formula (la) when the composition is exposed to the environment inside the rumen of a ruminant animal; or(2) a group that will be cleaved off the carbon atom shown in formula (la) when formula (la) is contacted with a second activating agent, wherein the second activating compound will come into contact with the formula (la) only when the composition is exposed to the environment inside the rumen of a ruminant animal; wherein cleavage of Z from formula (la) generates a compound of formula (lb)formula (lb) or a pharmaceutically acceptable salt thereof.

[0150] In a further aspect the disclosure provides a composition comprising a compound having the structure of formula (la),formula (la) or a pharmaceutically acceptable salt thereof, wherein each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl; and wherein Z is(1 ) a group that will be cleaved off the carbon atom shown in formula (la), such that Z is replaced by a hydrogen atom when the composition is exposed to the environment inside the rumen of a ruminant animal; or(2) a group that will be cleaved off the carbon atom shown in formula (la), such that Z is replaced by a hydrogen atom when formula (la) is contacted with a second activating compound that is comprised in said composition, wherein the second activating compound will come into contact with the formula (la) only when the composition is exposed to the environment inside the rumen of a ruminant animal.

[0151] In some embodiments, a compound of formula (lb) is directly generated after cleavage of Z from formula (la). In some embodiments, one or more intermediatesare formed before a compound of formula (lb) is generated after cleavage of Z from formula (la).

[0152] Embodiments of formula (I) concerning Y1 , Y2 and Y3 also apply to formula (la).Z

[0153] In some embodiments, Z is selected from the group consisting of COOH, optionally substituted Ci- -ester, optionally substituted Ci- -amide, an acid halide, an acid anhydride, OH, N(Ra)2, optionally substituted Ci-is-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl. In some embodiments, Z is selected from the group consisting of COOH, optionally substituted Ci- -ester, optionally substituted Ci- -amide, an acid halide, and an acid anhydride. In some embodiments, the acid anhydride formed by Z may be uniform (ie generate 2 compounds of formula (lb) on cleavage of formula (la)).

[0154] The group that will be cleaved off the carbon atom shown in formula (la) (residue Z) may among other things, be cleaved by enzymatic cleavage or by non- enzymatic cleavage, such as hydrolytic cleavage, or a sequential combination thereof, for example an enzymatic cleavage step followed by a non-enzymatic rearrangement. The process may be spontaneous and / or aided by further compounds or excipients included in the composition. Some compounds or excipients included in the composition may cause a catalytic acceleration of the release of a haloform, such as bromoform, or a dihalogenated methane compound from a compound as described herein.Further formulae

[0155] In some embodiments the compound has a formula according to any of formula III (tribromoacetic acid), IV, V, or VI, wherein L and R are as defined for formula (I) or any embodiment thereof. The structure formulae III, IV, V, or VI are provided as follows:formula (III) formula (IV) formula (V) formula (VI)

[0156] In some embodiments, the compound has a formula according to formula III (tribromoacetic acid) or IV.

[0157] In another embodiment the compound has a formula according to any of formula VII, VIII, IX or X: wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (optionally both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl. In another embodiment the compound has a formula according to any of formula VII, VIII, IX or X: wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (optionally both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are selected from H, I, F, Br and Cl (optionally selected from H, Br and Cl); and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl (optionally selected from Br and Cl). The structure formulae VII, VIII, IX or X are provided as follows:formula (VII) formula (VIII) formula (IX) formula (X)

[0158] In some embodiments, the compound has a formula according to any of formula VII, VIII, IX or X: wherein both R1 and R2 are each either H or methyl; and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl. In some embodiments, the compound has a formula according to any of formula VII, VIII, IX orX: wherein both R1 and R2 are each either H or methyl; and wherein Y1 , Y2 and Y3 are each selected from H, I, F, Br and Cl (optionally selected from H, Br and Cl); and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl (optionally selected from Br and Cl).

[0159] In some embodiments, the compound has a formula according to formulaVII, wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl. In some embodiments, the compound has a formula according to formula VII, wherein both R1 and R2 are each either H or methyl. In some embodiments, the compound has a formula according to formula VII, wherein both R1 and R2 are each H.

[0160] In some embodiments, the compound has a formula according to formulaVIII.

[0161] In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (optionally both R1 and R2 are each either H ormethyl); and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl; and wherein the composition further comprises a base, optionally selected from the group consisting of KOH and / or NaOH. In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (optionally both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are each individually selected from H, I, F, Br and Cl (optionally selected from H, Br and Cl); and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl (optionally selected from Br and Cl); and wherein the composition further comprises a base, optionally selected from the group consisting of KOH and / or NaOH. The structure formulae VII or IX are provided as follows:formula (VII) formula (IX)

[0162] In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (optionally both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl; and wherein the composition further comprises KOH and / or NaOH. In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (optionally both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are each selected from H, I, F, Br and Cl (optionally selected from H, Br and Cl); and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl (optionally selected from Br and Cl); and wherein the composition further comprises KOH and / or NaOH.

[0163] In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein both R1 and R2 are each either H or methyl; and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl; and wherein the composition further comprises a base, optionally selected from the group consisting of KOH and / or NaOH. In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein both R1 and R2 are each either Hor methyl; and wherein Y1 , Y2 and Y3 are each selected from H, I, F, Br and Cl (optionally selected from H, Br and Cl); and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl (optionally selected from Br and Cl); and wherein the composition further comprises a base, optionally selected from the group consisting of KOH and / or NaOH.

[0164] In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein both R1 and R2 are each either H or methyl; and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl; and wherein the composition further comprises KOH and / or NaOH. In some embodiments, the compound has a formula according to formula VII or IX or is tribromoacetic acid, wherein both R1 and R2 are each either H or methyl; and wherein Y1 , Y2 and Y3 are each selected from H, I, F, Br and Cl (optionally selected from H, Br and Cl); and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl (optionally selected from Br and Cl); and wherein the composition further comprises KOH and / or NaOH.

[0165] In some embodiments, the compound has a formula according to formula VII or is tribromoacetic acid, wherein both R1 and R2 are each either H or methyl; and wherein the composition further comprises a base. In some embodiments, the compound has a formula according to formula VII or is tribromoacetic acid, wherein both R1 and R2 are each either H or methyl; and wherein the composition further comprises KOH and / or NaOH.

[0166] In some embodiments, the compound is tribromoacetic acid the composition further comprises a base. In some embodiments, the compound is tribromoacetic acid and the composition further comprises KOH and / or NaOH.Specific compoundsIn some embodiments, the compound of formula (I) or formula (la) is selected from the group consisting of: tribromo acetic acid, (2,2,2-tribromoacetyl) 2,2,2-tribromoacetate, acetyl 2,2,2-tribromoacetate, (2,2,2-tribromoacetyl) propanoate, (2,2,2-tribromoacetyl) butanoate, (2,2,2-tribromoacetyl) pentanoate, (2,2,2-tribromoacetyl) heptanoate, methyl2,2,2-tribromoacetate, ethyl 2,2,2-tribromoacetate, propyl 2,2,2-tribromoacetate, butyl2,2,2-tribromoacetate, pentyl 2,2,2-tribromoacetate, hexyl 2,2,2-tribromoacetate, heptyl2,2,2-tribromoacetate, octyl 2,2,2-tribromoacetate, nonyl 2,2,2-tribromoacetate, decyl2,2,2-tribromoacetate, undecyl 2,2,2-tribromoacetate, dodecyl 2,2,2-tribromoacetate, propan-2-yl 2,2,2-tribromoacetate, butan-2-yl 2,2,2-tribromoacetate, pentan-2-yl 2,2,2- tribromoacetate, 2,2,2-tribromoacetyl chloride, 2,2,2-tribromoacetamide, 2,2,2-tribromo-N-methylacetamide, 2,2,2-tribromo-N-ethylacetamide, 2,2,2-tribromo-N- propylacetamide, 2,2,2-tribromo-N-butylacetamide, 2,2,2-tribromo-N-hexylacetamide, 2,2,2-tribromo-N-octylacetamide, 2,2,2-tribromo-N-decylacetamide, 2,2,2-tribromo-N- dodecylacetamide, 2,2,2-tribromo-N-octadecylacetamide, 2,2,2-tribromo-N,N- dimethylacetamide, 2,2,2-tribromo-N-ethyl-N-methylacetamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or formula (la) is tribromo acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or formula (la) is ethyl 2,2,2-tribromoacetate, or a pharmaceutically acceptable salt thereof.Additional agents

[0167] In some embodiments, the composition further comprises at least one further active agent.

[0168] In some embodiments, the further active agent is selected from the group consisting of a methane inhibiting agent, a hydrogen sequester, an anti-inflammatory agent, an analgesic, an anthelmintic, a nonsteroidal anti-inflammatory drug (NSAID), an antibiotic, a growth promoter, a lactation promoter, a sustainability improver, an antimicrobial, a ketosis prevention agent, a mineral / element / vitamin supplement and combinations thereof. In some embodiments, the further active agent is selected from the group consisting of a methane inhibiting agent, a hydrogen sequester, a nonsteroidal anti-inflammatory drug (NSAID), an anthelmintic and a ketosis prevention agent. In some embodiments, the further active ingredient is selected from a methane inhibiting agent, an antibiotic, and a ketosis prevention agent.

[0169] In some embodiments, the further methane inhibiting agent is selected from the group consisting of a haloform (for instance a haloform other than bromoform if the first methane inhibiting agent is bromoform) or a dihalogenated methane compound (for instance a dihalogenated methane compound other than dibromomethane if the first methane inhibiting agent is dibromomethane), monensin, a phospholipid (such as lecithin), and a fatty acid (such as lauric acid, myristic acid and linoleic acid); a plant extract or derivative including tannins, oils, essential oil; a fumarate (such as fumaric acid and sodium fumarate), an acrylate (such as sodium acrylate), a statin (such as atorvastatin and simvastatin), a sulfur-containing salt (such as sulfate and sodium sulfate), nitrate (such as potassium nitrate, calcium nitrate, calcium ammonium nitrate and sodium nitrate), malate, a Ce-ufatty acid (optionally a Ce-i2fatty acid such as aproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid,undecylic acid, lauric acid), an unsaturated fatty acid (such as a-Linolenic acid, Stearidonic acid, Eicosapentaenoic acid, Cervonic acid, Linoleic acid, Linolelaidic acid, y-Linolenic acid, Dihomo-y-linolenic acid, Arachidonic acid, Docosatetraenoic acid , Palmitoleic acid, Vaccenic acid, Paullinic acid, Oleic acid, Elaidic acid, Gondoic acid, Erucic acid, Nervonic acid, Mead acid), and a lipid (such as a fatty acyl, a glycerolipid, a glycerophospholipid, a sphingolipid, a sterol, a prenol, and a saccharolipid). In some embodiments, the further methane inhibiting agent is selected from the group consisting of a haloform (for instance a haloform other than bromoform if the first methane inhibiting agent is bromoform), a dihalogenated methane compound (for instance a dihalogenated methane compound other than dibromomethane if the first methane inhibiting agent is dibromomethane), monensin, a phospholipid (such as lecithin), a fatty acid (such as lauric acid, myristic acid and linoleic acid. In some embodiments, the further methane inhibiting agent is not 3-nitrooxypropanol (3-NOP). In some embodiments, the hydrogen sequester is selected from the group consisting of fumaric acid, sodium fumarate, a phenolic compound, phloroglucinol, gallic acid, resorcinol, catechols, hydroquinone and pyrogallol. In some embodiments, the antiinflammatory agent / analgesic / NSAID is selected from Nonsteroidal Anti-inflammatory Drugs (such as aspirin, ibuprofen, ketoprofen, carprofen, meloxicam, robenacoxib, firocoxib, mavacoxib, and flunixin), a corticosteroid, an alpha-2 antagonist, ketamine, and an opioid receptor agonist (such as tramadol). In some embodiments, the antiinflammatory agent / analgesic / NSAID is selected from meloxicam and ketoprofen. In some embodiments, the anthelmintic is selected from the group consisting of a benximidazole (such as mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole, netobimin, albendazole, and triclabendazole), an imidazothiazole (such as levamisole), a tetrahydropyrimidines (such as pyrantel tartarate or embonate, and oxantel), a macrocylic lactone (such as ivermectin, abamectin, doramectin, eprinomectin, selamectin, milbemycin oxime and moxidectin), a salicylanilide (brotianide, clioxanide, closantel, niclosamide, oxyclozanide, and rafoxanide), a substituted phenol (such as bithionol, disophenol, hexachlorophene, niclofolan, menichlopholan, and nitroxynil), an aromatic amide diamfenetide (such as diamphenethide), praziquantel, epsiprantel, an amino-acetonitrile derivative, a cyclic octadepsipeptide (such as emodepside), a spiroindoles (such as derquantel), piperazine, clorsulon, bunamidine, and nitroscanate. In some embodiments, theanthelmintic is albendazole. In some embodiments, the antibiotic is selected from the group consisting of meloxicam, ketoprofen, penicillin, a tetracycline, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, and tulathromycin. In some embodiments, the antimicrobial is selected from the group consisting of a tetracycline (such as chlortetracycline, oxytetracycline, doxycycline, tetracycline), an amphenicol (such as florfenicol, thiamphenicol), a penicillin and clavulanic acid (such as amoxicillin, ampicillin, cioxacillin, pennthamate, procaine benzylpenicillin, phenoxymethyphenicillin), a cephalosporin (such as cefalonium, cefalexin, cefaprin, cefoperazone, cefquinome, and ceftiofur), a lincoamide (such as lincomycin), a sulfonamide, trimethoprim, a macrolide (such as gamithromycin, tildipirosin, tilmicosin, tulathromycin, tylosin, and tylvalosin), a aminoglycoside (such as dihydrostreptomycin, apramycin sulfate, framycetin, neomycin, paromomycin, streptomycin, and spectinomycin), a fluoroquinolone (such as enrofloxacin, marbofloxacin, and danofloxacin), a polymyxins (such as colistin), a pleuromutilin (such as tiamulin), and chloramphenicol. In some embodiments, the ketosis prevention agent is monensin. In some embodiments, the mineral / element / vitamin supplement is selected from the group consisting copper, cobalt, selenium, manganese, magnesium, sodium and chloride, potassium, zinc, iodine, sulphur, chromium, vitamin A, vitamin E, vitamin D3, and combinations thereof. In some embodiments, the further active agent is selected from the group consisting of monensin, phloroglucinol, albendazole, ketoconazole, lecithin and combinations thereof.

[0170] The inclusion of multiple methane inhibiting agents may be beneficial, particularly if they act upon one or more of different pathways, enzymes and organisms of the methanogenic organisms of the rumen. The inclusion of a further active agent that ameliorates side-effects of the methane inhibiting agent may be beneficial, for instance if the methane inhibiting agent can lead to ketosis then inclusion of a ketosis prevention agent in the composition may be particularly useful. The inclusion of a further active ingredient that improves the release profile of the methane inhibiting agent may be beneficial. Often, a more extended release profile is beneficial. The inclusion of a further active agent that results in reduced need for administration, for instance through administration of at least 2 actives in a single instance is desirable.

[0171] Besides methane, also hydrogen gas may be produced in the rumen. Although hydrogen is a weaker greenhouse gas than methane, it would be ideal if also at least part of the hydrogen gas emission could be reduced. For this purpose, it wouldbe desirable to bind or remove at least part of the hydrogen gas that is generated in the rumen. Phloroglucinol degradation in the rumen was found to promote the sequestration of excess hydrogen, which would otherwise be used for methane production (see: Martinez-Fernandez G, et al., Front Microbiol. 2017 Oct 5;8:1871. doi: 10.3389 / fmicb.2017.01871 ). Also, other compounds can be used to promote the growth of microbes in the rumen which utilize hydrogen and therefore will reduce the partial pressure of hydrogen in the rumen and the amount of this gas eructated by the animals. Accordingly, in one embodiment the composition of the disclosure comprises a hydrogen sequester, optionally selected from the group of hydrogen-sequesters consisting of fumaric acid, sodium fumarate, a phenolic compound, phloroglucinol, gallic acid, resorcinol, catechols, hydroquinone and pyrogallol.

[0172] In some embodiments, in addition to a compound as defined herein the composition of the disclosure comprises a further active agent or prodrug form thereof, wherein said active agent or prodrug form thereof is not a methane inhibiting agent. In some embodiments the active agent or prodrug form thereof, which is not a methane inhibiting agent, is selected from the group consisting of anti-inflammatory agent, analgesic, and anthelmintic. The active agent may, however, be any health and / or growth promoting and / or sustainability improving agent known in the art or combinations of such agents. For instance, the anti-inflammatory agent and / or analgesic may be selected from nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments the active agent is selected from meloxicam and ketoprofen. For instance, the anthelmintic may be albendazole. The further active agent may also be an antibiotic, optionally selected from the group consisting of penicillin, tetracyclines, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, and tulathromycin. Thus, in some embodiments the active agent is selected from the group consisting of anti-inflammatory agent, analgesic, antibiotic and anthelmintic. In some embodiments the active agent is selected from the group consisting of meloxicam, ketoprofen, penicillin, tetracyclines, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, tulathromycin and albendazole. Other compounds routinely and commonly administrated to ruminants and substances with one or more advantageous effects on ruminant animals are known in the art and the average skilled person is aware how to suitably implement such substances in the composition of the disclosure. Such compounds also include, but are not limited to, growth promoters, lactation promoters and sustainability improvers. A sustainability improver is an agent that improves the sustainability of husbandry of aruminant. This improvement can a reduction in pollution, for instance a reduction in greenhouse gas emissions.

[0173] In some embodiments the composition comprises a first compound as defined herein and one or more compounds selected from the group consisting of a compound as defined herein above, wherein the compound is different from the first compound, cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3- Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate, a haloform and a dihalogenated methane compound. In some embodiments the composition comprises a first compound as defined herein and one or more compounds selected from the group consisting of a compound as defined herein above, wherein the compound is different from the first compound, cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3- Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate, and a haloform. In some embodiments the haloform is bromoform. In some embodiments the composition comprises a first compound as defined herein and one or more compounds selected from the group consisting of a compound as defined herein above, wherein the compound is different from the first compound, and a haloform.

[0174] In some embodiments the composition comprises a first compound as defined herein and monensin and / or nisin. Monensin is a carboxylic polyether ionophore which may modify rumen fermentation dynamics by selectively inhibiting growth of grampositive bacteria, which produce most of the acetate, lactate, and hydrogen in the rumen, which can contribute to methane formation. Monensin is also known to prevent ketosis in ruminants. Administration of a ketosis prevention agent can be beneficial when administering a methane inhibiting agent such as a haloform, or a prodrug thereof; or a dihalogenated methane compound, or a prodrug thereof. Another methane inhibiting agent, which may be used in addition or alternatively to monensin, is the bacteriocin nisin. Both nisin and monensin inhibit methanogenic bacteria by primarily increasing the permeability of their cell membrane.

[0175] In some embodiments the composition comprises a first compound as defined herein and lecithin. Lecithin is known have an effect on ruminal fermentationand digestion and may therefore contribute to methane inhibition. For instance, soybean lecithin may be suitable in this context.

[0176] Certain saturated and unsaturated fatty acids may also be used for their ability to influence ruminal fermentation and microbial composition in the rumen, thus influencing the methanogenic potential in the rumen. In one embodiment, the methane inhibiting agent is selected from lauric acid, myristic acid and linoleic acid.

[0177] Phospholipids are known to typically comprise a glycerol molecule, the carbon atoms of which are connected to two fatty acids and a phosphate group, wherein the fatty acids and phosphate group are attached to the glycerol molecule through an ester bond. In one embodiment a composition described herein comprises a methane inhibiting agent selected from the group consisting of phospholipids comprising a glycerol molecule linked via ester bonds to a phosphate group and to two fatty acids, optionally wherein the phospholipid comprises one or more polyunsaturated fatty acids, further optionally wherein the phospholipid comprises one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid.

[0178] In some embodiments, the phospholipid is a phospholipid that comprises one or more fatty acids with a methane mitigating effect. For instance, saturated fatty acids (SFAs) are known to suppress ruminal methanogenesis, including for instance lauric (C12), myristic (C14), or palmitic (C16) and stearic acid (C18).

[0179] In some embodiments the composition comprises a first compound as defined herein and one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs). Polyunsaturated fatty acids (PUFA) such as C12 and C18 PUFAs are known to be potent against methanogenesis. Without wishing to be limited to this supposed effect of these fatty acids, it is currently believed that the presence of these fatty acids in the rumen impacts the microbiome in the intestinal tract of ruminant animals. In particular, it is believed that such fatty acids can act against rumen methanogens colonizing the rumen, which otherwise scavenge H2 and CO2 produced by other fermentative members of the ruminal microbiome and produce methane (CPU). In some embodiments, the phospholipid is selected from lecithin, phosphatidylcholine and derivatives of the aforementioned compounds.

[0180] In some embodiments, the composition comprises a compound of formula III (tribromoacetic acid) and / or a compound of formula IV (tribromoacetic acid methyl ester) and / or bromoform.

[0181] In some embodiments, the composition comprises a compound of formula III (tribromoacetic acid) and a compound of formula IV (tribromoacetic acid methyl ester) and bromoform. In some embodiments, the composition comprises a compound of formula III (tribromoacetic acid) and bromoform. In some embodiments, the composition comprises a compound of formula IV (tribromoacetic acid methyl ester) and bromoform.

[0182] A composition comprising one or more compounds of the disclosure, for instance a compound of formula III or IV, and bromoform may provide a staggered release of the active compound bromoform from the composition. In this staggered release, bromoform, which in its “pure form”, i.e. not associated with further residues or molecule components, is directly available upon administration of the composition and provides an initial higher bromoform dose. This initial dose may act as an initial “boost” to effectively reduce previous methane production to a low level (or inhibit it altogether). A compound of the disclosure on the other hand may in some cases take longer to disintegrate and to thereby release further bromoform from the prodrug formulation. This provides an additional delayed and at the same time sustained dosage of bromoform, which helps to keep methane production levels low or completely abolish them over an extended period of time. In summary, combining bromoform and one or more compounds of the disclosure in a composition of the disclosure may provide a combined dosage profile for bromoform, including an initial release of bromoform and a sustained release enabling stable and increased bromoform levels for a prolonged period of time. The onset of the sustained release may optionally be delayed.Water / solvates

[0183] In some embodiments the composition does not comprise water or comprises less than 0.1 wt% of water.

[0184] Water or moisture content can for instance be determined by thermogravimetric analysis using a thermogravimetric moisture balance, which analysis is based on the loss-on-drying principle and determines moisture content in terms of the extent of weight loss that occurs as the sample is heated. Heating causes weight loss as volatile water components vaporize.

[0185] In another embodiment the composition of the disclosure, e.g. when isolated in crystalline form, may contain varying amounts of solvents. Included within the scope of the disclosure are therefore solvates and in particular hydrates of the compounds or composition of the present disclosure as well as solvates and in particular hydrates of the salts and / or physiologically functional derivatives of the compounds orcomposition of the present disclosure. Salts of solvates of compounds of the disclosure are also included within the disclosure. Similarly, co-crystals of compounds of the disclosure are also included within the disclosure.Physical state

[0186] In some embodiments, the compound of the disclosure is a solid under ambient conditions. In some embodiments, the compound of the disclosure is a solid under ambient conditions and the di- or tri-halogenated methane compound generated therefrom is a liquid under ambient conditions.

[0187] In some embodiments, the compound of the disclosure is crystalline under ambient conditions. In some embodiments, a crystalline solid may offer desired stability. In some embodiments, the compound of the disclosure is crystalline under ambient conditions and the di- or tri-halogenated methane compound generated therefrom is a liquid under ambient conditions.

[0188] In some embodiments, the composition of the disclosure is a solid under ambient conditions. In some embodiments, the composition of the disclosure is a solid under ambient conditions and the equivalent composition, comprising the di- or tri- halogenated methane compound generated from the compound of the composition rather than the compound of the composition, is a liquid under ambient conditions.

[0189] In some embodiments, the compound of the disclosure is an amorphous solid under ambient conditions. In some embodiments, an amorphous solid may offer desired solubility. In some embodiments, the compound of the disclosure is a solid that is substantially amorphous (optionally at least 70% amorphous, at least 80% amorphous, at least 90% amorphous, or at least 95% amorphous) under ambient conditions. In some embodiments, the compound of the disclosure is a solid that is amorphous or substantially amorphous under ambient conditions and the di- or tri- halogenated methane compound generated therefrom is a liquid under ambient conditions. In some embodiments, the composition of the disclosure is a solid that is amorphous or substantially amorphous under ambient conditions and the equivalent composition, comprising the di- or tri-halogenated methane compound generated from the compound of the composition rather than the compound of the composition, is a liquid under ambient conditions.

[0190] In some embodiments, the compound of the disclosure is a liquid under ambient conditions.

[0191] As used herein, “ambient conditions” refers to 25 °C and 1 atmosphere of pressure.Excipient

[0192] A veterinary acceptable excipient is an excipient which upon administration to an animal subject is typically not deleterious to the subject. A pharmaceutically acceptable excipient is an excipient which upon administration to a human subject is typically not deleterious to the subject. The skilled person will appreciate that in general veterinary acceptable excipients include pharmaceutically acceptable (ie acceptable for humans) excipients.

[0193] In some embodiments, the excipient is one or more of a carrier, filling agent, channelling agent, integrity agent, stabilizer, plasticizer, hardener and colorant. In some embodiments, the excipient is one or more of a carrier and filling agent. In some embodiments, the excipient is one or more of a carrier, filling agent, channelling agent, integrity agent and stabilizer. In some embodiments, the excipient is one or more of a plasticizer, hardener and colorant.

[0194] In some embodiments, the excipient is an integrity agent. Optionally, the integrity agent is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), carrageenan, guar gum, xanthan gum, sodium alginate, locust bean gum, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate co-polymer (PVP / VA), a polyacrylic acid and / or their co-polymer variants, combinations thereof, combinations with talc thereof, and copolymers thereof. Optionally, the integrity agent is at least about 10% w / w of the composition.Carriers

[0195] A carrier as used herein is a compound that can be mixed with an active ingredient or prodrug thereof without changing the chemical structure of the active ingredient or prodrug thereof. In some embodiments, the carrier when used in a composition of the disclosure delays the release of the active ingredient from the composition. In some embodiments, the carrier may 1 ) control the rate at which the compound of the disclsoure forms the methanogenic-inhibitory halogenated compound (such as bromoform); and / or 2) co-valently interact with the methanogenic-inhibitory halogenated compound (such as bromform), and thus modulates the diffusion rate from the composition / system / dosage form (including the bolus).

[0196] A range of substances may be suitable for use as a carrier in the compositions of the present disclosure and the following examples are not limiting. Numerous large molecules and / or particles dispersible or miscible in a di- or trihalogenated methane compound (including a haloform) or prodrug thereof with branching or surface modification able to associate with a di- or tri-halogenated methane compound (including a haloform) or a prodrug thereof are suitable. For instance, the carrier may be selected from the list of waxes, myristic acid, stearic acid, steryl alcohol, cetyl alcohol, cetosteryl alcohol or a combination thereof. The carrier may be a waxy substance, for example, the carrier may be selected from the list of bee’s wax, paraffin wax, PEG4000, Carnauba, castor wax, Candellila, Jojoba, or Lanolin wax or a combination thereof. The carrier may comprise a mixture of two or more components, such as at least one relatively polar substance with a relatively non-polar substance. As a result, the overall polarity of the carrier may be adjusted to achieve the desired affinity for the active ingredient or prodrug thereof. This can be used to achieve a desired release rate for the active ingredient. For instance, in some forms the carrier may include a mixture of paraffin wax (a mixture of alkanes with no polar functional groups) and castor wax and / or carnauba wax (which have a relatively high amount of polar functional groups).

[0197] In some embodiments, the carrier includes one or more biodegradable polymers. In some embodiments, the carrier consists of one or more biodegradable polymers. In some embodiments, the carrier includes two or more biodegradable polymers. In some embodiments, the carrier consists of two or more biodegradable polymers. In some embodiments, the carrier does not include a wax.

[0198] In some embodiments, the carrier includes one or more materials selected from the list consisting of polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-co-adipate (PBSA), polylactic acid (PLA), poly-lactic acid, poly- d-lactic acid, poly-L-lactic acid, poly-D,L-lactic acid (PDLLA), poly-lactide-co-glycolide, lignin, polybutylene adipate terephthalate (PBAT), styrene-acrylic copolymer (such as Joncryl®), talc-filled poly(D-lactide) (TALC PDLA), Poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), epoxy-based chain extenders, magnesium silicate, cellulosic materials, ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), fumed silica, gelatin, wax, castor wax, paraffin wax, silica, microcrystalline wax, methyl cellulose, starch, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, carboxymethyl cellulose, soluplus, Poly(acrylic acid) , poly(vinylpyrrolidone), poly(vinylalcohol), poly(acrylamide), poly(2-hydroxypropyl methacrylamide), poly(N,N- dimethylacrylamide), poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), poly(2-(methacryloyloxy)ethyl phosphorylcholine), poly(carboxybetaine methacrylamide), polyethylene glycol), polyethylene imine), polyearcosine), poly(2- methyl-2-oxazoline), polyamino esters, polyester amides, polyphosphoesters, poly(l- lysine), poly(l-proline) , polyphosphazenes, dextran, sodium alginate, gelatin, agarose, carrageenan, gellan, xantham gum, urea, sucrose, derivatives thereof, combinations thereof, and co-polymers thereof. In some embodiments, the carrier includes one or more materials selected from the list consisting of polycaprolactone (PCL), ethyl cellulose (EC), hydroxypropyl methylcellulose (HPMC), fumed silica / aerosil, castor wax, paraffin, stearic acid, microcrystalline wax, beeswax, polyethylene glycol (PEG), sodium starch glycolate, croscarmellose sodium, crospovidone, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), carrageenan, guar gum, xanthan gum, sodium alginate, locust bean gum, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate co-polymer (PVP / VA), a polyacrylic acid and / or their co-polymer variants, polyisobutylene, ethyl vinyl acetate (EVA), a functional wax with a melting point less than about 120 °C, combinations thereof, combinations with talc thereof, and copolymers thereof. In some embodiments, the carrier includes one or more biodegradable polymers selected from the list above, combinations thereof, combinations with talc thereof, and co-polymers thereof.

[0199] In some embodiments, the carrier includes one or more materials selected from the list consisting of carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), carrageenan, guar gum, xanthan gum, sodium alginate, locust bean gum, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate co-polymer (PVP / VA), a polyacrylic acid and / or their co-polymer variants, combinations thereof, combinations with talc thereof, and co-polymers thereof. In some embodiments, the carrier includes one or more materials selected from the list consisting of polyisobutylene, ethyl vinyl acetate (EVA), a functional wax with a melting point less than about 120 °C, combinations thereof, combinations with talc thereof, and co-polymers thereof.

[0200] In some embodiments, the carrier includes one or more cellulose derivative, combinations thereof, combinations with talc thereof, and co-polymers thereof. In some embodiments, the carrier consists of one or more cellulose derivative, combinations thereof, combinations with talc thereof, and co-polymers thereof. In some embodiments, the carrier includes ethyl cellulose, hydroxypropyl methylcellulose,combinations thereof, combinations with talc thereof, and co-polymers thereof. In some embodiments, the carrier consists of ethyl cellulose, hydroxypropyl methylcellulose, combinations thereof, combinations with talc thereof, and co-polymers thereof. In some embodiments, the carrier includes ethyl cellulose. In some embodiments, the carrier includes hydroxypropyl methylcellulose.

[0201] In some embodiments, the ethyl cellulose is about 15% to about 40%, about 15% to about 30%, or about 20% to about 30% w / w of the composition. In some embodiments, the ethyl cellulose is about 20.1 % w / w of the composition. In some embodiments, the ethyl cellulose is about 27.3% w / w of the composition.

[0202] In some embodiments, the hydroxypropyl methylcellulose is about 10% to about 30%, about 10% to about 25%, or about 12% to about 20% w / w of the composition. In some embodiments, the hydroxypropyl methylcellulose is about 14.3% w / w of the composition. In some embodiments, the hydroxypropyl methylcellulose is about 19.6% w / w of the composition.

[0203] In some embodiments, the ethyl cellulose is about 48.0 to about 49.5% w / w ethoxyl basis.

[0204] In some embodiments, the ethyl cellulose has a viscosity of about 10 cP, 20 cP, about 45 cP or about 100 cP at 5% w / w (80:20 Toluene / Ethanol)solution at 25 °C. In some embodiments, the ethyl cellulose has a viscosity of about 41 to about 49 mPa.s at 5% w / w (80:20 Toluene / Ethanol) solution at 25 °C.

[0205] In some embodiments, the hydroxypropyl methylcellulose of the carrier is E3 LV, E5 LV, E6 LV, E15 LV, E50 LV, and K100 LV, or combinations thereof.

[0206] In some embodiments, the hydroxypropyl methylcellulose has a viscosity from about 3 to about 100,000 cP (mPa-s) measured in 2 % w / w aqueous solution at 20 °C. In some embodiments, the hydroxypropyl methylcellulose has a viscosity of about 100,000 cP (mPa-s) measured in 2 % w / w aqueous solution at 20 °C. In some embodiments, the hydroxypropyl methylcellulose has a viscosity from about 75,000 to about 140,000 mPa.s measured in 2 % w / w aqueous solution at 20 °C. In some embodiments, the hydroxypropyl methylcellulose has a methoxyl content from about 19% to about 24%. In some embodiments, the hydroxypropyl methylcellulose has a hydroxypropyl content from about 7% to about 12%. In some embodiments, the hydroxypropyl methylcellulose has a methoxyl content from about 19% to about 24%, and a hydroxypropyl content from about 7% to about 12%.

[0207] In some embodiments, the hydroxypropyl methylcellulose is E3 LV, E5 LV, E6 LV, E15 LV, E50 LV, and K100 LV, or combinations thereof.

[0208] Optionally, the at least one carrier is about 5 to about 80%, about 10 to about 70%, about 20 to about 60%, about 30 to about 50% w / w of the composition.Further composition components

[0209] In some embodiments, the composition comprises a channeling agent. Channeling agents are substances that are soluble in the gastrointestinal tract and leach from the formulation, leaving capillaries through which the active ingredient may diffuse in order to be released. In some embodiments, the channeling agent is a hydrophilic polymer and / or polyol. In some embodiments, the channeling agent is selected from the list consisting of alginate, an osmotic agent (such as NaCI, mannitol), a phospholipid (such as lecithin), an alcohol or derivative (such as glycerol, triacetin), a polyethylene glycol (PEG), sorbitol, citric acid, sodium bicarbonate, triacetin, ethyl oleate, or suitable polymers such as sodium starch glycolate, croscarmellose sodium and crospovidone. In some embodiments, the carrier does not comprise a channeling agent.

[0210] In some embodiments, the composition does not include hydrophobic fumed silica. In some embodiments, the composition includes hydrophobic fumed silica. In some embodiments, the composition does not include silica. In some embodiments, the composition includes hydrophilic silica.

[0211] In some embodiments, the composition does not include an additional excipient. In some embodiments, the composition does not include a wax.

[0212] In some embodiments, the composition comprises a densifier. Incorporating a densifier in the composition adds density to the composition and allows the composition inserted into an animal’s rumen to be retained more effectively, reducing the regurgitation of the composition after administration. Inclusion of a densifier can be particularly useful when the composition is formulated as a bolus. In some embodiments, the densifier includes steel, iron, iron oxide, zinc, zinc oxide and combinations thereof. In some embodiments, the densifier includes steel. In some embodiments, the densifier includes iron and / or iron oxide. In some embodiments, the densifier does not include zinc and / or zinc oxide. Zinc is known to interact with oragnohalides, such as di- or tri-halogenated methane compounds (such as haloforms), potentially meaning that the incorporation of zinc (and / or zinc oxide) into a composition comprising haloform or generating a di- or tri-halogenated methane compound (such as a haloform) may be disadvantageous.

[0213] In some embodiments, the densifier includes the densifier as balls, optionally metal balls, further optionally steel balls. In some embodiments, the densifier includes the densifier as particles. Densifier balls and / or particles are advantageous given that they are less likely to aggravate the rumen than densifiers with sharp edges. Similarly, small and stable densifiers such as steel ball bearings or steel particles are also advantageous given that they are biologically inert, and unlikely to aggravate the digestive tract either chemically or physically, and can potentially be excreted by the animal. Similarly, biologically compatible yet unstable densifiers such as iron and iron oxide are also favourable: such densifiers can break down to particles (if not already delivered as such) in the digestive tract, facilitating excretion without aggravating the digestive tract.

[0214] In some embodiments, the densifier is a densifier matrix comprising densifier and at least one veterinary acceptable excipient. Optionally, the densifier matrix includes a matrix material more hydrophobic than the at least one carrier. Optionally, the densifier matrix includes a wax. Optionally, the densifier matrix includes a matrix material selected from castor wax, paraffin wax, stearic acid, microcrystalline wax, beeswax, stearyl alcohol, white wax, yellow wax, cetyl alcohol, cetyl esters wax, carnauba wax, ethyl vinyl acetate (EVA), and combinations thereof. Optionally, the densifier and / or densifier matrix includes metal. Optionally, the densifier and / or densifier matrix includes metal balls.

[0215] In some embodiments, the composition comprises a base. In some embodiments, the base is a hydroxide. In some embodiments the base is KOH and / or NaOH.

[0216] In some embodiments, the composition is associated with a gastric retention device, for instance, a device with retention means such that the composition is retained in the rumen after administration for a longer period than it would otherwise be retained in the absence of retention means. In some embodiments, the retention means are retention members for retaining a bolus, wherein the retention members are configured to transform between a collapsed configuration suitable for administration of the bolus to a stomach of an animal and an expanded configuration suitable for being retained in a stomach of an animal.

[0217] In some embodiments the composition comprises one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activatedcarbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, a pH modifier, an ester hydrolase and a carboxy lyase.

[0218] In some embodiments the composition comprises a metal particle, such as one or more metal particles (optionally steel particles). In some embodiments, the metal particles are rounded. For instance, when the composition is administered in an intraruminal bolus, the total of all particles per bolus may have a mass of at least 100 g. Incorporating metal particles in such an intraruminal bolus adds weight to the bolus and allows the bolus inserted into an animal’s rumen to be retained more effectively, preventing the regurgitation of the bolus after administration. This is particularly suitable when administering a bolus comprising a composition of the disclosure providing a sustained release of a di- or tri-halogenated methane compound (such as a haloform, including bromoform) over a prolonged period of time, for instance for at least 3 months.

[0219] In some embodiments the composition comprises silica. For instance, these silica may be hydrophobic fumed silica. In some embodiments, such fumed silica may be amorphous or consist of or comprise hydrophobic fumed silica particles (HFSPs). In some embodiments, the average particle diameter of said hydrophobic fumed silica may be between 5 nm and 15 nm. In some embodiments the hydrophobic fumed silica is silica producible by contacting silica with a hydrophobic silane and optionally contacting said silica with a compound selected from the group consisting of dimethyldichlorosilane (DDS), methyl acrylic silane, octyl silane, octamethylcyclotetrasiloxane, hexadecyl silane, octylsilane, methylacrylsilane, polydimethylsiloxane, hexamethyldisilazane (HMDS), silicone oil, silicone oil plus aminosilane, HMDS plus aminosilane, an organic phosphate, HMDS (hexamethyldisilazane), and combinations of the aforementioned compounds.

[0220] In some embodiments the composition comprises cellulose or cellulose derivatives, wherein derivatives optionally are alkyl cellulose, ethyl cellulose, and / or hydroxypropyl methyl cellulose (HPMC).

[0221] In some embodiments the composition comprises cyclodextrins. Among other things, cyclodextrins may be used for their beneficial capacity to hold (hydrophobic) compounds in an encapsulated core.

[0222] In some embodiments the composition comprises a buffering substance. For instance, the buffering substance may be selected from the group consisting of citrate, phosphate and acetate buffers, optionally selected from the group consisting of PBS, sodium acetate, ammonium chloride, sodium hydroxide and potassium hydroxide.

[0223] In some embodiments the composition comprises one or more pH modifiers. In some embodiments pH modifiers can aid to set the pH of the composition when contacted with water to a desired range, for instance a range of about pH 5 to 9, thus contributing towards maintaining the physicochemical stability of the composition.

[0224] In another embodiment, pH modifiers can aid to set the pH of the composition when contacted with water to a desired range, for instance a range of about pH 1 -5, which is reached at least inside of the bolus when the pH modifier is contacted with water. This mechanism may contribute towards speeding up the conversion of the compound(s) described herein to produce a di- or tri-halogenated methane compound (including a haloform, optionally bromoform). In a further embodiment, pH modifiers can aid to set the pH of the composition when contacted with water to a desired range, for instance a pH of about pH 9 or above, which is reached at least inside of the bolus when the pH modifier is contacted with water. This mechanism may contribute towards speeding up the conversion of the compound(s) described herein to produce a di- or trihalogenated methane compound (including a haloform, optionally bromoform).

[0225] pH modifiers may for instance be selected from the group consisting of a weak or strong base, ferric hydroxide (Fe(OH)a), zinc hydroxide (Zn(OH)2), trimethylamine (N(CHs)3), methylamine (CH3NH2), lactic acid, citric acid, sodium citrate, sodium carbonate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, adipic acid, tartaric acid, tannic acid, fumaric acid, malic acid, succinic acid and ascorbic acid and sodium or potassium bicarbonate.

[0226] In some embodiments the composition comprises an ester hydrolase and / or a carboxy-lyase. Enzymatic components such as ester hydrolase and carboxylyase may facilitate and thereby promote release of a di- or tri-halogenated methane compound (such as a haloform, including bromoform) from a compound of the disclosure by enzymatic. A step of enzymatic cleavage in the process of the di- or tri- halogenated methane compound (such as a haloform, including bromoform) being released from a compound of the disclosure may also be part of a sequence of steps in the process of the di- or tri-halogenated methane compound (such as a haloform, including bromoform) being released.Filling agent

[0227] A filling agent as used herein is a compound that is an inert filler or diluting agent in the composition.

[0228] In some embodiments, the filling agent is water soluble. In some embodiments, the filling agent is water insoluble.

[0229] In some embodiments the composition comprises one or more components selected from the group consisting of cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co- glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate. These components may, among other things, act as filling agents. In some embodiments, the filling agent is selected from the group consisting of cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, calcium carbonate, sodium carbonate, lactose, calcium phosphate, kaolin, sodium phosphate, gelatin, milk, milk derivatives, infant formula, milk powder, triglycerides, medium chain triglycerides and oil thereof, ethanol, lecithin, tween, xanthum gum, cellulose derivatives, alkyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), zein and surfactant. In some embodiments, the filling agent is selected from the group consisting of calcium carbonate, sodium carbonate, lactose, calcium phosphate, kaolin and sodium phosphate. A filling agent may provide an additional bulking substance to evenly distribute a compound described herein in the composition without the filling agent promoting any significant undesirable interactions and while at the same time being well tolerable to the ruminant animal. When using a composition of the disclosure for instance in a bolus, a pellet, a tablet or a lick block, a filling agent may provide additional internal substance of the bolus, pellet, tablet or lick block, providing sufficient stability from the inside to counteract forces acting on the bolus from the outside.

[0230] In some embodiments the filling agent is a stabilizer. In some embodiments the filling agent is selected from the group consisting of gelatin, milk, milk derivatives, infant formula, milk powder, triglycerides, medium chain triglycerides and oilthereof, ethanol, lecithin, tween, xanthum gum, cellulose derivatives, alkyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), zein and surfactant.Haloform and dihalogenated methane compound release

[0231] In some embodiments a haloform (optionally bromoform) is released from the compound when the composition is exposed to water. In some embodiments, a haloform (optionally bromoform) is released from the compound when the composition is exposed to water when said composition is placed in the rumen of a living ruminant animal.

[0232] Bromoform, by competitively reacting with coenzyme M and methyl coenzyme M reductase substrates, can inhibit methyl transfer from methyl-H4MPT (methyl-Tetrahydromethanopterin) to CoM-SH (coenzyme M -SH) and the reductive release of methane from methyl-coenzyme M (Glasson, Kinley et al.; Benefits and risks of including the bromoform containing seaweed Asparagopsis in feed for the reduction of methane production from ruminants, Algal Research, Volume 64, 2022, 102673, ISSN 2211 -9264). Via this inhibition mechanism, the presence of bromoform can reduce the production of methane in the intestinal tract of animals, such as in ruminant animals. Chloroform is known to have similar effects on methane production as bromoform. Thus, also haloform compounds with mixed Cl and Br substitution encompassed by the disclosure may provide this methane inhibiting effect particularly demonstrated for bromoform.

[0233] Bromoform is reactive and has a short half-life in animals (0.8 h in rats, 1 .2 hours in mice, US Dept of Health, 2003). It is a liquid at room temperature and is denser than water. Previous trials demonstrated no residues in meat and tissue from slaughtered steers, after 48 hour with holding period (Kinley et al. Mitigating the carbon footprint and improving productivity of ruminant livestock agriculture using a red seaweed, Journal of Cleaner Production 259 (2020) 120836), and no significant increase in the level in milk (Roque et al. Inclusion of Asparagopsis armata in lactating dairy cows’ diet reduces enteric methane emission by over 50 percent; Journal of Cleaner Production 234 (2019) 132-138).

[0234] Reducing production of methane may provide animal production benefits. Methane inhibition may improve the ruminant’s conversion of feed for animal production. For example, by reducing methane production during digestion, it is believed that this may lead to more efficient utilization of ingested feed, and result in improved growth and weight gain, or other production such as milk or meat production. As a result, farmersmay be able to improve efficiency by either securing greater productivity for a given feed volume or reduce feed accordingly, when efficiently inhibiting methane production in animals.

[0235] In some embodiments, a dihalogenated compound is released from the compound when the composition is exposed to water. In some embodiments, a dihalogenated compound is released from the compound when the composition is exposed to water when said composition is placed in the rumen of a living ruminant animal.

[0236] Release of a haloform, optionally bromoform, or a dihalogenated methane compound from a compound as defined herein may, among other things, occur by enzymatic cleavage or by non-enzymatic cleavage, such as hydrolytic cleavage, or a sequential combination thereof, for example an enzymatic cleavage step followed by a non-enzymatic rearrangement. Release of a haloform, optionally bromoform, from a compound as defined herein may, among other things, occur by enzymatic cleavage or by non-enzymatic cleavage, such as hydrolytic cleavage, or a sequential combination thereof, for example an enzymatic cleavage step followed by a non-enzymatic rearrangement. The process may be spontaneous and / or aided by further compounds or excipients included in the composition. Some compounds or excipients included in the composition may cause a catalytic acceleration of the release of a haloform, optionally bromoform, or a dihalogenated methane compound from a compound as described herein. Some compounds or excipients included in the composition may cause a catalytic acceleration of the release of a haloform, optionally bromoform, from a compound as described herein. The release of a haloform, optionally bromoform, from a compound described herein may for instance occur as mechanistically shown in figures 1 , 2 or 3. Equivalent mechanisms may also occur for a dihalogenated methane compound. In some cases hydrolysis in near neutral aqueous solution may suffice, while in other cases the addition of a base, such as a strong base such as for instance NaOH or KOH, may be beneficial to enhance the release process. In some embodiments, addition of an acid, for instance tartaric acid may be beneficial to enhance the release process.Solubility

[0237] In some embodiments the composition is dissolvable in water. In some embodiments the composition is dissolvable in water at a temperature of 15 °C or more. In some embodiments the composition is dissolvable in water at room temperature. Asused herein, the term “room temperature” relates to a temperature of from 20 to 25 °C, particularly about 22°C, unless specified otherwise.

[0238] Methods for determining dissolution properties, such as time to full dissolution and dissolution rate, are known in the art. For instance, testing whether and how quickly the composition is dissolved in water or in an animal’s rumen can be performed via in vitro testing. Dissolution in water can be tested by placing the composition into a known volume of water (e.g. 1 liter) tempered to 15 °C or more, optionally tempered to room temperature. Dissolution in the rumen can for example be tested by adding the composition to a solution with a milieu simulating the rumen milieu and determining whether and when the composition is dissolved, i.e. partially or entirely disintegrates over time. For in vitro testing the composition can for example be placed in a tank or vessel containing a known volume (e.g. 1 liter) phosphate buffer (pH: 6.5, 0.02 M) at 40°C. Optionally, the solution containing the composition can be agitated to simulate agitation in the rumen.Bolus

[0239] In another aspect the disclosure provides a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein.

[0240] A bolus described herein refers to large dosage form for delivering substances and / or instruments orally to an animal. In some embodiments, the bolus is at least externally solid. A bolus is generally suitable for administration with a bolus or balling gun. Without limiting the meaning of bolus, a bolus can be a large pill, capsule, tablet, case or container. A bolus can include a core and a housing surrounding the core. The housing of the bolus refers to a component of a bolus, specifically a housing that surrounds, covers at least a portion of or fully encases a core of the bolus. In some embodiments, a housing includes a cap. In some embodiments, a housing does not include a cap. The core of the bolus generally includes a substance for delivery to an animal. The housing can be a coating or something that is moulded to contain the core of the bolus. The core of the bolus refers to a component of a bolus, specifically the central portion of the bolus. Often the active ingredient, prodrug thereof, or substance to be delivered to the animal is in the core of the bolus.

[0241] In some embodiments, the bolus comprises a compound of formula (I). In some embodiments, the bolus comprises a compound of formula (la).

[0242] In some embodiments a bolus for administration to a ruminant animal that comprises a compound or composition as defined herein comprises: a core, wherein thecore comprises the compound or the composition and optionally a carrier; and a housing which covers at least a portion of the core. In some embodiments of the bolus, the material of the housing of the bolus comprises poly lactic acid (PLA) and polybutylene adipate terephthalate (PBAT) in a PLA:PBAT weight ratio of between 95:5 to 80:20. In some embodiments of the bolus, the material of the housing comprises poly lactic acid (PLA) and polybutylene adipate terephthalate (PBAT) in a PLAPBAT weight ratio of between 95:5 to 70:30, optionally in a PLAPBAT weight ratio of about 90:10. In some embodiments of the bolus the material of the housing comprises poly lactic acid (PLA) and polybutylene succinate (PBS) in a PLAPBS weight ratio of between 95:5 to 70:30. In some embodiments of the bolus the material of the housing comprises poly lactic acid (PLA) and polybutylene succinate adipate (PBSA) in a PLAPBSA weight ratio of between 95:5 to 70:30.

[0243] In some embodiments, the housing comprises a biodegradable polymer, such as polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate- co-10 adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene adipate terephthalate (PBAT), styrene-acrylic copolymer (such as Joncryl®), talc-filled poly(D-lactide) (TALC PDLA), Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), poly vinyl acetate (PVAc), polyglycolic acid (PGA), cellulose acetate, combinations thereof, and co-polymers thereof. In some embodiments, the the housing comprises a non-biodegradable polymer, such as high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polythene terephthalate (PET), polystyrene (PS), nylon, poly(methyl methacrylate) (PMMA), acetal (polyoxymethylene - POM), and combinations thereof. In some embodiments, at least one polymer of the housing is biodegradable and at least one polymer of the housing is non-biodegradable. In some embodiments, the polymer of the housing is selected from the group consisting of polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-co-10 adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene adipate terephthalate (PBAT), styrene-acrylic copolymer (such as Joncryl®), talc-filled poly(D-lactide) (TALC PDLA), Poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), poly vinyl acetate (PVAc), polyglycolic acid (PGA), cellulose acetate, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyethylene (PE), polythene terephthalate (PET), polystyrene (PS), nylon, poly(methyl methacrylate) (PMMA), acetal (polyoxymethylene - POM) combinations thereof, and co-polymers thereof. In someembodiments, the housing comprises polypropylene. In some embodiments, the housing comprises acetal (polyoxymethylene - POM). In some embodiments, the housing is polypropylene. In some embodiments, the housing is acetal (polyoxymethylene - POM).

[0244] In some embodiments of a bolus for administration to a ruminant animal that comprises a compound or composition as defined herein, a haloform released from a compound of the disclosure comprised by the composition of the disclosure can perfuse through the housing material of the bolus. In some embodiments of a bolus for administration to a ruminant animal that comprises a compound or composition as defined herein, a dihalogenated methane compound released from a compound of the disclosure comprised by the composition of the disclosure can perfuse through the housing material of the bolus. In some embodiments the housing of the bolus has a wall thickness of below 2 mm, optionally a wall thickness in the range of 0.3-1 .5 mm, further optionally a wall thickness of about 1 .2 mm. wherein the housing completely covers and surrounds the core.

[0245] In some embodiments the housing material of the bolus has a Shore D hardness of at least 20. Methods to determine Shore D hardness are known in the art and will be clear to the skilled person. For instance, this may be done by use of a durometer, which determines Shore D hardness by the penetration of the Durometer indenter foot into the sample under a defined spring force.

[0246] In some embodiments the housing of the bolus completely covers and surrounds the core of the housing.

[0247] In some embodiments, the disclosure provides a bolus for administration to a ruminant animal that comprises the compound or the composition as defined herein, wherein the bolus comprises: a core, wherein the core comprises the compound or the composition and optionally a carrier; and a housing which covers at least a portion of the core; wherein the material of the housing comprises poly lactic acid (PLA) and polybutylene adipate terephthalate (PBAT) in a PLAPBAT weight ratio of about 90:1 0; optionally wherein the housing of the bolus completely covers and surrounds the core of the housing and further optionally wherein a haloform released from a compound of the disclosure comprised by the composition of the disclosure can perfuse through the housing material of the bolus; further optionally wherein the housing of the bolus has a wall thickness in the range of 0.3-1.5 mm. In some embodiments, the disclosure provides a bolus for administration to a ruminant animal that comprises the compoundor the composition as defined herein, wherein the bolus comprises: a core, wherein the core comprises the compound or the composition and optionally a carrier; and a housing which covers at least a portion of the core; wherein the material of the housing comprises poly lactic acid (PLA) and polybutylene adipate terephthalate (PBAT) in a PLA:PBAT weight ratio of about 90:10; optionally wherein the housing of the bolus completely covers and surrounds the core of the housing and further optionally wherein a dihalogenated methane compound released from a compound of the disclosure comprised by the composition of the disclosure can perfuse through the housing material of the bolus; further optionally wherein the housing of the bolus has a wall thickness in the range of 0.3-1 .5 mm.

[0248] It should be appreciated by the person skilled in the art that the size, thickness and / or dimensions of the bolus, including the core and a housing if provided can be adjusted depending on the dose of haloform (including bromoform) / dihalogenated methane compound to be delivered to the ruminant, without departing from the spirit and scope of the disclosure. For example, a smaller size bolus can be adapted for use in smaller ruminant animals such as sheep or goats, while a larger sized bolus can be used in larger ruminant animals such as cattle. In some embodiments, the bolus has a weight of less than 180g.

[0249] It may be suitable to incorporate in the housing of the bolus one or more openings in order to facilitate release of the compound comprised by the composition of the disclosure from the bolus. In some embodiments a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein comprises: a core, wherein the core comprises the compound or the composition of the disclosure and a carrier; and a housing which comprises said core; wherein the housing comprises at least one opening exposing the core to the environment surrounding the bolus. In some embodiments, the housing material comprises PLA and PBAT. In case the bolus housing comprises one or more opening(s), these one or more opening(s) allow stomach fluids and possibly fibrous matter to come into contact with the core

[0250] In some embodiments a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein comprises: a core, wherein the core comprises the compound or the composition; and a housing which covers the outer surface of the bolus, wherein at least part of the housing is configured to form one or more openings when exposing the housing to a temperature of between 28°C and 42°C, allowing the methane inhibiting agent to exit the bolus through said opening oropenings. A temperature of between 28°C and 42°C includes the temperature which the bolus will be exposed to when administered to the rumen of a ruminant animal.

[0251] In some embodiments, the portion of the housing, where the opening or openings form, comprises or consists of a compound selected from the group consisting of a temperature responsive hydrogel, an oleogel, an organogel, a phase changing material (PCM), a fatty acid, an alkane, an alkene, a gelator and a wax, an L-alanine amino acid or L-alanine amino acid derivative, poly(methyl methacrylate) (PMMA), (1 ,3:2,4) dibenzylidene sorbitol (DBS), hydroxy stearic acid, paraffin wax, gelatin, 1 - tetradecanol, polyethylene glycol, octadecane, nonadecane, eicosane, a pluronic polymer or a mixture of pluronics, an emulsifier, sucrose acetate isobutyrate (SAIB), derivatives of the aforementioned and combinations of one or more of the aforementioned compounds and wherein said compound or combination of compounds optionally has a melting temperature of between 28°C and 42°C, further optionally between 28°C and 35°C. When the portion of the housing, where the opening or openings form, comprises or consists of a compound as outlined above, this compound will be removed from the opening(s) after administration to the rumen, allowing stomach fluids and possibly fibrous matter to come into contact with the core of the bolus through the openings.

[0252] In some embodiments, openings comprised by the bolus housing or openings forming in the bolus housing have an average diameter of, for example, from about 0.1 mm to about 1 mm. The individual opening diameter can vary within a given housing.

[0253] In some embodiments, a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein is producible by carrying out the following steps:(i) provision of a housing wherein the housing material comprises PLA and PBAT, optionally in a wt% ratio of about 90:10 PLAPBAT and further optionally with a wall thickness of about 0.5 to 2 mm;(ii) filling into the housing at least 20 g of steel balls;(iii) mixing ethyl cellulose (or another suitable filling agent ad defined herein or other excipient) with the compound or the composition of the disclosure;(iv) optionally mixing the composition obtained from (iii) with further compounds such as for instance hydroxypropyl methylcellulose, silica, or another compound as defined herein;(v) filling the obtained mixture from (iv) into the housing provided in (i);(vii) closing the housing by spin-welding a cap onto it; and wherein the housing is configured such that its permeability to the compounds comprised by the composition of the disclosure or released from the composition of the disclosure is increased when exposing the housing to the rumen of a living animal; and / or wherein at least part of the housing is configured to form one or more openings when exposing the housing to the rumen of a living animal, allowing the methane inhibiting agent to exit the bolus through said opening or openings.

[0254] In another embodiment a bolus for administration to a ruminant animal that comprises a compound or composition as defined herein comprises: a core, wherein the core comprises the compound or the composition of the disclosure, and wherein the bolus does not comprise a housing. The core of a bolus not comprising a housing as described herein may be selected to provide sufficient sustainability of said uncased bolus in the rumen environment. In some embodiments the bolus has a Shore D hardness of at least 20 or even at least 40. Shore D hardness may for instance be adjusted via the selection of core materials or the manufacturing process of the core. It will be clear to an average skilled person that the bolus hardness may be selected so that the bolus is able to persist in the environment of the rumen, withstanding the physical and chemical influences.

[0255] In some embodiments, a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein comprises: a core, wherein the core comprises the compound or the composition and optionally a carrier; and a housing which covers at least a portion of the core, wherein the housing has at least one opening, wherein only through said at least one opening the core of the bolus is exposed to the rumen fluid, optionally wherein at the same time the remaining core is at least initially not exposed to the rumen fluid. Such embodiments are suitable to be used as sustained release formulations. In some embodiments, the bolus comprises only one opening. In a bolus with a housing which has (at least) one opening, wherein only through said (at least one) opening the core of the bolus is exposed to the rumen fluid, a compound as disclosed herein comprised by a composition of the disclosure may be continuously eroded and / or dissolved from the bolus core at the limited contact surface between the bolus core and the rumen fluid or water in the rumen. The exposure of the core at the opening to the rumen fluids may be promoted by a mechanism employed within the bolus to provide the core or core components at the opening of the housing,including for instance a spring-fed mechanism for protruding the core or core components or a tablet based bolus core. In some embodiments, bolus designs as described in US6974587 or NZ535258A could for instance be applied.

[0256] In a further embodiment a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein comprises: a core, wherein the core comprises the compound or the composition and optionally a carrier; and a housing which covers at least a portion of the core, optionally wherein the housing fully surrounds the core, wherein the housing is permeable to water and a haloform, optionally bromoform. In a further embodiment a bolus for administration to a ruminant animal that comprises a compound or a composition as defined herein comprises: a core, wherein the core comprises the compound or the composition and optionally a carrier; and a housing which covers at least a portion of the core, optionally wherein the housing fully surrounds the core, wherein the housing is permeable to water and a dihalogenated methane compound. In some embodiments the bolus housing which is permeable to water and haloform, optionally bromoform, comprises or consists of a material which is permeable to water and a haloform. In another embodiment the bolus housing which is permeable to water and haloform comprises one or more perforations such as pores through which water and haloform can permeate. In a bolus with a permeable housing an ingress of water and subsequent contact of the composition comprising the compound with the water may allow for a controlled haloform (optionally bromoform) release from a compound described herein, while the compound itself is not released from the inside of the bolus but only the haloform, optionally bromoform, is released into the rumen. In some embodiments the bolus housing which is permeable to water and a dihalogenated methane compound, comprises or consists of a material which is permeable to water and a dihalogenated methane compound. In another embodiment the bolus housing which is permeable to water and a dihalogenated methane compound comprises one or more perforations such as pores through which water and the dihalogenated methane compound can permeate. In a bolus with a permeable housing an ingress of water and subsequent contact of the composition comprising the compound with the water may allow for a controlled dihalogenated methane compound release from a compound described herein, while the compound itself is not released from the inside of the bolus but only the dihalogenated methane compound is released into the rumen.

[0257] A ruminant animal can also be treated by multiple boluses in order to achieve a desired dosage of haloform (such as bromoform). A ruminant animal can also be treated by multiple boluses in order to achieve a desired dosage of a dihalogenated methane compound. For example, each animal (such as cattle) could be administered two boluses, each having a dimension of about 75 mm in length and about 34 mm in width, whereby each of these boluses may have a weight of about 80. This can allow a bolus to be manufactured which has a concentration and total load of compound(s) of the disclosure. Multiple of those boluses can be administered to an animal concurrently or sequentially. This will allow the desired dosage to be provided to the animal. This can be particularly beneficial to allow the bolus to be used with animals requiring different doses of haloform (such as bromoform) e.g. larger or smaller animals, or to compensate for natural growth over time. This can be particularly beneficial to allow the bolus to be used with animals requiring different doses of a dihalogenated methane compound e.g. larger or smaller animals, or to compensate for natural growth over time. The same is applicable to adjusting dosages via other administration forms, such as via pellets, lick block, or drinking water.

[0258] In some embodiments, the bolus is administered orally. In some embodiments, the bolus is configured to remain in the rumen after administration. In some embodiments the bolus is configured to release a haloform, such as bromoform over a period of at least 4 months, such as about 6 months. In some embodiments, the bolus may be adapted to exhibit a release rate of about 0.1 to 0.5g of haloform (such as bromoform) per day. In some embodiments the bolus is configured to release a dihalogenated methane compound over a period of at least 4 months, such as about 6 months. In some embodiments, the bolus may be adapted to exhibit a release rate of about 0.1 to 0.5g of dihalogenated methane compound per day. When a bolus exhibits such release rates for the haloform, such as bromoform, or the dihalogenated methane compound, this can reduce methane production. The rate of release into the rumen may increase overtime, i.e. the rate of release starts from zero on administration to the animal and increases to a maximum due to several factors. However, the foregoing should not be seen as limiting, and other release rates are envisaged as within the scope of the present disclosure. To reach a desired release rate, also in smaller farm animals, the concentration of a compound described herein, or the housing material thickness may for instance be adjusted

[0259] The release rate of a haloform, optionally bromoform, or a dihalogenated methane compound from a composition / dosage form (such as a bolus) described herein can for example be determined via in vitro testing by placing the composition / dosage form (such as a bolus) in a solution with a milieu simulating the rumen milieu and measuring the concentration of the released haloform (such as bromoform) in the solution over time. For instance, for in vitro release testing a bolus may be placed in a tank or vessel containing a known volume (e.g. 1 litre) phosphate buffer (pH:6.5, 0.02M) at 40°C as release medium and the amount of released haloform / bromoform in the medium may be quantified (see further method description herein above). Determining the amount of haloform (such as bromoform) or the dihalogenated methane compound released into the medium per release time, i.e. testing time, gives the release rate (i.e. release per time). An exemplary method of determining the release rate is further described in Example 6 herein.Animal

[0260] In some embodiments, the animal for administration is a ruminant. In some embodiments, the ruminant animal is bovine, ovine, caprine or cervine. In some embodiments, the ruminant is bovine. In some embodiments, the ruminant is ovine.

[0261] In some embodiments, the animal for administration is a pseudo-ruminant. In some embodiments, the pseudo-ruminant animal is camelid.

[0262] In some embodiments, the ruminant animal may include beef or dairy cattle, sheep, goats, buffalo, deer, elk, giraffes or camels. In some embodiments of any embodiment described herein, the ruminant animal is cattle. In some embodiments, the ruminant animal is dairy cattle. In some embodiments, the ruminant animal is beef cattle. Pellets

[0263] In another aspect the disclosure provides a pellet for administration to a ruminant animal that comprises a compound or a composition as defined herein.

[0264] In some embodiments, the pellet comprises a compound of formula (I). In some embodiments, the pellet comprises a compound of formula (la).

[0265] A pellet for administration to a ruminant animal that comprises the composition as defined herein may further comprise cereal grains commonly used in animal, e.g. cattle, feed pellets, including for instance alfalfa, hay, barley, corn, cotton, oats, sorghum, soybeans and hull, wheat and wheat bran and broken rice. Such ingredients may act as a filling agent, adding substance to the pellet. The composition of the disclosure may be admixed with further common feed pellet ingredients known inthe art. The ingredient may be milled and mixed with a composition described herein (and optionally moistened) to form a moist mash which is then compacted and extruded into pellets, which are subsequently dried. Pellets for administration to a ruminant animal that comprise the composition as defined herein may be admixed with the feed of the animal or may be configured such that they replace the animal feed, i.e. they can be used as the principal feed of the animal. The dosage of the composition of the disclosure in the pellets can be adjusted depending on whether the pellets are offered to the animal ad libitum or at intervals. When a composition of the disclosure is comprised in a bolus, in some embodiments the composition comprises one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, an ester hydrolase and a carboxy-lyase.Feed supplements

[0266] In another aspect the disclosure provides a feed supplement for a ruminant animal that comprises a compound or a composition as defined herein.

[0267] In some embodiments, the feed supplement comprises a compound of formula (I). In some embodiments, the feed supplement comprises a compound of formula (la).

[0268] In some embodiments, the feed supplement is in the form of a pellet, a tablet, a pill, a capsule, a powder or a lick block.

[0269] Any other conventional dosage forms may also be used, such as tablets, lozenges and syrups. The pharmaceutical compositions according to the present disclosure can be formulated, for example, into tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g. sterile solutions), emulsions, suspensions, oils or gels. Additionally, the composition can for instance be prepared as systems in which the active compound is coupled to polymers (e.g. soluble or biodegradable polymers). In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form. Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under differentconditions (e.g. pH conditions) or by coupling the active compound to a biodegradable polymer.

[0270] In some embodiments the feed supplement is in the form of a lick block. The lick block may comprise the composition of the disclosure mixed with further components commonly used for lick block preparations, including for instance molasses, urea, wheat bran, rice bran, soybean meal, cottonseed meal, olive cake, sunflower meal, corn, soybean, barley, fava bean, moringa oleifera leaf, citrus pulp, tomato pulp, cucumber waste, mango waste, avocado waste, grape marc, cactus waste, corn distiller’s dried grains with solubles, bagasse and poultry manure, quicklime, salt and minerals.Di- or tri-halogenated methane release system

[0271] In an aspect of the disclosure, there is provided a di- or tri-halogenated methane release system, the release system comprising: a compound of the disclosure, a housing, and a solid with a melting point from about 28 °C to about 45 °C, wherein the compound and the solid are within the housing, wherein the solid, or the combination of both the solid and the housing encapsulate or substantially encapsulate the compound.

[0272] On administration of the system to the rumen of a ruminant, the solid melts or softens, such that the solid or the combination of both the solid and the housing no longer encapsulate or substantially encapsulate the compound (though the housing may still encapsulate or substantially encapsulate the compound). This means that on melting / softening of the solid, the compound is more accessible for reaction, for instance with a solvent, and thus di- or tri-halogenated methane generation.

[0273] In some embodiments, the compound of the disclosure is present as part of a composition of the disclosure.

[0274] In some embodiments, the housing encapsulates or substantially encapsulates the compound and the solid.

[0275] In some embodiments, the system further comprises a solvent, wherein the solvent comprises water. In some embodiments, the solvent is an aqueous solution. In some embodiments, the solvent is water. In embodiments comprising a solvent, the solid separates or substantially separates the compound and the solvent. In some embodiments, the solvent is of non-neutral pH. In some embodiments, the solvent is ofneutral pH. In embodiments that do not comprise a solvent, solvent (such as ruminal fluid) may enter the housing on administration, for instance through an opening / orifice or through degradation of the housing over time.

[0276] In some embodiments, the solvent is of acidic pH, for instance from about pH 1 to about 6.5, about 2 to about 6.5, about 3 to about 6.5, about 4 to about 6.5. In some embodiments, the solvent is of basic pH, for instance from about pH 7.5 to about 13, about 7.5 to about 12, about 7.5 to about 1 1 , about 7.5 to about 10. In some embodiments, the solvent is buffered. In some embodiments, the solvent is buffered at an acidic pH. In some embodiments, the solvent is buffered at a basic pH.

[0277] Embodiments of the housing discussed with respect to a bolus are also suitable for the system.

[0278] The skilled person will appreciate that numerous solids with a melting point from about 28 °C to about 45 °C are suitable for the system. In some embodiments, the solid is a mixture of materials. In some embodiments, the solid is a single material. In some embodiments, the solid is a compound selected from the group consisting of a hydrogel, an oleogel, an organogel, a phase changing material (PCM), a fatty acid, an alkane, an alkene, a gelator, a wax, an L-alanine amino acid, an L-alanine amino acid derivative, poly(methyl methacrylate) (PMMA), (1 ,3:2,4) dibenzylidene sorbitol (DBS), hydroxy stearic acid, paraffin wax, gelatin, 1 -tetradecanol, polyethylene glycol, octadecane, nonadecane, eicosane, a pluronic polymer or a mixture of pluronics, an emulsifier, sucrose acetate isobutyrate (SAIB), derivatives of the aforementioned and combinations of one or more of the aforementioned compounds and wherein said compound or combination of compounds has a melting point from about 28 °C to about 45 °C. In some embodiments, the solid comprises eicosane. In some embodiments, the solid is eicosane.

[0279] In some embodiments, the solid has a melting point from about 35 °C to about 45 °C. In some embodiments, the solid has a melting point from about 28 °C to about 35 °C.Uses and methods of administration

[0280] In an aspect the disclosure relates to the use of the compound, the composition, the bolus, the release system, the pellet or the feed supplement as defined herein for use in reducing methane production in a ruminant animal.

[0281] In an aspect the disclosure relates to a method of treating a ruminant animal to reduce methane production in said animal, comprising administering to saidanimal the compound, the composition, the bolus, the release system, the pellet and / or the feed supplement as defined herein in an effective amount.

[0282] Methane production in a ruminant animal is considered to be reduced in comparison to a ruminant animal not treated with a composition, bolus, pellet or the feed supplement of the disclosure. In some embodiments methane production in a ruminant animal may be reduced by at least 30 %, optionally by as at least 50 %, further optionally by at least 70%, further optionally by at least 80%, further optionally by at least 90%. In another embodiment methane production in a ruminant animal may be reduced at least 99%. A composition bolus, pellet or feed supplement may comprise the compounds of the composition described herein in an effective amount to treat an animal treated therewith.

[0283] In another aspect the disclosure relates to the use of the compound, the composition, the bolus, the release system, the pellet or the feed supplement as defined herein for use in improving production of a ruminant animal.

[0284] In another aspect, the disclosure relates to a method of improving production of a ruminant animal, comprising administering to said animal the compound, the composition, the bolus, the release system, the pellet and / or the feed supplement as defined herein in an effective amount.

[0285] In some embodiments, improved production can be one or more of improved feed conversion, improved growth, improved weight gain, improved milk production (quality and / or quantity), improved meat production (quality and / or quantity) and improved reproduction (one or more of offspring birth weight, offspring growth rate, offspring mortality, and fertility).

[0286] In some embodiments, production is improved by at least 2.5%, at least 5%, at least 10% at least 15%, at least 20%, at least 30%, at least 40% or at least 50%. Optionally, the improved production occurs by about 5, about 10, or about 15 days following administration. Optionally, the improved production continues for about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks or about 20 weeks.

[0287] In some embodiments of the methods of administration of the disclosure, the compound, the composition, the bolus, the release system, the pellet or the feed supplement administers haloform or a dihalogenated methane compound to the rumen of the ruminant animal for at least about 1 week, about 2 weeks, about 4 weeks, about 8 weeks after administration. Optionally, the compound, the composition, the bolus, therelease system, the pellet or the feed supplement administers haloform or a dihalogenated methane compound to the rumen of the ruminant animal for at least about 20 weeks after administration.

[0288] In some embodiments of the methods of administration of the disclosure concerning bolus or the release system, administration, following administration of the bolus or the system, the bolus or system sinks below the liquid surface or to the bottom of the rumen.

[0289] In some embodiments of the methods of administration of the disclosure, following administration of the compound, the composition, the bolus, the release system, the pellet or the feed supplement the methane emitted by the ruminant is reduced by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80% by g / day. Optionally, this reduction occurs by about 5, about 10, or about 15 days following administration. Optionally, the reduction continues for about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks or about 20 weeks. Optionally, the reduction continues at about 40 to about 90%, about 40 to about 70%, about 40 to about 50%, about 60 to about 90%, or about 70 to about 90% by g / day over the about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks or about 20 weeks.

[0290] In some embodiments of the methods of administration of the disclosure, a second administration of the compound, the composition, the bolus, the release system, the pellet or the feed supplement is administered to the ruminant at about 8 to about 20 weeks, about 12 to about 20 weeks, about 8 to about 16 weeks or about 12 to about 16 weeks following the initial administration. Optionally, further administration occurs regularly at these intervals. Optionally, this dosage regimen results in ongoing methane reduction of about 40 to about 90%, about 40 to about 70%, about 40 to about 50%, about 60 to about 90%, or about 70 to about 90% by g / day. Optionally, this dosage regimen results in ongoing improved production of at least 2.5%, at least 5%, at least 10% at least 15%, at least 20%, at least 30%, at least 40% or at least 50%.

[0291] Optionally, administration results in reduced methane production and increased production.

[0292] In some embodiments of the methods of the disclosure, administration of the compound, the composition, the bolus, the release system, the pellet or the feed supplement generates bromoform and bromoform release reaches a maximum release rate of approximately 0.1 - approximately 0.5 g per day, and optionally approximately0.2 g per day. In some embodiments, the compound, the composition, the bolus, the pellet or the feed supplement exhibits a release rate of between 0.02 g and 2 g per day into the rumen, optionally a release rate of approximately 0.1 to 0.5 g of bromoform per day. The foregoing should not be seen as limiting, and other release rates are envisaged as within the scope of the present disclosure.

[0293] In some embodiments of the methods of the disclosure, a compound of formula (I) is administered. In some embodiments of the methods of the disclosure, a compound of formula (la) is administered.

[0294] In another aspect the disclosure relates to the use of the feed supplement as defined herein for admixing the feed supplement to drinking water of a ruminant animal, optionally wherein the feed supplement is dissolvable in water. The feed supplement may be employed to be dissolved in water in an effective amount to treat an animal ingesting said water. Methods for determining dissolution properties are known in the art and described herein further above.

[0295] As used herein, the term “treating” includes complete or partial elimination of a condition, prevention of a condition, alleviation of a condition or of a symptom of said condition. In the present case, the condition may be methane production and / or emission from an animal.

[0296] The term "effective amount" means an amount of the composition, the bolus, the pellet and / or the feed supplement sufficient to induce an effect of the treatment in the animal, i.e. a reduction in methane production in the animal.

[0297] The exact amount of active compound used in a composition of the disclosure can be adapted in accordance to the further factors known to those skilled in the art, such as the physical and chemical nature of the compound, the nature of further components of the composition and the administration form and possibly dosing regimen. However, it is anticipated that the composition of the disclosure will contain sufficient active ingredient to provide a suitable dose to a subject. Said dose can vary within wide limits and is to be suited to the individual conditions in each individual case. The appropriate dosage will vary depending on the mode of administration and the properties of the animal to be treated, including size / weight and age as well as species of the animal. For administration of bromoform for example, satisfactory methane mitigation results are achievable at dosages from about 0.28 - 0.4 mg / kg animal weight per day. In some embodiments, a haloform, optionally bromoform, is also released from a compound comprised by the composition of the disclosure when exposed to waterand optionally when placed in the rumen of a living ruminant animal. In some embodiments, one haloform, optionally bromoform, molecule will be released from one compound molecule of the disclosure. In some embodiments, a dihalogenated methane compound is also released from a compound comprised by the composition of the disclosure when exposed to water and optionally when placed in the rumen of a living ruminant animal. In some embodiments, one dihalogenated methane compound molecule will be released from one compound molecule of the disclosure. In some embodiments, two haloform molecules, optionally two bromoform molecules, or two dihalogenated methane compound molecules will be released from one compound molecule of the disclosure. Therefore, the dosage of a compound according to the disclosure can be adjusted following the dosage of haloform, optionally bromoform, or the dihalogenated methane compound administered in pure form, taking into the further dissolution and release parameters that may arise given the particular properties of a respective compound in a composition of the disclosure. In some embodiments, the compound of the disclosure is administered as a daily or continuous dosage, i.e. the compound is administered to a subject at short intervals or without significant interruptions.Methods of preparation

[0298] In another aspect, the disclosure provides a method of preparing a compound, composition, bolus, pellet and / or feed supplement as defined herein.

[0299] In some embodiments, the method of preparing a compound, composition, bolus, release system, pellet and / or feed supplement includes synthesising the compound of the disclosure. Obtaining compounds of the disclosure may include allowing a haloform, such a bromoform, to react to form a compound as described herein, which may later on release the haloform, e.g. bromoform, after administration to the rumen of an animal. In some embodiments, the compound of the disclosure is synthesised from a starting material other than a haloform. Obtaining compounds of the disclosure may include allowing a dihalogenated methane compound to react to form a compound as described herein, which may later on release the dihalogenated methane compound after administration to the rumen of an animal. In some embodiments, the compound of the disclosure is synthesised from a starting material other than a dihalogenated methane compound. Methods of obtaining compounds as used in the composition of the disclosure are known in the art and are for instance described in Clayden, Jonathan, Nick Greeves, and Stuart Warren, Organic chemistry, OxfordUniversity Press, USA, 2012, and in Carruthers, William, and lain Coldham, Modern methods of organic synthesis, Cambridge University Press, 2004.

[0300] The compounds to be included in the composition, bolus, pellet and / or feed supplement may alternatively be obtained as such from a supplier.

[0301] In some embodiments, the method may further include mixing a carrier with a compound to be included in the composition. In some embodiments, the method may further include mixing a filling agent with a compound to be included in the composition. In some embodiments, the method may further include mixing an excipient acceptable for a veterinary composition with a compound to be included in the composition.

[0302] In some embodiments, components of the composition are mixed in a dry mixture. In some embodiments, components of the composition are mixed in a moist mixture. In some embodiments, components of the composition are mixed in a wet mixture. In some embodiments, the method may further include drying wet or moist mixtures, for instance, by freeze drying. In some embodiments, the mixture comprises less than 0.1 wt% of water. In some embodiments, the mixture comprises less than 0.1 wt% of water after drying.

[0303] In some embodiments the method comprises the step of mixing a compound of the disclosure as disclosed herein with a further component such as components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose , activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, pH modifiers, an ester hydrolase, a carboxy-lyase, cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18- carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3-Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate and a haloform, optionally bromoform, and a weak or strong base as defined herein; and optionally formulating the composition for example in the form of a pellet or bolus. In some embodiments the method comprises the step of mixing a compound of the disclosure as disclosed herein with a further component such as components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica,cellulose, ethyl cellulose, hydroxypropyl methylcellulose , activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, pH modifiers, an ester hydrolase, a carboxy-lyase, cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3- Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate and a dihalogenated methane compound, and a weak or strong base as defined herein; and optionally formulating the composition for example in the form of a pellet or bolus.

[0304] In some embodiments comprising a bolus, the method includes: selecting a compound of the disclosure and a housing optionally selecting a core inserting the compound into the housing, and inserting the core into the housing (if present) optionally closing the housing to encapsulate or substantially encapsulate the compound and the core (if present) in the housing; wherein the core (if present) comprises the compound. In embodiments where the core is present, typically all of the compound of the disclosure will be present in the core.In some embodiments, the core further comprises a pharmaceutically or veterinary acceptable excipient. In some embodiments, the core further comprises one or more of a carrier and filling agent. Optionally, the bolus further includes a densifier either dispersed in the core, in or on the housing, or separate to the core and housing (optionally within the housing). Optionally, the bolus further includes a retention means, typically attached or associated with the housing.

[0305] This method may be used to prepare bolus dosage forms according to the disclosure.

[0306] In some embodiments, inserting the core into the housing occurs prior to inserting the densifier into the housing. In some embodiments, inserting the densifier into the housing occurs prior to closing the closing region of the housing.

[0307] In some embodiments, closing the closing region comprises closing two sections of the housing together. Alternatively, the closing includes closing of a cap. For example, closing the closing region comprises attaching a cap to the closing region ofthe housing or closing a cap already attached to the housing over the core (optionally attaching to another portion of the closing region of the housing). In some embodiments, the closing is by sealing or stitching. Optionally, the closing includes soldering and / or spin welding.

[0308] In some embodiments, the closing region includes a means to close the housing and the housing is closed using the means to close. Optionally, the means to close the housing is a cap.

[0309] In some embodiments, following closing of the closing region a closed region is formed from previously separate portions of housing that have been melted and / or soldered together.

[0010] In some embodiments, the densifier is above room temperature when it is inserted in the housing. In some embodiments, at least a component of the densifier and / or densifier matrix is liquid when it is inserted in the housing.

[0311] In some embodiments, the housing is prepared by injection molding.

[0312] In some embodiments, the densifier and / or densifier matrix is in direct contact with the core. In some embodiments, the densifier and / or densifier matrix is in direct contact with the closed region. Optionally, the densifier is in direct contact with the core and the closed region. In some embodiments, the densifier and / or densifier matrix does not directly contact one or both of the core and the closed region (for instance, a further spacing component may be present preventing directing contact).

[0313] In some embodiments, the closing region includes a means to close the housing. In some embodiments, the means to close the housing is a cap. In some embodiments, the closing region includes previously separate portions of housing that are melted and / or soldered together.Methods of preparation of the release system

[0314] In an aspect of the disclosure there is provided a method for producing a di- or tri-halogenated methane release system according to the disclosure, the method comprising: selecting a compound of the disclosure, a housing and a solid, wherein the solid has a melting point from about 28 °C to about 45 °C, inserting the compound into the housing, inserting the solid in the housing, either by a) melting the solid or obtaining the solid as a molten liquid,pouring the molten solid in the housing such that once it solidifies the combination of both the solid and the housing encapsulate or substantially encapsulate the compound, and allowing the molten solid to cool and solidify, or b) forming a matrix with the compound prior to insertion of the compound in the housing, optionally closing the housing to encapsulate or substantially encapsulate the compound and the solid or molten solid in the housing.In some embodiments, inserting the solid in the housing involves melting the solid or obtaining the solid as a molten liquid, pouring the molten solid in the housing such that once it solidifies the combination of both the solid and the housing encapsulate or substantially encapsulate the compound, and allowing the molten solid to cool and solidify.

[0315] In some embodiments, inserting the solid in the housing involves forming a matrix with the compound prior to insertion of the compound in the housing. In some embodiments, the solid-compound matrix solidifies before insertion in the housing. In some embodiments, the solid-compound matrix solidifies after insertion in the housing. In some embodiments, the solid-compound matrix is a substantially uniform mixture of solid and compound. In some embodiments, the solid-compound matrix is a non-uniform mixture of solid and compound, where the compound is of a greater concentration in the internal region of the matrix.

[0316] In some embodiments, the method further comprises introducing a solvent that includes water into the housing in contact with the solid and / or solid-compound matrix, such that the compound and the solvent are separated or substantially separated, at least in part by the solid.

[0317] In some embodiments, the compound of the disclosure is present as part of a composition of the disclosure.

[0318] Embodiments concerning methods of production of a bolus also apply to embodiments methods of production of the release system.

[0319] The inventors deem the technology described herein may provide a number of benefits. It should be appreciated any aspect or embodiment described herein, or the interaction of two or more aspects / embodiments, may form a distinct disclosure.

[0320] Unless stated otherwise herein any described embodiment disclosed herein can be freely combined with any other embodiment disclosed herein. Although embodiments of the present disclosure have been described and illustrated in detail, it is to be clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, the scope of the present disclosure being limited only by the terms of the appended claims.Brief description of the drawings

[0321] Figure 1 shows an exemplary mechanism of how a haloform, such as bromoform may be released from a compound of the disclosure. Shown is a release of bromoform from a compound in accordance with formula III as defined herein and as shown in the figure. “B-” represents a generic base in solution (such as OH- or acetate). In this reaction of pH 4.5 and higher may for instance be suitable, as a higher CHBra formation may occur when (tribromo) acetic acid is deprotonated. The arrow sign toward the step of bromoform formation signifies that there could be other intermediate reaction steps, which are not included in the scheme. When CBra- exits, it regenerates the basic environment by forming CHBra + OH-. The formation of stable CHBra breaks a reversible condition of the process and pushes the reaction toward further bromoform formation. CHBr3 is a typical byproduct of the a-bromination of carboxylic acids, which is known as Heil-Volhard-Zelinsky reaction, and which is the likely mechanism of bromoform formation from (tribromo) acetic acid (Farinelli, Giulio, et al. "Formation of halogenated byproducts upon water treatment with peracetic acid." Environmental Science & Technology 56.8 (2022): 5123-5131 .).

[0322] Figure 2 shows an exemplary mechanism of how a haloform, such as bromoform may be released from a compound of the disclosure. Shown is a release of bromoform from a compound in accordance with formula VII as defined herein and as shown in the figure. A bromoform reaction on molecule 5 leads to the formation of bromoform (7) and glutaric acids (9). The bromoform Relaxation was for instance described by Vorlander and Kohlmann (1899) and by Gust Komppa (1899) (D. Vorlander, M. Kohlmann (1899), Ueberfuhrung der Hydroresorcine in Glutarsauren, 32(2), 1878-1879. doi:10.1002 / cber.18990320285; Gust Komppa (1899), Ueber p-|3- Dimethylglutarsaure, 32(2), 1421-1424, doi:10.1002 / cber.18990320215).

[0323] Figure 3 shows an exemplary mechanism of how a haloform, such as bromoform may be released from a compound of the disclosure. Shown is a release ofbromoform from a compound in accordance with formula VIII as defined herein and as shown in the figure. Bromoform is released from 1 ,1 ,1 -Tribromo-2-propanone by hydrolytic cleavage of the C-C bond to furnish bromoform and acetic acid.

[0324] Figure 4a shows an exemplary bolus comprising the composition or compound of the disclosure, wherein the bolus (100) comprises a core (1 10), a housing (120), which may comprise an open end (160) and a closed end (170), wherein the open end (160) may be closed by a cap, for instance by spin welding the cap onto the housing. Figure 4b depicts an alternative exemplary bolus comprising the composition or compound of the disclosure, wherein the bolus (100a) includes a housing (101 a), a core (102a), a closed region (103a) (for instance, a cap) and a densifier (104a).

[0325] Figure 5 depicts the rate of formation of tribromomethane (TBM) from tribromoacetic acid (TBAA) in water, as described in Example 10.

[0326] Figure 6 depicts the rate of release of tribromomethane (TBM) from boluses containing 2 or 4 g of tribromo acetic acid (TBAA) along with Hydroxypropyl methylcellulose (HPMC) and stainless steel (SS), as described in Example 11.

[0327] Figure 7 depicts the rate of release of tribromomethane (TBM) from polypropylene (PP) tubes loaded with 10 g of tribromoacetic acid (TBAA) and water in presence of other excipients (sodium hydroxide, dimethylsulfoxide (DMSO) or hydroxypropyl methylcellulose (HPMC), as described in Example 12.

[0328] Figure 8 depicts the rate of release of tribromomethane (TBM) from polypropylene (PP) tubes loaded with 40 g of tribromoacetic acid (TBAA) with or 20 g of water or other excipients (sodium hydroxide, dimethylsulfoxide (DMSO) and hydroxypropyl methylcellulose (HPMC), citric acid, eicosane, as described in Example 13.

[0329] Figure 9 depicts the rate of release of tribromomethane (TBM) from tubes loaded with TBAA and different amounts of water, as described in Example 14.

[0330] Figure 10 depicts the rate of release of tribromomethane (TBM) from ethyl tribromoacetate (ETBA) in water with or without sodium hydroxide (NaOH), as described in Example 15.

[0331] Figure 11 depicts the rate of release of tribromomethane (TBM) from tubes containing ethyl tribromoacetate (ETBA) with or without water), as described in Example 16.

[0332] Figure 12a depicts an exemplary release system (200) of the disclosure prior to administration, wherein the housing (201 ) encapsulates thecompound / composition (202), the solid with a melting point from about 28 °C to about 45 °C (203) and a solvent that comprises water (204). The solid (203) separates the compound / composition (202) from the solvent (204). Figure 12b depicts an exemplary release system (200) of the disclosure following administration to the rumen of a ruminant, where the solid (203) has melted and the solvent (204) and compound / composition (202) are now in contact, facilitating more rapid generation of a di- or tri-halogenated methane compound than in the absence of solvent.ExamplesExample 1 : Exemplary compositions

[0333] In an exemplary formulation of a composition as described herein, the composition comprises a compound as defined herein or a pharmaceutically acceptable salt thereof. Optionally, the composition comprises tribromoacetic acid or tribromoacetic acid methyl ester or a pharmaceutically acceptable salt thereof. The composition may also comprise both of these components or a pharmaceutically acceptable salts thereof. Additionally, each composition can also comprise bromoform. Exemplary compound combinations of a composition as claimed can include:- tribromoacetic acid alone,- tribromoacetic acid methyl ester alone,- combination of tribromoacetic acid and tribromoacetic acid methyl ester,- combination of tribromoacetic acid and bromoform,- combination of tribromoacetic acid methyl ester and bromoform, and- combination of combination of tribromoacetic acid, tribromoacetic acid methyl ester and bromoform.

[0334] An exemplary composition may further comprise a base, optionally a strong base such as KOH and / or NaOH. Incorporation of a base can facilitate the release of a haloform, such as bromoform, or a dihalogenated methane compound from a compound as described herein. The composition allows the release of haloform, such as bromoform, or a dihalogenated methane compound from the compound(s) when the composition is exposed to water. The contact with water can be established when the composition is placed in the rumen of a living ruminant animal. Since the pH of rumen fluid is usually between 6.0 and 6.4, while the rumen pH can fluctuate in a maximum range of from about pH 5 to about pH 7, the effect of a (strong) base on the release of a haloform (such as bromoform) or a dihalogenated methane compound in anexemplary composition will not be cancelled out by acidity when an appropriate quantity and strength of base is employed.

[0335] An exemplary composition may further comprise one or more compounds selected from a further different compound as defined herein. The exemplary formulation can also comprise further functional compounds known to have methane mitigating activity, such as cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18- carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3-Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate, other haloforms (besides bromoform) and a dihalogenated methane compound. The exemplary formulation can also comprise further functional compounds known to have methane mitigating activity, such as cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3-Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate and other haloforms (besides bromoform). This can be helpful to enhance the effect of methane inhibition and reduction of methane emission.

[0336] In one exemplary composition no water or substantially no water, i.e. less than 0.1 wt% of water, may be comprised. This is useful to increase stability of the composition. It can further enable further forms of administration. A composition comprising no or close to no water may be present in the form of a powder. The powder can be stored more easily, may be handled with less risk of spilling and can be admixed with dry feed as well as with animal drinking water or incorporated into further administration forms such as an intraruminal bolus or into pellets. However, the composition could also be used in or incorporated into said administration forms in a liquid state, possibly also comprising water.

[0337] An exemplary composition may further comprise one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alphahydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, an ester hydrolase and a carboxy-lyase.

[0338] Particularly, silica and cellulose and cellulose derivatives, as well as gelatin can provide substance to the composition, allowing more even dispersion of a compound or compounds contained in the composition. Metal particles and other high density components can add weight to the composition, which can be particularly suitable when the composition is included in a bolus. The additional weight of such components, such as metal particles, will help to weigh down the bolus and prevent the bolus containing a composition according to the disclosure form being regurgitated.

[0339] The exemplary composition can be dissolvable in water. When an exemplary composition is dissolvable in water, it can be that certain compounds or components within this composition are not dissolvable, such as metal particles. Following dissolution of the composition these insoluble parts will remain as nondissolved parts of the composition.Example 2: Particularly useful compositions of the disclosure

[0340] The following 3 compositions are examples that can among others be useful in the context of the present disclosure:

[0341] One exemplary composition of the disclosure may comprise a compound of formula III (tribromoacetic acid). The compound of formula III is known and can be mixed with a base (e.g. NaOH, Na2CO3) to neutralize its acidity as well as to allow for effective bromoform release from the compound of formula III, which may optionally occur at a pH above 4.5, further optionally at a pH of about 7 or more. Optionally, this exemplary composition further comprises one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, pH modifiers, an ester hydrolase and a carboxylyase.

[0342] A further exemplary composition of the disclosure may comprise a compound of formula VII. The compound of formula VII can be mixed with a base (e.g. NaOH, Na2CO3) to allow for effective bromoform release from the compound of formula VII, which may optionally occur at a pH of 7 or more. Optionally, this exemplary composition further comprises one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethylcellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic- co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, pH modifiers, an ester hydrolase and a carboxylyase.

[0343] Another exemplary composition of the disclosure may comprise a compound of formula VIII. The compound of formula VIII is known and can be mixed with a base (e.g. NaOH, Na2CO3) to allow for effective bromoform release from the compound of formula VIII, which can optionally occur by aqueous alkali at a pH of 7 or more. The in the exemplary composition, a compound of formula VIII can optionally be mixed with hydrolytic enzymes, such as oxygenases and / or hydrolases, to allow for effective bromoform release from the compound of formula VIII. When hydrolytic enzymes are included in the composition it may be suitable to select enzymes which have a working optimum in the range of an animal’s rumen, for instance a range of pH 5 to pH 8, and which may therefore perform enzymatic cleavage upon administration to an animal’s rumen. Optionally, this exemplary composition further comprises one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, pH modifiers, an ester hydrolase and a carboxy-lyase.Example 3: Exemplary preparation of composition

[0344] An exemplary method of preparing a composition of the disclosure may include the following steps, but can also be extended to further steps or comprise less or alternative steps.

[0345] One step may include obtaining compounds to be included in the composition. Obtaining compounds of the disclosure may include allowing a haloform, such a bromoform, to react to form a compound as described herein, which may later on release the haloform, e.g. bromoform, after administration to the rumen of an animal. Obtaining compounds of the disclosure may include allowing a dihalogenated methane compound to react to form a compound as described herein, which may later on releasethe dihalogenated methane compound after administration to the rumen of an animal. Methods of obtaining compounds as used in the composition of the disclosure are known in the art and are for instance described in Clayden, Jonathan, Nick Greeves, and Stuart Warren, Organic chemistry, Oxford University Press, USA, 2012, and in Carruthers, William, and lain Coldham, Modern methods of organic synthesis, Cambridge University Press, 2004.

[0346] The compounds to be included in the composition may alternatively be purchased as such from a supplier.

[0347] In another step, suitable filling agents may be mixed with the compounds to be included in the composition. Suitable filling agents may be selected, for instance in accordance with the intended administration form of the composition. Components of the composition can be mixed in dry form or in moist or liquid form (where applicable). In some embodiments, components of the composition are mixed in dry form.

[0348] Optionally, if the composition is in liquid, wet or moist form, it can be dried to provide the composition in a powder form comprising no water or less than 0.1 wt% of water. Drying can for instance be performed by freeze drying.Example 4: Administration via a bolus and exemplary boluses

[0349] A composition as described herein can be incorporated in a bolus for administration to a ruminant animal. A bolus comprising the composition of the disclosure may be administered per os. (oesophagus) into the rumen of a ruminant animal, such as cattle. After administration of the bolus, animals can be left to graze freely, while retaining the bolus in the rumen. Administering the composition of the disclosure in a bolus, which may provide a sustained release of active compounds from the composition of the disclosure, has the advantage that the composition need not be re-administered on a regular basis.

[0350] Boluses for administration to ruminant animals are known. They can therefore be made as known in the art and for example as described in WO2022124914, incorporated herein by reference. The following includes some non-limiting general examples how to make such a bolus for administration to a ruminant animal from which it will also be apparent how to make also alternative boluses.

[0351] A bolus used with the composition of the disclosure may comprise a housing and a core. In a first step of making such a bolus, a housing is made by 3D print or by injection molding. The housing can have various bottle-like shapes and is optionally shaped like a cylinder, further optionally shaped like a rounded cylinder. Thehousing can for instance be made from a biodegradable polymer and the housing material can comprises, for example, PLA and PBAT. The housing can for instance have a wall thickness of about 1.2 mm and a dimension of for example about 35 mm (diameter) x about 72 mm (length). The housing can be left intact to be able to fully enclose the core of the bolus or the housing can be perforated for example by drilling openings or holes into it. Such openings can have an average diameter of, for example, from about 0.1 mm to about 1 mm, wherein the individual opening diameter can vary within a given housing. Openings may additionally be closed by filling into them a compound that melts between 28°C and the temperature present in the rumen of a living animal, which may allow the openings to become free and permeable only after melting of the opening filling compound inside of the animal. Alternatively, the perforated bolus can also be wrapped into a foil having the mentioned melting temperature.

[0352] In a next step, the composition of the disclosure may be mixed with filling agents, such as one or more compounds selected from cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co- glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate and ethylene-vinyl acetate, until a homogenous paste / dough is obtained. This paste / dough (for example 60 grams) can then be filled and optionally pushed into the prepared housing. Optionally, a part of the volume inside of the housing can be filled by a densifier composition comprising for example steel balls.

[0353] In a further step, the housing may be closed by adding a cap that is spin welded onto the housing to close it. The steps to produce the bolus can also be carried out in any alternative order, for example by perforating a housing after having filled the housing with the core material and / or by sealing openings in a housing in a last step.

[0354] A bolus can also comprise the composition as described herein in microencapsulated particles, which are dispersed in a composition comprising a carrier and optionally also comprising a dispersing agent. These components may form a core, which is at least partly covered by a housing. Methods for producing microencapsulated substances are known for example from US64581 18B1 or US7105158B1 , both incorporated herein by reference. In such system small amounts of the drug, e.g. 1 microgram, are encapsulated in an inert material, e.g. a stable polymer. Such approach can be applied to encapsulate a methane inhibiting agent, for example bromoform. Following the encapsulation, the encapsulated composition is then filled into a bolus asdescribed above. This embodiment can also be manufactured by including a porous carrier such as mesoporous silica in the bolus core.

[0355] A bolus can also be housing-free, and can be made for example by following the steps described for a bolus above, but not using a housing. Instead the core material can be further densified by adding additional filling agents such as fumed silica or gelatin etc. A pellet (or rather multiple of such pellets) for administration to a ruminant animal that comprises the composition of the disclosure is particularly suitable to be admixed with animal feed. The composition of the disclosure can also directly be incorporated into common feed pellets, which are formed on the basis of feed components, including alfalfa, hay, barley, corn, cotton, oats, sorghum, soybeans and hull, wheat and wheat bran and broken rice, as described elsewhere in the description herein above. The core of a bolus without a housing compressed and can for instance also form pellets or similar administration forms. To shape the bolus without a housing, a core excipient mixture comprising the composition of the disclosure may be filled manually into a mold, optionally letting the mixture set and / or solidify. The mold may then be dismantled to recover the shaped core without a housing. For pellet formation, typical pelleting techniques using an extruder, which are known in the art, can be applied, as described elsewhere herein.

[0356] A bolus for administration to a ruminant animal may also comprise additional or alternative methane inhibiting compounds. Such compounds include 3- NOP, monensin, lauric acid, myristic acid and linoleic acid and other compounds described herein. Such a bolus, which comprises a core and a housing, can be made by following the steps outlined for a bolus above and incorporating the (additional) methane inhibiting compounds. Such a bolus can have a housing comprising at least one opening exposing the core to the environment surrounding the bolus. In such a bolus embodiment it is also possible to not fill the openings of the bolus.

[0357] A bolus as described herein can comprise an active agent with a further effect besides methane inhibition / reduction, which may be selected from the group consisting of an anti-inflammatory agent, an analgesic, an antibiotic and an anthelmintic. For instance, the active agent can be selected from the group consisting of meloxicam, ketoprofen, penicillin, a tetracycline, a macrolide, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, tulathromycin and an albendazole. A bolus comprising a composition of the disclosure as well as such further active agents can be made in accordance with the steps outlined above. Furthermore, the active agent with a furthereffect besides methane inhibition / reduction can also be directly incorporated into the composition of the disclosure, which does not necessarily have to be incorporated into a bolus or pellet, but which can also be administered as such or can be administered via drinking water (see below) or other feed supplement forms known in the art, such as a lick block.

[0358] The following describes an exemplary way of making a bolus housing and bolus core as described above. A bolus housing may be 3D printed on a FlashForge Creator Pro 3D printer using E-Sun PLA+ at 100% fill, standard resolution, print speed 60 mm / s, extruder temperature 200°C and plate temperature 50°C. Alternatively, a bolus housing may be formed by injection moulding, for instance by filling mixture of PLA and PBAT (e.g. ratio PLAPBAT 90:10) in a mould and letting the mixture set and solidify.

[0359] A mixture of the composition of the disclosure and possibly further compounds such as ethyl cellulose, fumed silica and / or HPMC but also other components and filling agents described herein is prepared, which is thoroughly mixed to be homogenous. The mixture can be filled into the housing, optionally before or after inserting component conferring additional weight to the bolus, such as metal / steel particles. A cap can be mounted and sealed to the housing using a soldering gun or by means of friction welding.

[0360] For instance, one of the three exemplary compositions described in Example 2 above, which may be particularly useful in the context of the present disclosure, may be incorporated in a bolus as described herein. For this, a bolus comprising or forming one or more openings as described herein, such as a perforated bolus, may be particularly suitable, to allow the bolus core to be contacted by the rumen liquids and to facilitate the release of bromoform from the compounds as described herein, i.e. the compounds of formulas III, VII or VIII, respectively.Example 5: Further advantageous bolus features

[0361] Certain carriers / components mixed with the composition of the disclosure to be included in a bolus as described herein can allow to load particularly high amounts of bromoform as well as compounds as described herein into the bolus while at the same time providing a sustained release of these compounds from the bolus over a prolonged period of time. Furthermore, certain bolus housing materials comprising blends of PLA (mixed with other compounds) can provide advantageous mechanical properties, such as for instance durability, as exemplarily outlined in the following.5.1 Exemplary bolus components mixed with the composition of the disclosure

[0362] Colloidal silicon dioxide (hydrophobic), ethyl cellulose (ethoxy content of 48.2%), castor wax, Polycaprolactone (PCL) (Mw 600), stainless steel granules, bromoform and compounds as defined herein, for instance compounds according to formula III, VII or VIII, may be among the materials for preparing a bolus core as described herein. Four ethoxy grade types are defined for ethyl cellulose, which are G- type (44.5%-45.5%), K-type (45.5%-46.8%), N-type (47.5%-49.0%), and T-type (49.0% and higher). The N-type may exemplarily be used; however, other grades may also be suitable.Exemplary densifier

[0363] The following is an exemplary procedure of producing a densifier for a bolus as described herein, wherein the densifier is a bolus component adding weight to the bolus to which is useful a bolus as described herein is not to be regurgitated by a ruminant animal.

[0364] Paraffin wax (10g) may be melted at 100°C. Next, stainless-steel granules (90 g) may be added to prepare a slurry before pouring the slurry into a bolus at approximately 85°C.

[0365] In combination with bolus materials enduring higher temperatures, paraffin wax (8g) can be initially melted at 100°C. Next, stainless-steel microparticles (92 g for a bolus of 72 mm x 35 mm dimensions) can be added to prepare a slurry before pouring into a bolus at 65°C.

[0366] For scalable processing the paraffin wax and densifier can be pre-formed into a tablet to be inserted into the housing which may contain compounds of the disclosure and optionally bromoform and which can comprise one or more components selected from the group consisting of sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (optionally tartaric acid), a buffering substance, pH modifiers, an ester hydrolase and a carboxylyase, and optionally an RFID (radio frequency identification)chip.Exemplary carrier 1

[0367] An exemplary carrier mixture comprising colloidal silicon dioxide and wax (ASL-65-W) may be prepared using materials and ratios summarized in Table 1 . Silicon dioxide powder (ASL) (1 .6 g) can be manually mixed with compounds of the disclosureand optionally also with haloform(s) / bromoform (52 g) using a glass rod. Castor wax (26.4 g) can be melted in a separate beaker at 100°C using hot plate stirrer. The mixture may then be added to the melted wax. The mixture may be removed from the hot plate and homogenized for 7500 rpm for 1 min using a homogenizer (Daihan Scientific, China). The mixture may be poured into a bolus (e.g. dimensions of about 75x34 mm, for instance in a 3-D printed PLA housing) when the temperature has cooled to about 75-80°C. A stainless steel granule-wax mixture (see description above) may be poured into the cap of a bolus described herein (to be attached to the open end of the bolus) and on top of the mixture poured into the bolus housing. The bolus cap can be sealed onto the bolus housing using a soldering iron or friction welding. An equivalent composition can also be prepared with one or more dihalogenated methane compounds in addition to or as an alternative to the optional haloforms.Table 1 : Composition of an ASL-wax carrier mixtureExemplary carrier 2

[0368] For a further exemplary carrier ethyl cellulose (EC) powder (20 g) may be mixed with compounds of the disclosure and optionally also with haloform(s) / bromoform (56 g) using mortar and pestle (see composition in Table 2). Silicon dioxide (4 g) can be gradually added and mixed into this mixture. The obtained paste (ASL-70-EC) may be loaded into a 75 mm bolus (e.g. dimensions of about 75x34 mm, for instance in a 3-D printed PLA housing). A (densifier) mixture of paraffin wax and stainless-steel granules can be prepared as described above. The mixture may be poured on top of the mixture (ASL-70-EC) filled into the bolus housing and partly inside the bolus’s cap until the bolus volume is completely filled. The bolus cap can be sealed onto the bolus housing using a soldering iron or friction welding. An equivalent composition can also be prepared with one or more dihalogenated methane compounds in addition to or as an alternative to the optional haloformsTable 2: Composition of an ASL-Ethyl cellulose carrierExemplary carrier 3

[0369] Compounds of the disclosure and optionally also haloform(s) / bromoform (52 g) may be mixed with silicon dioxide (12 g) using a mortar and pestle. PCL (16 g) may be melted on a hot magnetic stirrer at 100°C. The melted PCL may then be added to this mixture (see composition in Table 3) and may be mixed thoroughly using a mortar and pestle until a homogenous dough (ASL-65-PCL) is obtained. The obtained paste may be loaded into a bolus (e.g. dimensions of about 75x34 mm, for instance in a 3-D printed PLA housing). A stainless-steel granule wax mixture as described above may be added on top of the ASL-65-PCL paste and in the cap of the bolus. The bolus cap can be sealed onto the bolus housing using a soldering iron or friction welding. An equivalent composition can also be prepared with one or more dihalogenated methane compounds in addition to or as an alternative to the optional haloforms.Table 3: Composition of an ASL-PCL carrier5.2 Determining content of compounds of the disclosure / haloform(s) / bromoform in a bolus

[0370] To quantify the content of compounds of the disclosure and optionally of haloform(s) / bromoform in a prepared bolus, a known amount of a mixture comprising the composition of the disclosure and further components described herein (such as the further components described for exemplary carriers 1 -3 above) can be weighed right after preparation (TO) and then be incubated at about 40 °C. The weight of the incubated mixture can be recorded every day until a constant weight is reached (T1 ), i.e. until no further evaporation of compounds of the disclosure and optionally of haloform(s) / bromoform is observed. The content (% w / w) of compounds of thedisclosure and optionally of haloform(s) / bromoform (“content”) can for instance be calculated using the following equation.> . . > _Content 100An equivalent procedure can also be applied with respect to dihalogenated methane compounds.5.3 In vitro release testing

[0371] The following provides one exemplary method of testing the release of compounds of the disclosure and optionally of haloform(s) / bromoform from a bolus as described herein. Phosphate buffer (pH:6.5) at 40°C may be used as solution simulating rumen conditions. The pH of the solution may optionally be determined (for instance an average pH of amount 6.5 ± 0.2). The solution can be replaced with fresh solution (1 L, 0.02M) daily. The released compounds of the disclosure and optionally of haloform(s) / bromoform may be extracted using organic solvent and may be analyzed by GC-FID (gas chromatography in connection with flame ionization detector).

[0372] Release testing can provide an indication of the effect different components in a bolus used herein can have on the release rate of compounds of the disclosure and optionally of haloform(s) / bromoform from the bolus.

[0373] For instance, ethyl cellulose (EC) may increase bolus loading capacity. It may also provide a matrix to bind colloidal silicon dioxide and compounds of the disclosure and optionally of haloform(s) / bromoform and may improve the texture properties of the mixture, leading to increased homogeneity. EC may contribute to the mechanical stability of a bolus from within, as the stiffness of a paste comprising EC may increase over time. Furthermore, incorporation of EC may lead to tuned release rates of compounds of the disclosure and optionally of haloform(s) / bromoform from a bolus, i.e. lead to a prolonged release and reduced fluctuation.

[0374] For instance, PCL may provide a slow release and possibly an elongated lag time before a release of compounds of the disclosure and optionally of haloform(s) / bromoform from a bolus. A bolus with a long release time, which may be based on a slow-release PCL formulation described herein or coupled with a shorter release formulation can be made, which overall achieves a prolonged release pattern and cumulatively a higher release rate. For instance, a co-extruded carrier, in which there are different inner and outer layers of the extruded carrier dough with different release characteristics, is one option of such coupled release systems. Furthermore, a bolus comprising PCL and compounds of the disclosure and optionallyhaloform(s) / bromoform could also be used for smaller size ruminants like sheep or immature cattle, wherein the effective release to the animal may be lower than for larger ruminants to cause the intended effect, e.g. to mitigate methane production.

[0375] For instance, the component hydroxypropyl methylcellulose (HPMC), a swellable hydrophilic polymer, may stabilize release rates, i.e. reduce fluctuation of release rates and provide a steady prolonged release. Furthermore, it may improve the mechanical integrity of a bolus due to its swelling properties. Once the bolus releases compounds of the disclosure and optionally haloform(s) / bromoform, the swellable HPMC may occupy the void space which may contribute to improve the mechanical stability of the bolus.

[0376] For instance, when using fumed silica, a more sustained release compared to a wax based system may be obtainable. The inclusion of ethyl cellulose and fumed silica may allow for a greater loading capacity of compounds of the disclosure and optionally of haloform(s) / bromoform than a wax-based system, a better control of release rates and potentially a greater release duration.

[0377] An equivalent procedure can also be applied with respect to dihalogenated methane compounds. Equivalent release factors also apply with respect to dihalogenated methane compounds.5.4 Exemplary bolus housing components

[0378] The mechanical properties of bolus housing components and of bolus housing blends comprising mixtures of such components can be tested by forming these components and component blends into polymeric dog bones and examining them for instance by using a tensile testing machine (Instron 5982) with a 5kN load cell following ASTM D638 method. Standard dog bone specimens may be 13 mm wide and 3.2 mm thick for each dog bone. The probes may be mounted onto the analyzer and may be pulled away at a rate of 5 mm / min to measure the tensile strength and elongation at break.

[0379] PLA alone may in some cases be brittle and in some cases bolus housings made of only PLA may have a higher chance of fracturing prematurely. The brittleness of PLA may be further enhanced by the presence of aggressive compounds, such as in the presence of bromoform.

[0380] For suitable ductility and homogeneity, a range of different polymers and polymer blends may be applicable (Table 4). To adapt mechanical properties blends ofPLA may be prepared, however, a bolus prepared with a neat PLA housing may already stay intact in an animal’s rumen for 6-8 weeks or even longer.Table 4. Exemplary suitable housing polymers and polymer blends (J* = epoxide based chain extender). Compared to 3D printed PLA dog bones. Injectability refers to the process of injection molding. Polymer blends indicated to have “less ideal” features are less ideal in their properties compared to those candidate blends found to have the most suitable properties in the respective category, i.e. indicated as “good”. All polymers and polymer blends may be suitable for a housing of a bolus described herein.*1Note: At ratios of the minor polymer of about 20% or greater the blend tensile strength may decrease, which may in some cases increase the likelihood of release rates from a bolus being potentially high. Furthermore, in some cases the mechanical strength of the bolus may be decreased. With ratios of the minor component of less than about 10% the blend properties may be more like those of a bolus housing made of PLA alone, wherein a tendency may be brittle, and in these blends the ductile characteristic of the minor blend can be reduced.

[0381] The following blends may be particularly suitable based on their good mixing homogeneity, compatibility and (low) brittleness properties:1 ) PLA PBAT (ratio of 90 / 10)2) PLA PBS (ratio of 80 / 20)3) PLA PBSA (ratio of 80 / 20)

[0382] The ductile property of neat PLA may be improved by the incorporation of either PBS, PBSA or PBAT. Furthermore PLA / PBAT and PLA / PBS blends may provide particularly homogenous housings (i.e. the housing components are mixed well. Furthermore, PLA / PBAT in a ratio of 90:10 may be particularly suitable, as it can provide a high ductility with a good mechanical strength and may have a potential to absorb energy (forces exerted by the rumen) and thereby remain intact to deliver the sustained release of compounds over a desired time period, e.g. over at least 1 , at least 3 or at least 6 months.

[0383] The suitable selection of polymers and polymer blends may have a window of particularly suitable ratios of major polymer to minor polymer (c.f. Table 4). For example, if PLA may be present in an amount of more than 90 wt%, a polymer blend further comprising PBS, PBSA or PBAT may be observed to retain most of PLA’s characteristics and particularly its brittleness. In some cases, this can be less desirable when aiming at a bolus that can flexibly yield to the forces of the rumen to some extent. On the other hand, if the minor polymer, such as PBS, PBSA or PBAT, may be present in an amount of more than 20 wt%, the release rates from a respective bolus may tend to be higher. Again, in some cases, this can be less desirable when aiming for a sustained release bolus, even though advantageous more ductile characteristics of the minor polymer are retained by the bolus. In some cases, a bolus as described herein comprises a housing wherein the housing material comprises PLA and one or more of the further compounds PBS, PBSA and PBAT wherein the ratio of PLA:PBAT is in the range of 95:5 to 80:20. For other polymer blends than PLA with PBS, PBSA or PBAT, varying ratio ranges may be observed. The applicability of a housing described herein may also depend on the type and amounts of compounds of the disclosure and optionally haloform(s) / bromoform comprised by the bolus. Similarly, housing applicability may also depend on the presence / generation of dihalogenated methane compounds in the bolus.Morphology of Fracture Surface

[0384] In addition to testing the above properties, the morphology of the fracture surface of the polymer / polymer blend dog bones may be observed using Scanning Electron Microscope (SEM). For this a sample may be adhered to a carbon stud and coated with platinum until 5 nm coating thickness is obtained. The morphology of the impact section may be observed under different magnifications.

[0385] For instance, the impact fracture surface of injection molded PLA may be flat and may exhibit a brittle fracture, with little heterogeneity, pores, or plastic deformation. In contrast, a more ductile deformation may be for instance observed for a PLA / PBAT 90:10 blend. The impact fracture surface may be non-homogenous with brittle fracture on the sides and ductile fracture in the middle of the dog bone. The dog bone fracture may include protruding ductile polymeric fibers out of the matrix at the site of the fracture, wherein long and thin filaments at the ductile deformation site may indicate increased ductility, such as increased ductility of PLA / PBAT compared to PLA alone.In vivo trial: mechanical integrity of the housing

[0386] In addition, in vivo testing of resistance and sustainability of the bolus housing may be performed. Polymer blend housings may be extruded and filled with a high concentration of compounds of the disclosure and optionally of haloform(s) / bromoform as well as further components. Polymer blend housings may be extruded and filled with a high concentration of compounds of the disclosure and optionally of dihalogenated methane compound(s) as well as further components. The housing thickness may for instance be about 1 ,2mm for bolus dimensions of 35 mm x 72mm. Possible further components may be ethyl cellulose and fumed silica as carrier material and stainless steel microparticles (balls) embedded in paraffin wax as densifier component. The initial target period may be a durability in the rumen for at least three months and up to even at least 6 months. Boluses may be assessed for discoloration, sturdiness against breaking.

[0387] The thickness of the bolus housing wall may have an influence as well. For instance, if the wall thickness exceeds 1 ,5mm this may in some cases result in a long release lag period and a lower release rate. The bolus housing wall may have a suitable thickness to enable injection molding and reasonable mechanical strength to withstand rumen forces, as well as enabling suitable release rates as described further herein.Example 6: Exemplary testing of release from a bolus (Rissington trial)

[0388] For release testing, a bolus may be placed in 2 L polypropylene bottles with approximately 380 ml 0.02M phosphate buffer (Merck) in distilled water, prepared in 2L or greater batches, adjusted to pH 6.5 using 1 M HCI (Merck) and a pre-calibrated pH meter (using pH 4, 7, and 10 pH buffers). The bottles may be sealed and placed in an incubator at 40°C. 10 ml samples may be collected for assessments and the entire solution may be exchanged with fresh solution about every 24 hours.

[0389] 10 ml samples may be collected using a 10 ml autopipette in 15 ml Falcon tubes and 1 g of sodium chloride can be added to each Falcon tube. Gas chromatography-mass spectrometry (GC-MS) analysis may then be performed on the samples. For GC-MS analysis, 1 ml of ethyl acetate (analytical grade, Merck) can be added to each Falcon tube. When using Gas Chromatography-Flame Ionization Detection (GC-FID) 2 ml of ethyl acetate may be added to each Falcon tube. The Falcon tubes are capped, well mixed using a Vortex, and centrifuged at 4000 rpm for 15minutes. Before GC-MS analysis, ethyl acetate is then recovered from the samples using a graduated glass syringe. 0.5 ml of ethyl acetate may be recovered.

[0390] 200 ul of recovered sample can be injected using an autosampler, and can be analysed using a ZB5HT 30 m capillary column using a temperature ramp of 30- 300°C over 20 minutes, at 5 ml / min nitrogen gas flow, in splitless mode. Peak areas of the respective compound(s) comprised by the composition of the disclosure may be assessed according to their respective retention times in chromatography, wherein for instance bromoform may have a retention time of 7.5 minutes in the setting exemplarily described. The peak areas may be compared to calibration standards made up in ethylene acetate to determine the mass of compounds and of haloforms such as bromoform (mg). This is divided by the volume injected to obtain the concentration of compounds and haloforms, such as bromoform, in ethyl acetate (mg / L). The concentration in ethyl acetate may be multiplied by the total volume of ethyl acetate added to the sample and divided by the recovery to obtain mass of compounds / haloforms (such as bromoform) in the sample. This may then be divided by the volume of sample collected to obtain a concentration in the solution, which may then be multiplied by the volume of solution in the polypropylene bottles used for release testing to obtain the amount of compound / haloform (such as bromoform) transferred from the bolus to the solution. Recovery of compounds / haloforms from the release testing solution can be confirmed using standard solutions with different concentrations of compounds / haloforms. Recovery may for instance be about 40% to 50%. GC-FID performance may be checked for each run of ten samples using a calibration sample as a reference. An equivalent procedure can also be applied with respect to dihalogenated methane compounds.

[0391] A bolus may be recovered from the release testing solution in 2 L polypropylene bottles after for instance 6 days of study and examined visually to determine whether the bolus remained intact with no or little signs of any breakage or deformations.Example 7: Administration via drinking water

[0392] A composition of the disclosure can also be administered via drinking water. For this, a composition or a feed supplement comprising the composition is useful, which is admixed to drinking water of a ruminant animal and which is dissolvable in water. The composition or the feed supplement comprising the composition can for instance be provided in the form of a powder or in the form of pellets, which are addedto drinking water of animals. The composition is left to dissolve (e.g. from the feed supplement) and the drinking water is then offered to the animals. Such offering of water may be ad libitum. For ad libitum offering of water comprising the dissolved composition, the dose of the composition may be adjusted to the size of the animal receiving the drinking water and to the amount of drinking water consumed on average.Example 8: Administration via a feed supplement

[0393] The composition of the disclosure can be administered as or as part of a feed supplement, which is optionally in the form of a pellet, a tablet, a powder or a lick block. These administration forms comprising the composition of the disclosure can be used to reduce methane production in a ruminant animal.

[0394] For instance, one of the three exemplary compositions described in Example 2 above, which may comprise a compound of formula III, VII or VIII, respectively, and which may be particularly useful in the context of the present disclosure, may be incorporated in a feed supplement as described herein. Administration via a pellet or tablet, which is ingested by the animal, allows the composition of the disclosure comprised in said pellet or tablet to be contacted by the rumen liquids and to facilitate the release of bromoform from the compounds as described herein, such as a compound of formula III, VII or VIII.

[0395] A pellet or tablet comprising the composition of the disclosure, or multiple such tablets or pellets, can either be directly administered to a ruminant animal or can be included in animal feed or dissolved in animal drinking water to be ingested during feeding or drinking, respectively. Likewise, a powder comprising the composition of the disclosure can also be admixed with animal feed or dissolved in drinking water.

[0396] A lick block comprising the composition of the disclosure can be made by mixing the composition of the disclosure with components commonly used for lick block preparations, including for instance molasses, urea, wheat bran, rice bran, soybean meal, cottonseed meal, olive cake, sunflower meal, corn, soybean, barley, fava bean, moringa oleifera leaf, citrus pulp, tomato pulp, cucumber waste, mango waste, avocado waste, grape marc, cactus waste, com distiller’s dried grains with solubles, bagasse and poultry manure, quicklime, salt and minerals. The lick block may then be shaped / moulded and left to dry.Example 9: Quantifying reduction of methane production

[0397] To determine the effectivity of a composition administered via one or more of the various administration forms described herein and to determine the tolerability ofthe administered forms and of the composition and of the compound(s) comprised by the composition, certain parameters can be assessed. This allows to for instance improve the dosing regimen for the respective compound(s) and administration type employed. For instance, feed intake by the animals, such as dry-matter intake, as well as animal liveweights may be recorded as an indicator of animal welfare. The effect of the composition of the disclosure on greenhouse gas such as methane emissions may be quantified by observing the animals’ gas emissions, such as methane, hydrogen, and carbon dioxide emissions, in respiration chambers, for instance using a 4900C Continuous Emission Analyser and measuring emissions every 3 min over a 48-hour period. If the bolus is to (additionally) release an antibiotic or anthelmintic, the effect on microbiome or parasites may be assessed by taking a sample from the animals intestine and assessing it for presence of microbiota or parasites. Methods to assess and quantify microbiota and parasites include microscopy and cell culture methods, antibiotic challenging of bacteria and molecular methods such as polymerase chain reaction (PCR). The described assessments of animals may be repeated regularly during the assessment period to verify the development of effectiveness over time.Example 10: Release of tribromomethane from tribromo acetic acid

[0398] 150 mg of tribromo acetic acid (TBAA) (Sigma-Aldrich, assay- 99%) was dissolved in a Schott bottle containing 500 mL water. The solution was left standing at 40 °C and 10 mL of sample was taken to evaluate the bromoform content on days 1 , 3, and 5.

[0399] The conversion of TBAA to tribromomethane (TBM) was evaluated by quantifying the amount of TBM in the solution using GC-FID (Shimadzu, Nexus GC- 2030). Briefly, 10 mL sample was collected using a 10 mL autopipette in 15 mL Falcon tubes. To this, 1 mL of ethyl acetate (analytical grade, Merck) was added to each Falcon tube as extraction solvent for TBM. The Falcon tubes were capped, well mixed using a Vortex, and centrifuged at 4000 rpm for 15 minutes. 0.5 mL of ethyl acetate was recovered and loaded in GC vial. 200 pl of sample was injected using an autosampler and analysed using a ZB5HT 30 m capillary column using a temperature ramp of 30- 300 °C over 20 minutes, at 5 mL / min nitrogen gas flow, in splitless mode. TBM had a retention time of ~5 minutes. Peak areas were compared to calibration standards made up in ethyl acetate to determine the mass of TBM (mg) in the solution and correlated to quantity TBM release per day in the 1 L buffer solution.

[0400] Figure 5 shows that TBM is formed from TBAA in solution. The graph suggests that TBAA undergoes rapid hydrolysis in water to form TBM at 40 °C. The halflife of TBAA in presence of sufficient water at 40 °C was <3 days.Example 11 : Release of tribromomethane from boluses comprising tribromo acetic acid

[0401] Injection moulded housings (PLA (average molecular weight- -145000 g / mole; D lactic acid- 1.2%):PBAT (average molecular weight- -80000 g / mol)- 9:1 ; thickness- 1 .5 mm, length= 75 mm, and width= 35 mm) were loaded with either 2 g or 4 g of TBAA along with 10 g of hydroxypropyl methylcellulose (HPMC) (Methoxyl content- 19-24%;Hydroxypropyl content- 7-12%;Apparent Viscosity- 75000-140000 mPa.s). The remaining space was filled with stainless steel shots (0.5 mm diameter, grade 304). The purpose of the stainless steel was only to fill up the space and provide enough density so the bolus would sink when placed in water / buffer. The caps on the boluses were sealed using a spin-welder.

[0402] Once the boluses were prepared, these were kept in Schott bottles containing 1 L of 0.02M phosphate buffer (pH 6.5) and stored at 40 °C (±2 °C). The buffer was changed everyday except over weekends. Nevertheless, minimum 2 daily release data points were collected per week in all cases. TBM was quantified as described in Example 10.

[0403] Figure 6 shows the release of TBM from TBAA containing boluses. It was observed that boluses with higher TBAA loading started to release TBM at a significant level at around day 15.Example 12: Release of tribromomethane from compositions comprising tribromo acetic acid

[0404] 15 mL polypropylene (PP) falcon tube were loaded with 10 g of TBAA along with water and other excipients including sodium hydroxide, dimethyl sulfoxide (DMSO) or HPMC as shown in Table 5.Table 5. Composition of formulations for example 12.TBAA (g) Water (g) NaOH (g) DMSO (g) HPMC (g)10 1010 10 1.310 10 - 2.210 10 - - 0.4

[0405] Once falcon tubes were loaded as described in Table 5, these were kept in Schott bottles containing 1 L of 0.02M phosphate buffer (pH 6.5) and stored at 40 °C (±2 °C). The buffer was changed everyday except over weekends. Nevertheless, minimum 2 daily release data points were collected per week in all cases. TBM was quantified as described in example 10.

[0406] As shown in Figure 7, all the PP tubes started releasing TBM >50 mg / day from day 6. Formulations containing TBAA / water, TBAA / water / NaOH, and, TBAA / water / HPMC released TBM in a near zero order in higher rates around 100-150 mg / day compared to formulation containing TBAA / water / DMSO (release rate = around 60-80 mg / day).Example 13: Release of tribromomethane from compositions comprising meltable barrier

[0407] 50 mL polypropylene (PP) falcon tube were loaded with 40 g of TBAA along with water and other excipients sodium hydroxide, citric acid, eicosane, or HPMC as shown in Table 6. In case of formulation containing eicosane, first TBAA was loaded into the falcon tube, then molten eicosane was added and allowed to solidify. Water was then added on top of the eicosane solid layer. This design was conceived with the idea that in actual application, TBAA hydrolysis to TBM would only occur once the bolus is administered to the animal. One skilled in the art would appreciate that this can be achieved using any suitable material with a melting of around 40 °C.Table 6. Composition of formulations for Example 13.TBAA (g) Water (g) NaOH (g) Citric acid (g) HPMC (g) Eicosane (g)40 . . . . .40 20 - - - -40 20 2.3 - - -40 20 - 2.3 -40 20 - - 6.840 20 - - - 3.5

[0408] Once falcon tubes were loaded as described in Table 6, these were kept in Schott bottles, containing 1 L of 0.02 M phosphate buffer (pH 6.5) and stored at 40 °C (± 2 °C). The buffer was changed every day except over weekends. Nevertheless, minimum 2 daily release data points were collected per week in all cases. TBM was quantified as described in example 10.

[0409] As shown in Figure 8, all the PP tubes containing TBAA and water started releasing TBM (> 100 mg / day) from day 10. Formulations without water released <5 mgTBM / day. Unlike in example 3, it was interesting to note that formulation containing sodium hydroxide started to release TBM relatively earlier. Nevertheless, this formulation exhibited a near zero order release during the period of testing. Here, the amount of NaOH taken was equimolar to TBAA so that a neutral pH would be achieved in the solution. One skilled in the art would appreciate that any other excipients which modulate pH may be used to modulate release directly or indirectly. Further for formulation containing eicosane, it was visually observed that eicosane gradually melted when placed at 40 °C and allowed water to come in contact with TBAA for its hydrolysis to occur and form TBM (GC quantified). One skilled in the art would appreciate that the release of TBM from such system may be modulated either by modulating factors which control the hydrolysis (Example 5) or indirectly by using excipients (examples: cellulose (ethyl cellulose, etc), medium chain triglycerides or their derivatives ( Miglyol), solvents (ethanol, DMSO, etc), esters or their derivatives (Sucrose acetate isobutyrate), surfactants (sorbitan fatty acid ester, etc)) which non-covalently interact with TBM once it is formed and modulate its release.Example 14: Release of tribromomethane from tribromo acetic acid at different aqueous concentrations

[0410] 15 mL PP falcon tube were loaded with 10 g of TBAA with different amount of water as shown in Table 7.Table 7. Composition used for example 14.TBAA (g) Water (g)10 1010 710 410 1

[0411] Once falcon tubes were loaded as described in Table 7, these were kept in Schott bottles, containing 1 L of 0.02 M phosphate buffer (pH 6.5) and stored at 40 °C (± 2 °C). The buffer was changed every day except over weekends. Nevertheless, minimum 2 daily release data points were collected per week in all cases. TBM was quantified as described in example 10.

[0412] It was observed that the release of TBM from the systems were proportionate to the amount of water in the system suggesting water content can potentially be used as a strategy to modulate hydrolysis rate of TBAA and release of TBM from the system (Figure 9).Example 15: Release of tribromomethane from ethyl tribromo acetate

[0413] Around 700 mg of ethyl tribromo acetate (ETBA) (Sigma-Aldrich, assay- 97%) was added to two Schott bottles containing 500 mL water. To one of the solutions, around 20 mg of NaOH was added to make it alkaline. The solutions were left standing at 40 °C and 10 mL of sample was taken to evaluate the TBM content on day 1 , 3, and 5. On each day the 10 mL sample was replaced with 10 mL of fresh water.

[0414] The TBM concentrations in the solutions were quantified as described in example 10.

[0415] As shown in Figure 10, it was observed that TBM was formed from ETBA in the solution and the formation of TBM was accelerated in the beginning in alkaline condition in presence of sodium hydroxide.Example 15: Role of water in rate of release of tribromomethane from ethyl tribromo acetate

[0416] 15 mL PP falcon tube were loaded with 2 g of ETBA with and without water. The sample containing water had 10 mL of water.

[0417] Once falcon tubes were loaded with ETBA and water as described earlier, these were kept in Schott bottles, containing 1 L of 0.02 M phosphate buffer (pH 6.5) and stored at 40 °C (± 2 °C). The buffer was changed every day except over weekends. Nevertheless, minimum 2 daily release data points were collected per week in all cases. TBM was quantified as described in example 10.

[0418] As shown in Figure 11 , it was observed that the tube containing both ETBA and water was releasing TBM relatively higher compared to the one which had only ETBA. The low release profile in the case, even when hydrolysis was possible, was likely due to hydrophobicity of ETBA which resulted into biphasic system. One skilled in the art would appreciate that in such cases, rate of hydrolysis can be improved by using appropriate catalyst or by simply increasing the contact area between ETBA and water via formulation approaches such as emulsion.Statements of disclosure1. A composition comprising a compound having the structure of formula (Hi) or formula (llii),formula (Hi) formula (llii) or a pharmaceutically acceptable salt thereof, wherein(1 ) each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl;(2) L is CH2, O, NH, or absent (preferably L is O or NH); and(3) R is an optionally substituted group selected from the group consisting of OH, Ci- -alkyl, Ci- -alkoxy and Ci-s-alkyl-COOH; wherein if R is substituted, then it is substituted by one or more groups independently selected from the group consisting of Ci -s-alkyl, -OH, halogen, NH2, -COOH, -CO-Ci-4-alkyl, -COO-C1- 4-alkyl, -NO2, and more particularly is substituted with one or more groups selected from the group consisting of C-i-2-alkyl, -OH, halogen, NH2, -COOH, - COMe, and -COOMe.2. A composition comprising a compound having the structure of formula (la),Y1Y22- C I> - ZY I3formula (la) or a pharmaceutically acceptable salt thereof, wherein each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl; and wherein Z is(1 ) a group that will be cleaved off the carbon atom shown in formula (la), such that Z is replaced by a hydrogen atom when the composition is exposed to the environment inside the rumen of a ruminant animal; or(2) a group that will be cleaved off the carbon atom shown in formula (la), such that Z is replaced by a hydrogen atom when formula (la) is contacted with a second activating compound that is comprised in said composition, wherein the second activating compound will come into contact with the formula (la) only when the composition is exposed to the environment inside the rumen of a ruminant animal. The composition of any one of statements 1 or 2, wherein the compound has a formula according to any of formula III (tribromoacetic acid), IV, V, or VI,formula (III) formula (IV) formula (V) formula (VI) wherein L and R are as defined in statement 1 . The composition of any one of statements 1 or 2, wherein the compound has a formula according to any of formula VII, VIII, IX or X:formula (VII) formula (VIII) formula (IX) formula (X) wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (preferably both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl. The composition of any one of statements 1 or 2, wherein the compound has a formula according to formula VII or IX or is tribromoacetic acid,wherein R1 and R2 are each independently selected from H, methyl, ethyl, propyl and butyl (preferably both R1 and R2 are each either H or methyl); and wherein Y1 , Y2 and Y3 are each individually selected from Br and Cl; and wherein the composition further comprises a base, preferably KOH and / or NaOH. The composition according to any of the preceding statements, wherein the composition comprises a first compound as defined in any one of claims 1 -5 and one or more compounds selected from the group consisting of a compound as defined in any one of claims 1 -5, wherein the compound is different from the first compound, cyclodextrin, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, phospholipid comprising one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFAs), palmitic acid, stearic acid and oleic acid, 3-Nitrooxypropanol, bromochloromethane, 2-bromoethane sulfonate and a haloform, preferably bromoform, preferably wherein the composition comprises tribromoacetic acid and / or tribromoacetic acid methyl ester and / or bromoform, more preferably wherein the composition comprises tribromoacetic acid and bromoform or tribromoacetic acid methyl ester and bromoform. The composition of any one of statements 1 to 6, wherein the composition does not comprise water or comprises less than 0.1 wt% of water. The composition of any one of statements 1 to 7, wherein the composition comprises one or more components selected from the group consisting of a metal particle, sodium chloride, a solid polyol, silica, cellulose, ethyl cellulose, hydroxypropyl methylcellulose, activated carbon, gelatin, chitosan, poly(lactic-co- glycolic acid) (PLGA), cyclodextrin, collagen, poly alpha-hydroxy ester, hydroxy alkanoat, dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide,polyethylene terephthalate, ethylene-vinyl acetate, a solid organic acid (preferably tartaric acid), a buffering substance, pH modifiers, an ester hydrolase and a carboxy-lyase. The composition of any one of statements 1 to 8, wherein a haloform (preferably bromoform) is released from the compound when the composition is exposed to water and preferably when said composition is placed in the rumen of a living ruminant animal. The composition of any one of statements 1 to 9, wherein the composition is dissolvable in water. A bolus for administration to a ruminant animal that comprises the compound or the composition as defined in any one of the preceding statements. A pellet for administration to a ruminant animal that comprises the composition as defined in any one of statements 1 to 10. A feed supplement for a ruminant animal that comprises the composition as defined in any one of statements 1 to 10; wherein the feed supplement is preferably in the form of a pellet, a tablet, a pill, a capsule, a powder or a lick block. Use of the composition, the bolus, the pellet or the feed supplement of any one of the preceding statements for use in reducing methane production in a ruminant animal. Use of the feed supplement of statement 13 for admixing the feed supplement to drinking water of a ruminant animal, preferably wherein the feed supplement is dissolvable in water. A method of treating a ruminant animal to reduce methane production in said animal, comprising administering to said animal the composition, the bolus, the pellet and / or the feed supplement of any one of the preceding statements in an effective amount.17. A method of preparing a composition according to any one of statements 1 -10.

Claims

Claims1 . A veterinary composition, the veterinary composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically or veterinary acceptable excipient,formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), OH, H, optionally substituted Ci-is-aliphatic, optionally substituted Ci-w-heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

2. The veterinary composition of claim 1 , wherein X is formula (li).

3. The veterinary composition of claim 1 , wherein X is formula (lii).

4. The veterinary composition of any one of claims 1 -3, wherein L is absent.

5. The veterinary composition of any one of claims 1 -4, wherein R is selected from the group consisting of OH, H, halo, N(Ra)2, and optionally substituted Ci-is-aliphatic.

6. The veterinary composition of any one of claims 1 -4, wherein R is selected from the group consisting of OH, N(Ra)2, and optionally substituted Ci -is-aliphatic.

7. The veterinary composition of claim 1 , wherein X is formula (liii).

8. The veterinary composition of any one of claims 1 -3 or 7, wherein L or Lais O.

9. The veterinary composition of any one of claims 1 -3 or 7, wherein L or Lais NRa.

10. The veterinary composition of any one of claims 1 -3 or 7, wherein L or Lais CH2.11 . The veterinary composition of any one of claims 1 -10, wherein Rais independently selected from the group consisting of H and optionally substituted Ci-is-aliphatic.

12. A veterinary composition comprising a compound having the structure of formula (la) or a pharmaceutically acceptable salt thereof; and a pharmaceutically or veterinary acceptable excipient,formula (la) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl; and wherein Z is(1 ) a group that will be cleaved off the carbon atom shown in formula (la) when the composition is exposed to the environment inside the rumen of a ruminant animal; or(2) a group that will be cleaved off the carbon atom shown in formula (la) when formula (la) is contacted with a second activating agent, wherein the second activating compound will come into contact with the formula (la) only when the composition is exposed to the environment inside the rumen of a ruminant animal; wherein cleavage of Z from formula (la) generates a compound of formula (lb)Y1Y2- C - HY I3formula (lb) or a pharmaceutically acceptable salt thereof.

13. The veterinary composition of claim 12, wherein Z is selected from the group consisting of COOH, optionally substituted Ci- -ester, optionally substituted C1-18- amide, an acid halide, and an acid anhydride.

14. The veterinary composition of any one of claims 1 -13, wherein each of Y1 , Y2 and Y3 is independently selected from the group consisting of I, F, Br and Cl15. The veterinary composition of any one of claims 1 -14, wherein each of Y1 , Y2 and Y3 is independently selected from the group consisting of Br and Cl.

16. The veterinary composition of any one of claims 1 -15, wherein each of Y1 , Y2 and Y3 are Br.

17. The veterinary composition of any one of claims 1 -16, wherein the composition further comprises a base.

18. The veterinary composition of claim 1 or 12, wherein the compound of formula (I) or formula (la) is selected from the group consisting of: tribromo acetic acid, (2,2,2- tribromoacetyl) 2,2,2-tribromoacetate, acetyl 2,2,2-tribromoacetate, (2,2,2- tribromoacetyl) propanoate, (2,2,2-tribromoacetyl) butanoate, (2,2,2-tribromoacetyl) pentanoate, (2,2,2-tribromoacetyl) heptanoate, methyl 2,2,2-tribromoacetate, ethyl2,2,2-tribromoacetate, propyl 2,2,2-tribromoacetate, butyl 2,2,2-tribromoacetate, pentyl2,2,2-tribromoacetate, hexyl 2,2,2-tribromoacetate, heptyl 2,2,2-tribromoacetate, octyl2.2.2-tribromoacetate, nonyl 2,2,2-tribromoacetate, decyl 2,2,2-tribromoacetate, undecyl 2,2,2-tribromoacetate, dodecyl 2,2,2-tribromoacetate, propan-2-yl 2,2,2- tribromoacetate, butan-2-yl 2,2,2-tribromoacetate, pentan-2-yl 2,2,2-tribromoacetate,2.2.2-tribromoacetyl chloride, 2,2,2-tribromoacetamide, 2,2,2-tribromo-N- methylacetamide, 2,2,2-tribromo-N-ethylacetamide, 2,2,2-tribromo-N-propylacetamide,2.2.2-tribromo-N-butylacetamide, 2,2,2-tribromo-N-hexylacetamide, 2,2,2-tribromo-N- octylacetamide, 2,2,2-tribromo-N-decylacetamide, 2,2,2-tribromo-N-dodecylacetamide,2.2.2-tribromo-N-octadecylacetamide, 2,2,2-tribromo-N,N-dimethylacetamide, 2,2,2- tribromo-N-ethyl-N-methylacetamide, or a pharmaceutically acceptable salt thereof.

19. A bolus for administration to a ruminant animal that comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof,formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), H, optionally substituted Ci-is-aliphatic, optionally substituted Ci-w-heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

20. A bolus for administration to a ruminant animal that comprises the veterinary composition as defined in any one of claims 1 -18.21 . A di- or tri-halogenated methane release system, the release system comprising: a compound of formula (I), or a pharmaceutically acceptable salt thereof, a housing, and a solid with a melting point from about 28 °C to about 45 °C, wherein the compound and the solid are within the housing, wherein the solid, or the combination of both the solid and the housing encapsulate or substantially encapsulate the compound,formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted Ci-18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionallysubstituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), H, optionally substituted Ci-is-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

22. A di- or tri-halogenated methane release system, the release system comprising: the veterinary composition of any one of claims 1 -18, a housing, and a solid with a melting point from about 28 °C to about 45 °C, wherein the compound and the solid are within the housing, wherein the solid, or the combination of both the solid and the housing encapsulate or substantially encapsulate the compound.

23. A pellet for administration to a ruminant animal that comprises the veterinary composition of any one of claims 1 to 18.

24. A feed supplement for a ruminant animal that comprises the composition as defined in any one of claims 1 to 18.

25. The feed supplement of claim 24, wherein the feed supplement is in a form selected from the group consisting of a pellet, a tablet, a pill, a capsule, a powder or a lick block.

26. A method of treating a ruminant animal to reduce methane production in said animal, comprising administering to said animal a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an effective amount;formula (I)wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), H, optionally substituted Ci-is-aliphatic, optionally substituted Ci-w-heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

27. A method of treating a ruminant animal to reduce methane production in said animal, comprising administering to said animal the veterinary composition of any one of claims 1 -18, the bolus of claim 19 or 20, the release system of claim 21 or 22, the pellet of claim 23, or the feed supplement of claim 24 or 25, in an effective amount.

28. A method of improving production of a ruminant animal, comprising administering to said animal a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an effective amount;formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br and Cl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), H, optionally substituted Ci-is-aliphatic, optionally substituted Ci-w-heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

29. A method of improving production of a ruminant animal, comprising administering to said animal the veterinary composition of any one of claims 1 -18, the bolus of claim 19 or 20, or the release system of claim 21 or 22, the pellet of claim 23, or the feed supplement of claim 24 or 25, in an effective amount.

30. A method of preparing the veterinary composition of any one of claims 1 -18, the bolus of claim 19 or 20, the pellet of claim 23, or the feed supplement of claim 24 or 25.31 . A method for producing the release system of claim 21 , the method comprising: selecting a compound of formula (I) or a pharmaceutically acceptable salt thereof, a housing and a solid, wherein the solid has a melting point from about 28 °C to about 45 °C, inserting the compound into the housing, inserting the solid in the housing, either by a) melting the solid or obtaining the solid as a molten liquid, pouring the molten solid in the housing such that once it solidifies the combination of both the solid and the housing encapsulate or substantially encapsulate the compound, andallowing the molten solid to cool and solidify, or b) forming a matrix with the compound prior to insertion of the compound in the housing, optionally closing the housing to encapsulate or substantially encapsulate the compound and the solid or molten solid in the housing;formula (I) wherein each of Y1 , Y2 and Y3 is selected from the group consisting of H, I, F, Br andCl; and at least two of Y1 , Y2 and Y3 are selected from I, F, Br and Cl;X is selected from the group consisting of formula (li), formula (lii) and formula (liii);formula (li) formula (lii) formula (liii)L is selected from the group consisting of CH2, O, NRa, or absent;Lais selected from the group consisting of CH2, O or NRa;R is selected from the group consisting of OH, H, halo, N(Ra)2, optionally substituted C1- 18-aliphatic, optionally substituted Ci- -heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl; andRais independently selected from the group consisting of C(Y1 )(Y2)(Y3), H, optionally substituted Ci-is-aliphatic, optionally substituted Ci-w-heteroaliphatic, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-10 membered aryl, and optionally substituted 3-10 membered heteroaryl.

Images