Improved pill design for administration to ruminants and uses thereof

Abstract

The present disclosure provides an improving pill formulated for administration to an animal, wherein the pill is configured to release a methane inhibiting agent or another active agent to the animal. Preferably, the methane inhibiting agent is haloform, but the pill may be engineered as described herein to contain other active agents, such as other methane inhibiting agents. The invention also provides application and a production method of the pill.

Description

Invention Field

[0001] This disclosure relates to improvements in devices and methods for delivering substances to animals, and in particular to devices and methods for administering at least one substance to the rumen of ruminants, as well as methods for manufacturing such devices. Background of the Invention In agriculture, it is often necessary to deliver substances to animals. This can be used for any of a variety of purposes, including but not limited to the treatment or prevention of diseases and increasing animal production.

[0003] Various devices (e.g., dosage forms) and methods exist for delivering substances, such as pharmaceuticals, to animals. Some substances are administered to the rumen of ruminants. Some dosage forms are used for extended release (i.e., sustained release) of substances into the rumen of ruminants. Some dosage forms are used for administering multiple active ingredients to the rumen of ruminants. However, the administration of substances to animals is still necessary, without requiring repeated administration by farmers or animal handlers. Extended-release dosage forms present challenges related to the extended control of the amount of dose released, and the reliability of such control over time and across batches. Similarly, the release control of multiple active ingredients also presents challenges in terms of release profile and reliability.

[0004] The prolonged release and / or dispersal of multiple active ingredients in the rumen presents further challenges due to the local environment, which is less studied, particularly for extended-release formulations, compared to the digestive tract of monogastric organisms such as humans. Controlled prolonged release of substances in the rumen can increase the efficacy of the administered formulation and reduce side effects by reducing the maximum concentration of the active substance to a concentration more consistent with its effective concentration and maintaining such effective concentrations throughout the extended period. Release of multiple active ingredients from a single formulation reduces the number of administrations required. Administration of formulations to large animals such as ruminants can require significant investment of time and infrastructure. However, the potential for multiple active ingredients to affect the release profile makes such formulations challenging, especially extended-release formulations.

[0005] There is a need for improved dosage forms for prolonged release and / or release of multiple active ingredients into the rumen. Preferably, these dosage forms provide controlled prolonged release into the rumen, and more preferably, controlled and maintained until most of the substance is released from the rumen-releasing dosage form.

[0006] Sustained release may be particularly desirable, where low doses of the active substance used to prolong the duration may provide optimal therapeutic efficacy.

[0007] The challenges associated with prolonged release of a substance increase with the amount of release required to be prolonged. Extending release by hours, days, weeks, and months becomes progressively more difficult, as does controlling release to deliver a bioeffective and non-toxic dose across the extended timeframe. There is a need for improved formulations for delivering substances with extended release profiles to the rumen of ruminants over extended periods of time. Preferably, the extended release is properly controlled within this timeframe.

[0008] Any reference to prior art in the specification is not an admission or implication that such prior art constitutes part of the common knowledge of any jurisdiction, or that such prior art could reasonably be expected to be understood by a person skilled in the art as relevant and / or combined with other parts of the prior art.

[0009] One aspect of the present invention is to provide an improved apparatus and method for delivering substances, such as methane inhibitors, to animals.

[0010] One aspect of the present invention is to provide apparatus and methods for reducing greenhouse gas (“GHG”) emissions.

[0011] One aspect of the present invention is to provide apparatus and method for improving animal production gains, for example, by reducing methane production.

[0012] One aspect of the present invention is to provide a formulation for reducing GHG emissions by one or more animals, such as ruminants.

[0013] One aspect of the present invention is to provide apparatus and methods for releasing substances at different rates over a period of time, such as sustained-release formulations containing a methane inhibitor.

[0014] Another aspect of the invention is to provide apparatus and methods adapted to the specific properties of certain GHG inhibitors.

[0015] Alternatively, one aspect of the present invention is to overcome some of the disadvantages of the prior art.

[0016] Alternatively, one aspect of the invention is to provide the public with a useful selection of methane inhibitors and corresponding apparatus and methods for applying these methane inhibitors. Invention Overview This disclosure relates to apparatus and methods for delivering a substance to animals. In a preferred form further outlined herein, the substance is a methane inhibitor. This disclosure is illustrated with reference to preferred embodiments; however, these preferred embodiments are not to be considered as limiting the scope of this disclosure. All documents referenced herein are incorporated by reference. Unless otherwise stated, all embodiments disclosed herein can be combined.

[0018] In a first aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: a core containing the methane inhibitor; and a shell surrounding (or covering at least a portion or completely surrounding) the core, said shell being configured such that its permeability to the methane inhibitor is increased when the shell is exposed to the rumen of an animal; and / or wherein, when the shell is exposed to the rumen of an animal, at least a portion of said shell is configured to form one or more openings allowing increased release of the methane inhibitor from within the pellet through said one or more openings.

[0019] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: A core, wherein the core comprises a methane inhibitor; and a shell covering at least a portion of the core. The shell is configured such that, relative to the permeability of the shell after being exposed to phosphate buffer (pH: 6.5, 0.02 M) without agitation for the same duration at a reference temperature on the same day, when the shell is exposed to phosphate buffer (pH: 6.5, 0.02 M) without agitation at 40°C, its permeability to the methane inhibitor is increased by at least 5%. The permeability was evaluated based on the release rate of the methane inhibitor.

[0020] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: The core comprises a methane inhibitor in microencapsulated particles and the microencapsulated particles are dispersed in a composition comprising a carrier and optionally also comprising a dispersant; and a shell covering at least a portion of the core.

[0021] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: The carrier and microencapsulated particles, wherein the microencapsulated particles contain a methane inhibitor, and wherein the microencapsulated particles are dispersed in the carrier, preferably wherein the carrier has a porous structure, such as mesoporous silica.

[0022] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising a core containing the methane inhibitor and a carrier, and said pellet excluding a shell.

[0023] In a further aspect, this disclosure relates to pellets for administration to ruminants, said pellets being configured to release a methane inhibitor into the animal, said pellets comprising: a core containing the methane inhibitor and a carrier; and a shell including the core; The methane inhibitor is selected from monensin, lauric acid, myristic acid, and linoleic acid; and The shell includes at least one opening that exposes the core to the environment surrounding the pellet.

[0024] In a further aspect, this disclosure relates to pills of this disclosure, wherein the methane inhibitor is added to or replaced by the methane inhibitor, and the pills further comprise an active agent, wherein the active agent is selected from anti-inflammatory agents, analgesics, antibiotics, and anthelmintics.

[0025] In a further aspect, a pellet is provided for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: core; A shell covering at least a portion of the core; The core comprises at least one methane inhibitor and at least one further activator.

[0026] In a further aspect, a pellet is provided for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core comprises a methane inhibitor dispersed in one or more of a hydrogel, oleogel, or organic gel, or constituting a part of one or more of a hydrogel, oleogel, or organic gel; and A shell that covers at least a portion of the core.

[0027] In another aspect, this disclosure relates to pills of the present disclosure for treating animals, preferably ruminants. In yet another aspect, this disclosure relates to pills of the present disclosure for reducing and / or inhibiting methane emissions in ruminants. This disclosure also provides a method of treating an animal, comprising administering the pills of the present disclosure to the animal.

[0028] In a further aspect, this disclosure relates to a method of manufacturing the pills of this disclosure.

[0029] In a further aspect, this disclosure relates to a methane inhibitor for reducing methane emissions from ruminants, wherein the methane inhibitor is selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid, and phospholipids.

[0030] In a further aspect, this disclosure relates to a method of treating ruminants to reduce methane emissions from said ruminants, comprising administering to said animal a methane inhibitor selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid and phospholipids.

[0031] In another aspect, this disclosure provides a method for applying a methane inhibitor to a ruminant, the method comprising administering a pellet according to this disclosure into the rumen of the ruminant.

[0032] In another aspect, this disclosure provides a method for reducing methane production in the rumen of a ruminant, the method comprising administering a pill according to this disclosure into the rumen of the ruminant.

[0033] In another aspect, this disclosure provides a method for preparing pills, the method comprising: Choose the core and shell Insert the core into the casing. Optionally, the shell is closed to surround or substantially surround the core within the shell; The core contains a methane-inhibiting agent. Optionally, the molten core is poured into the shell and solidified within the shell. Optionally, after the core has solidified, the shell is sealed around the core.

[0034] In some embodiments, the shell is configured such that its permeability to the methane inhibitor is increased when the shell is exposed to the rumen of a living organism.

[0035] In a further aspect, materials comprising acrylate-based polymers are provided when used for packaging the pills of this disclosure.

[0036] Further aspects of this disclosure and further embodiments of the aspects described in the foregoing paragraphs will become apparent from the following description, given by way of example, and with reference to the accompanying drawings. Brief description of the attached diagram Figure 1 Release profile of pellets containing a matrix of 60% tribromomethane, 20% EC and 20% HPMC when placed in buffer solutions at room temperature (RT: 25°C), 30°C and 40°C.

[0038] Figure 2 Release profile of pellets containing a matrix of 58.4% tribromomethane, 27.3% HPMC and 14.3% EC when placed in buffer solutions at room temperature (RT: 25°C), 30°C and 40°C.

[0039] Figure 3Release profile of pellets loaded with a matrix consisting of 58.4% tribromomethane, 27.3% HPMC and 14.3% EC, having shell thicknesses of 0.9, 1.2 and 1.5 mm, when placed in a buffer solution at 40°C.

[0040] Figure 4 An inverted vial containing lecithin-TBM gel.

[0041] Figure 5 Release profile of pills containing a matrix composed of the following components over 30 days: lecithin 55% / tribromomethane 45%, lecithin 40% / tribromomethane 60%, and lecithin 30% / tribromomethane 70%.

[0042] Figure 6 Release profile of pills containing a matrix of 55% lecithin and 45% tribromomethane over 120 days.

[0043] Figure 7 An inverted vial containing PMMA-TBM gel.

[0044] Figure 8 Release profile of pills containing a matrix consisting of 55% PMMA / 45% tribromomethane and 30% PMMA / 70% tribromomethane over 45 days.

[0045] Figure 9 Release profile of pills containing a matrix of 55% PMMA and 45% tribromomethane over 90 days.

[0046] Figure 10 Release profile of pills containing a matrix consisting of 30% MCW / 70% tribromomethane and 35% MCW / 65% tribromomethane over 30 days.

[0047] Figure 11 Release profile of pills containing a matrix of 35% MCW and 65% tribromomethane over 80 days.

[0048] Figure 12 Release profile of pills containing 17, 34, 52, and 70 g MCW 35% / tribromomethane 65% matrix.

[0049] Figure 13 Release profile of pills containing a matrix composed of 30% stearic acid / 70% tribromomethane and 35% stearic acid / 65% tribromomethane.

[0050] Figure 14 Changes in the release profile of pills containing 35% eicosane and 65% tribromomethane when moved from room temperature to 40°C.

[0051] Figure 15 Release profile of MCW 35% / tribromomethane 65% with or without shell (PLA / PBAT= 9 / 1).

[0052] Figure 16 Release profile of MCW 55% / tribromomethane 45% with or without shell (PLA / PBAT= 9 / 1).

[0053] Figure 17 The effect of lecithin (5% w / w) on the release profile of a stearic acid matrix loaded with 65% TBM was investigated. The increase in lecithin concentration (5%) was compensated by a corresponding decrease in stearic acid from 35% to 30% w / w.

[0054] Figure 18 The effects of monensin (2% and 5% w / w) on the release profile of TBM-loaded EC / HPMC matrices were analyzed. Increases in monensin concentrations (0, 2, and 5%) were compensated for by corresponding decreases in HPMC content (20, 18, and 15%). EC and TMB concentrations were consistent at 20% and 60% w / w, respectively.

[0055] Figure 19 The effects of phloroglucinol (2% and 5% w / w) on the release profile of TBM-loaded EC / HPMC matrices were investigated. Increases in phloroglucinol concentrations (0, 2, and 5%) were compensated for by corresponding decreases in HPMC content (20, 18, and 15%). EC and TMB concentrations were consistent at 20% and 60% w / w, respectively.

[0056] Figure 20 The effects of albendazole (2% and 5% w / w) on the release profile of TBM-loaded EC / HPMC matrices were analyzed. Increases in albendazole concentrations (0, 2, and 5%) were compensated for by corresponding decreases in HPMC content (20, 18, and 15%). EC and TMB concentrations were consistent at 20% and 60% w / w, respectively.

[0057] Figure 21 The effects of ketoprofen (2% and 5% w / w) on the release profile of TBM-loaded EC / HPMC matrices were analyzed. Increases in ketoprofen concentrations (0, 2, and 5%) were compensated for by corresponding decreases in HPMC content (20, 18, and 15%). EC and TMB concentrations were consistent at 20% and 60% w / w, respectively.

[0058] Figure 22 The pill (100) disclosed herein includes a shell (101), a core (102), a sealed region (103), and a densifying agent (104).

[0059] Figure 23 Release profile of 60 g pellets containing 65% TBM / 35% MCW over 12 days, the pellets having a shell with high amorphous or high crystalline PLA content.

[0060] Detailed description of the implementation plan In the context of prolonged release delivery to the rumen, certain substances present particular challenges. One class of compounds that are difficult to deliver to animals are hydrophobic compounds. A further class of compounds that are particularly difficult to deliver to animals in sustained release are volatile or slightly volatile compounds. The properties of these compounds present challenges to the development of technologies for these hydrophobic and / or volatile / slightly volatile substances, especially for sustained release via the animal's stomach. Halogenated compounds, such as bromoform, are examples of such substances. Surprisingly, the inventors have developed extremely prolonged-release (monthly) formulations for delivering hydrophobic and / or volatile / slightly volatile substances to the rumen of ruminants, a relatively less studied environment compared to the gastrointestinal tract of monogastric animals. Even more surprisingly, the inventors have improved the release kinetics of the formulation and controlled the duration of release by developing core components.

[0061] One specific purpose of administering substances to animals is to reduce the adverse effects of agriculture. For example, it is known to administer various methane and nitrification inhibitors to animals to reduce or mitigate the adverse effects of methane and nitrogen-containing compounds produced by animals.

[0062] However, despite current efforts, climate change continues to have a wide range of environmental and social impacts globally. It is widely understood that these impacts only continue to increase over time. Therefore, global efforts are underway to reduce harmful greenhouse gas (GHG) emissions to avert the most severe effects of climate change.

[0063] The agricultural sector is considered a major source of GHG emissions. Total methane emissions from global livestock farming account for an estimated 7.1 billion tons of CO2 equivalent per year, representing 14.5% of all anthropogenic GHG emissions. Therefore, this sector will play a crucial role in reducing overall GHG emissions.

[0064] The main GHGs released through agriculture are methane (CH4) and nitrous oxide (N2O), with livestock farming being the primary source of methane emissions. Most methane is emitted when cattle or other ruminants burp. The amount of methane produced per farm is directly related to the total feed intake of animals and is typically measured as dry matter intake (DMI).

[0065] Countries with strong agricultural sectors, such as New Zealand and others, face formidable targets in reducing agricultural emissions. For example, the New Zealand government has introduced policies aimed at reducing methane emissions by 24-50% by 2050. In New Zealand, livestock methane production is estimated to account for more than half of the country's total GHG emissions. Reducing methane emissions is a key component in meeting GHG emission targets and mitigating the effects of global warming.

[0066] GHG release from animals also has a detrimental effect on animal productivity. Any feed converted into compounds that are subsequently excreted or released by the animal is not converted into energy for production purposes. Therefore, for efficiency, it is important to optimize feed conversion into animal productivity, including in the form of weight gain or milk production.

[0067] According to existing technical devices known in the literature for administering methane inhibitors or other active ingredients to animals, further improvements can still be made, for example, in the following aspects: durability, control of the release rate of the active agent, versatility of drug forms such as pills, and reduction in the size and manufacturing cost for preparing powders or preferably pills.

[0068] definition Unless otherwise defined herein, the following terms shall be understood to have the following general meanings.

[0069] As used in this article, “carboxylate glass” refers to glass formed when one or a mixture of metal carboxylate salts is heated to its melting temperature or above and allowed to cool.

[0070] As used herein, “bromoform-rich seaweed extract” refers to an extract that contains non-trace seaweed components in addition to bromoform. Bromoform with a purity of at least 90% (w / w), at least 95% (w / w), at least 96% (w / w), and at least 99% (w / w) is not “bromoform-rich seaweed extract”.

[0071] "Active agent" can be any substance that provides a benefit to animals, such as a drug used to treat or prevent disease, that improves animal productivity, or mitigates at least one adverse effect of agriculture. For example, an active agent can regulate an animal's metabolism, such as affecting the amount or quality of methanogenesis.

[0072] Veterinary acceptable excipients are those that are generally harmless to animal subjects when administered to them. Technicians should understand that, in general, veterinary acceptable excipients include pharmaceutically acceptable (i.e., acceptable to humans) excipients.

[0073] As used herein, “haloform” is CHX3, where X is a halogen and each X atom can be a different halogen. Therefore, “haloform” includes CHClBr2, etc. As used herein, “mixed haloform” refers to a haloform in which not every X atom attached to a carbon atom is the same. In some embodiments, each X atom is identical. The terms “bromoform” and “tribromomethane” are used interchangeably herein.

[0074] As used in this article, “degrade” and “degradation” do not require the pill to be completely broken down into other substances that are completely absorbed by rumen fluid, but only require that the pill be sufficiently broken down so that it can leave the rumen, for example, through the animal’s digestive tract or be ruminated.

[0075] As used in this article, "feed" refers to dry matter intake (DMI), supplements, pasture, grains or other raw materials.

[0076] As used herein, the term "effective amount" means an amount of such an active ingredient that will elicit a biological or medical response in a tissue, system, or animal, as sought, for example, by a researcher or veterinarian. Furthermore, the term "therapeutic effective amount" means any amount that, compared to a corresponding subject who has not received such an amount, results in the treatment, healing, prevention, or relief of a disease, symptom, or side effect, or a reduction in the rate of progression of the disease or symptom. The term also includes, within its scope, amounts that effectively enhance normal physiological function. For example, a therapeutically effective amount of a methane inhibitor, such as haloform, reduces methane output in animals, preferably ruminants.

[0077] It is important to note that, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” as used herein and in the appended claims include plural indicators. Thus, for example, reference to “polymer” may include a variety of polymers, and reference to “at least one carrier” may include one or more carriers, and so on.

[0078] The term “and / or” can mean “and” or “or”.

[0079] The term “(s)” following a noun considers either the singular or plural form, or both.

[0080] As used herein, a "methane inhibitor" is an active agent, such as a compound or mixture of compounds, that inhibits or reduces the production of methane gas in the rumen of ruminants. The methane inhibitor can suppress methanogenesis. As used herein, the "methane inhibitor" is preferably haloform, more preferably bromoform.

[0081] The term "around the core" can mean completely surrounding the core. This disclosure also considers partially surrounding the core.

[0082] Unless the context requires otherwise, as used herein, the term “comprise” and its variations, such as “comprising,” “comprises,” and “comprised,” are not intended to exclude further additives, components, integers, or steps.

[0083] Various features of this disclosure are described with reference to specific values ​​or ranges of values. These values ​​are expected to relate to results from various suitable measurement techniques and should therefore be interpreted as including the error magnitude inherent in any particular measurement technique. Some values ​​mentioned herein are indicated by the term “about” to at least partially account for this variability. When used to describe values, the term “about” may mean a quantity within ±25%, ±10%, ±5%, ±1%, or ±0.1% of that value.

[0084] Increased permeability and / or openings In a first aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: a core containing the methane inhibitor; and a shell surrounding (or covering at least a portion or completely surrounding) the core, said shell being configured such that its permeability to the methane inhibitor is increased when the shell is exposed to the rumen of an animal; and / or wherein, when the shell is exposed to the rumen of an animal, at least a portion of said shell is configured to form one or more openings allowing increased release of the methane inhibitor from within the pellet through said one or more openings.

[0085] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: A core, wherein the core comprises a methane inhibitor; and a shell covering at least a portion of the core. The shell is configured such that, relative to the permeability of the shell after being exposed to phosphate buffer (pH: 6.5, 0.02 M) without agitation for the same duration at a reference temperature on the same day, when the shell is exposed to phosphate buffer (pH: 6.5, 0.02 M) without agitation at 40°C, its permeability to the methane inhibitor is increased by at least 5%. The permeability was evaluated based on the release rate of the methane inhibitor.

[0086] In some embodiments, the reference temperature is 20°C, 25°C, or 30°C. In some embodiments, the difference in shell permeability is evaluated based on the release rate with respect to the seventh, fourteenth, thirtieth, or sixtieth day. In some embodiments, the difference in permeability is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

[0087] Further provided are pellets for administration to ruminants, wherein the pellets are configured to release a methane inhibitor into the animal, wherein the pellets comprise: a core containing the methane inhibitor; and a shell surrounding (or covering at least a portion or completely enclosing) the core, wherein the shell is configured such that its permeability to the methane inhibitor increases when the shell is exposed to a temperature between 28°C and the temperature present in the rumen of a living animal, preferably between 28°C and 42°C; and / or wherein when the shell is exposed to a temperature between 28°C and the temperature present in the rumen of a living animal, preferably between 28°C and 42°C, at least a portion of the shell is configured to form one or more openings allowing the methane inhibitor to exit the pellet through the one or more openings.

[0088] In some implementations, the shell surrounds the core.

[0089] The release behavior of the active agent from the pellet to the outside of the pellet can be determined by immersing a pellet containing the active agent according to this disclosure in a tank filled with 25 liters of phosphate buffer (pH: 6.5, 0.02 M) at a constant temperature of 40°C, wherein the liquid buffer surrounding the pellet is continuously stirred using a magnetic stirrer. After a given time, the concentration of the active agent in the phosphate buffer is quantified (e.g., using GC-FID (gas chromatography with a flame ionization detector)). The quantification can be repeated at intervals, for example, once daily.

[0090] In a preferred embodiment, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: a core containing the methane inhibitor; and a shell surrounding (or covering at least a portion or completely enclosing) the core, said shell being configured such that its permeability to the methane inhibitor increases when the shell is exposed to a temperature of at least 38°C; and / or wherein when the shell is exposed to a temperature of at least 38°C, at least a portion of the shell is configured to form one or more openings allowing the methane inhibitor to exit the pellet through said one or more openings.

[0091] Some embodiments disclosed herein relate to pellets for administration to ruminants, said pellets being configured to release a methane inhibitor into the animal, said pellets comprising: a core containing the methane inhibitor; and a shell surrounding (or covering at least partially or completely surrounding) the core, wherein the shell becomes permeable to the methane inhibitor when exposed to a temperature at least physiological temperature or rumen temperature; and / or wherein, when exposed to a temperature at least physiological temperature or rumen temperature, at least a portion of the shell is configured to form one or more openings allowing the methane inhibitor to exit the pellet through said one or more openings. In a preferred embodiment, the shell surrounds the core.

[0092] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: a core containing the methane inhibitor; and a shell surrounding (or covering at least a portion or completely surrounding) the core, said shell being configured such that when the shell is exposed to a temperature between 28°C and the temperature present in the rumen of the animal, preferably between 28°C and 42°C, the permeability of the shell to the methane inhibitor is increased; and / or wherein when the shell is exposed to a temperature between 28°C and the temperature present in the rumen of the animal, preferably between 28°C and 42°C, at least a portion of the shell is configured to form one or more openings allowing increased release of the methane inhibitor from within the pellet through said one or more openings.

[0093] In a preferred embodiment, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: a core containing the methane inhibitor; and a shell surrounding (or covering at least a portion or completely enclosing) the core, said shell being configured such that the permeability of the shell to the methane inhibitor increases when the shell is exposed to a temperature of at least 38°C; and / or wherein when the shell is exposed to a temperature of at least 38°C, at least a portion of the shell is configured to form one or more openings allowing increased exit of the methane inhibitor from the pellet through said one or more openings.

[0094] In a preferred embodiment of the above-described pill type, the shell includes a plurality of openings, each having an average diameter, for example, from 1 micrometer to 0.5 mm, and wherein each opening is filled with a substance, such as a wax or hydrocarbon composition, that melts at a temperature between 28°C and the temperature present in the rumen of a living animal, preferably between 28°C and 42°C. In an alternative or further preferred embodiment of the pill, the shell including the openings is surrounded by a thin film of wax or hydrocarbon, which preferably melts at a temperature between 28°C and the temperature present in the rumen of a living animal, preferably between 28°C and 42°C, for example, a wax or hydrocarbon composition.

[0095] Increased permeability In some embodiments, when the shell is exposed to the rumen of a live animal, the permeability of the methane inhibitor increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, relative to the permeability of the shell after exposure to phosphate buffer (pH: 6.5, 0.02 M) at 20°C without agitation for the same duration on the same day. The permeability was evaluated based on the release rate of the methane inhibitor.

[0096] In some embodiments, when the shell is exposed to the rumen of a live animal, the permeability of the methane inhibitor increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, relative to the permeability of the shell after exposure to phosphate buffer (pH: 6.5, 0.02 M) at 25°C without agitation for the same duration on the same day. The permeability was evaluated based on the release rate of the methane inhibitor.

[0097] In some embodiments, when the shell is exposed to the rumen of a live animal, the permeability of the methane inhibitor increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, relative to the permeability of the shell after exposure to phosphate buffer (pH: 6.5, 0.02 M) at 28°C without agitation for the same duration on the same day. The permeability was evaluated based on the release rate of the methane inhibitor.

[0098] In some embodiments, compared to the permeability of the shell after being exposed to phosphate buffer (pH: 6.5, 0.02 M) at 30°C without agitation for the same duration on the same day, when the shell is exposed to the rumen of a live animal, the permeability of the shell to the methane inhibitor increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. The permeability was evaluated based on the release rate of the methane inhibitor.

[0099] In some embodiments, when the shell is exposed to the rumen of a live animal, the permeability of the methane inhibitor increases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, relative to the permeability of the shell after being exposed to phosphate buffer (pH: 6.5, 0.02 M) for the same duration at 38°C without agitation on the same day. The permeability was evaluated based on the release rate of the methane inhibitor.

[0100] In some embodiments, the difference in shell permeability after exposing the pill to the rumen of a live animal is evaluated based on the release rate at day 7, day 14, day 30, or day 60, relative to the release rate of the pill on the same day after exposure to phosphate buffer (pH: 6.5, 0.02 M) for the same duration at a defined temperature without agitation.

[0101] In some embodiments, compared to the permeability of the pills exposed to phosphate buffer (pH: 6.5, 0.02 M) at 20°C without agitation for the same duration on the same day, when the pills are exposed to phosphate buffer (pH: 6.5, 0.02 M) at 40°C without agitation, the permeability of the shell to the methane inhibitor is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

[0102] In some embodiments, compared to the permeability of the pills exposed to phosphate buffer (pH: 6.5, 0.02 M) at 25°C without agitation for the same duration on the same day, when the pills are exposed to phosphate buffer (pH: 6.5, 0.02 M) at 40°C without agitation, the permeability of the shell to the methane inhibitor is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

[0103] In some embodiments, compared to the permeability of the pills exposed to phosphate buffer (pH: 6.5, 0.02 M) at 30°C without agitation for the same duration on the same day, when the pills are exposed to phosphate buffer (pH: 6.5, 0.02 M) at 40°C without agitation, the permeability of the shell to the methane inhibitor is increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

[0104] In some embodiments, the difference in shell permeability compared to the permeability of the pills after exposure to phosphate buffer (pH: 6.5, 0.02 M) at 40°C without agitation for the same duration at a defined temperature on the same day is evaluated based on the release rate on the seventh, fourteenth, thirtieth, or sixtieth day.

[0105] When the concentration of the methane inhibitor unbound by the carrier inside the pill is greater than its concentration outside the pill, the increased permeability of the shell to the methane inhibitor causes the methane inhibitor to diffuse out of the pill. The permeability of the shell to the methane inhibitor can be evaluated by any suitable means, such as the diffusion of the methane inhibitor from the pill. Diffusion from the pill can be measured by any suitable means, such as GC-FID analysis of the surrounding mixture. GC-FID is suitable for quantifying bromoform and therefore quantifying the permeability of the shell to bromoform. Samples from the rumen of living animals can be collected from animals with fistulas.

[0106] case As used herein, the term "shell" is generally understood to mean an outer shell surrounding, covering, or completely enclosing a core, said core comprising at least one methane inhibitor and possibly further activators. The shell may include a cap.

[0107] In some embodiments, the shell surrounds the core. In some embodiments, the shell substantially surrounds the core. The substantially surrounded core has about 70 to about 99%, about 80 to about 99%, about 85 to about 99%, or about 90 to about 99% of the core surface area covered by the shell.

[0108] The shell can be made, for example, from a composition comprising a biodegradable plastic. In some embodiments, the shell comprises one or more biodegradable polymers. In some embodiments, the shell is composed of one or more biodegradable polymers. In some embodiments, the shell does not include a non-biodegradable polymer. In some embodiments, the shell comprises one or more non-biodegradable polymers, including polyvinyl chloride (PVC), polyethylene terephthalate (PET), Buna-S, nylon, polyvinyl butyral, polyethylene (low-density, medium-density, high-density, or ultra-high-density), polypropylene (PP), and combinations thereof. In some embodiments, the shell comprises one or more non-biodegradable polymers, including high-density polyethylene (HDPE), polypropylene (PP), and combinations thereof. Optionally, the non-biodegradable polymer in the shell is combined with a biodegradable polymer, or is degradable in the presence of haloform and / or the core.

[0109] In some implementations, materials, such as plastics, are considered biodegradable if they are considered biodegradable under the standards set forth in ISO 14855-1:2012 (Biodegradability of plastic materials under controlled composting conditions). According to this method, the percentage of biodegradation is given by the ratio of CO2 produced by the test material to the maximum theoretical amount of CO2 that can be produced by the test material (excluding the amount of carbon converted into new cell biomass, i.e., not metabolized into CO2). The maximum theoretical amount of CO2 produced is calculated from the total organic carbon content of the test material. The threshold for biodegradability in industrial composting is at least 90% biodegradation by weight of the total mass of the test material within less than 6 months. Therefore, for example, for a test material considered biodegradable, 90% of the carbon in the test material should be converted into CO2 within less than 6 months.

[0110] Preferably, the shell material is compatible with waste disposal regulations applied to slaughterhouse facilities. The shell material can generally comprise any material that is non-toxic when applied to the rumen of an animal. Particularly relevant is any food animal that, upon exposure to the material in the pellet, results in a non-toxic food (meat or milk). The shell material is further preferably thick enough (wall thickness) to resist mechanical stresses and abrasive forces within the rumen, allowing it to remain intact inside the rumen and preventing breakage or collapse for at least several weeks.

[0111] The shell is shaped to fit with the core and any other components in the pill, so that there are no air gaps in the pill.

[0112] The shell can be made of a material through which methane inhibitors can migrate, for example, via a mass diffusion process. In a preferred embodiment, the shell can be made of at least one plastic material, such as a biodegradable plastic or material that degrades over time in the rumen. In one embodiment, the shell can be made of a material selected from polylactic acid (PLA), polyglycolic acid (PGA), polylactic-glycolic acid (PLGA), polypropylene, polycaprolactone (PCL), poly(d-lactic acid) (PDLA), polybutylene succinate (PBS), polybutylene terephthalate (PBAT), SLA polymer, ABS, or combinations thereof.

[0113] In any embodiment of this document, a pill comprising the shell described herein may comprise a shell, said shell or a portion thereof comprising at least one compound selected from the group consisting of: polylactic acid (PLA), polybutylene succinate-adipate (PBSA), polybutylene succinate (PBS), polyhydroxybutyrate-co-hydroxyvalerate, polyvinyl acetate (PVA), polybutylene terephthalate-adipate (PBAT), polycaprolactone (PCL), wood flour and cellulose materials, ethyl cellulose and hydroxypropyl methylcellulose, and mixtures of two or more of the above.

[0114] In alternative embodiments, the shell comprises one or more hydrophobic polymers. Optionally, the shell comprises one or more hydrophobic biodegradable polymers. In alternative embodiments, the shell is composed of one or more hydrophobic polymers. Optionally, the shell is composed of one or more hydrophobic biodegradable polymers.

[0115] In some implementations, the shell comprises one or more ester-based polymers.

[0116] In some embodiments, the housing comprises one or more polymers selected from: high-density polyethylene (HDPE), polypropylene (PP), polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene terephthalate-adipate (PBAT), styrene-acrylic acid copolymers (e.g., Jonathani), etc. ®Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), combinations thereof, and copolymers thereof. In some embodiments, the shell is composed of one or more polymers selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene terephthalate-adipate (PBAT), styrene-acrylic acid copolymers (e.g., Joncryl) ® The housing comprises talc-filled poly(D-lactide) (TALCPDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), combinations thereof, and copolymers thereof. In some embodiments, the housing comprises one or more polymers selected from: high-density polyethylene (HDPE), polypropylene (PP), combinations thereof, and copolymers thereof. In some embodiments, the housing comprises one or more polymers selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene terephthalate-adipate (PBAT), styrene-acrylic acid copolymers (e.g., Joncryl) ® Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), combinations thereof, and copolymers thereof. In some embodiments, the shell is composed of one or more polymers selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene terephthalate-adipate (PBAT), styrene-acrylic acid copolymers (e.g., Joncryl) ® Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), combinations thereof, and copolymers thereof.

[0117] In some embodiments, the housing comprises one or more of the following: polylactic acid (PLA), polyglycolic acid (PGA), polylactic-glycolic acid (PLGA), polypropylene, polycaprolactone (PCL), poly(d-lactic acid) (PDLA), polybutylene succinate (PBS), polybutylene terephthalate (PBAT), SLA polymers, or one or more thermosetting polymers and / or resins, ABS, combinations thereof, and copolymers thereof. In some embodiments, the housing comprises one or more of the following: polylactic acid (PLA), polybutylene succinate (PBSA), polybutylene succinate (PBS), polyhydroxybutyrate-co-hydroxyvalerate, polyvinyl acetate (PVA), polybutylene terephthalate (PBAT), polycaprolactone (PCL), wood flour and cellulose materials, ethyl cellulose and hydroxypropyl methylcellulose, combinations thereof, and copolymers thereof.

[0118] In some embodiments, the shell comprises one or more polymers selected from polylactic acid, polybutylene terephthalate, combinations thereof, and copolymers thereof. In some embodiments, the shell is composed of one or more polymers selected from polylactic acid, polybutylene terephthalate, combinations thereof, and copolymers thereof.

[0119] In some embodiments, the PLA:PBAT ratio is about 95:5 to about 70:30 wt / wt, about 95:5 to about 80:20 wt / wt, or about 95:5 to about 85:15 wt / wt. In some embodiments, the PLA:PBAT ratio is about 90:10 wt / wt.

[0120] Blends of such materials can be particularly advantageous. For example, mixing / blending polybutene polymers, such as PBAT, with PLA increases the plasticity and strength of the shell compared to shells made from PLA alone, while preserving the biodegradability of the shell material. This stability-enhancing effect is particularly beneficial when using, for example, haloform as a methane inhibitor, as such compounds can otherwise contribute to the brittleness of the shell material. Furthermore, the use of polybutene polymer / PLA blends improves the durability of the shell compared to PLA alone and reduces the risk of breakage under mechanical stress, such as when placed in the rumen of an animal.

[0121] The components used or mixed to form the shell material can be selected based on their suitability for the intended use in forming the pellet shell. When heated to form the pellet shell, the mixture should not become too viscous for 3D printing or injection molding, and the blending of two or more polymers should result in a homogeneous mixture without extensive bubble formation. 3D printing includes stereolithography (SLA) and digital light processing (DLP).

[0122] The shell of the pill may, for example, contain biodegradable and / or non-biodegradable materials, but preferably biodegradable polymers. Such materials may be synthetic or naturally or substantially naturally derived. Preferably, the material is selected from biodegradable polymers. Examples of such polymers include, but are not limited to, polylactic acid (PLA), polybutylene terephthalate (PBT), polybutylene terephthalate-adipate (PBAT), polybutylene succinate (PBS), and polybutylene succinate-adipate (PBSA). Biodegradability allows for repeated administration of the pill while preventing the accumulation of pill material in the rumen of ruminants, as the pill components can be at least partially or even completely degraded in the rumen environment. However, it should be understood that even if the pill shell is biodegradable, it will not completely degrade to the extent that the pill would decompose for a duration of at least 7 days when held in the rumen. Suitable non-biodegradable polymers include high-density polyethylene (HDPE), polypropylene (PP), combinations thereof, and copolymers thereof.

[0123] Therefore, the shell used for any pill containing the shell described herein can be configured to have sufficient structural integrity to remain intact for a predetermined time period. In a preferred embodiment, the shell can be configured to degrade within a predetermined time period. The predetermined time period can refer to the period during which the methane inhibitor is released into the animal. In a particularly preferred embodiment, the predetermined time period can be at least two months, preferably six months, and more preferably 12 months. In some embodiments, the time period is at least two weeks, three weeks, four weeks, or six weeks.

[0124] In one embodiment, the shell material may comprise polylactic acid (PLA) and polybutylene terephthalate (PBAT), preferably in a PLA:PBAT weight ratio of 95:5 to 70:30 or about 90:10. Unless otherwise defined, as used herein, ratios refer to weight ratios (or “weight ratio”, “w / w”), which are calculated with reference to the total weight of the shell components used.

[0125] The material used for the casing may also contain PLA, PBAT, PBSA and / or PBS in different ratios as shown in the table below: Table 1. Materials used for the casing.

[0126] Optionally, the shell is 5 to 100% or 10 to 100% PLA w / w. Optionally, the shell is 20 to 90% or 30 to 80% PBS w / w. Optionally, the shell is 20 to 100% or 30 to 90% PBAT w / w. Optionally, the shell is 20 to 100% or 30 to 90% PBSA w / w. Optionally, the shell is 5 to 100% or 10 to 100% PLA w / w, and (i) 20 to 90% or 30 to 80% PBS w / w, (ii) 20 to 100% or 30 to 90% PBAT w / w, or (iii) 20 to 100% or 30 to 90% PBSA w / w.

[0127] As summarized above, the shell of the pills disclosed herein can be designed to allow the active ingredient (i.e., the methane inhibitor) to pass through the shell. This can provide sustainable controlled release. In one embodiment, the methane inhibitor can permeate through the shell material of the pills disclosed herein. Optionally, the methane inhibitor diffuses through the shell material.

[0128] Alternatively, the shell can be made of one or more non-adsorbent materials, i.e., materials into which the methane inhibitor does not migrate or through. Using a non-adsorbent material for the shell can help control the release rate of the methane inhibitor, for example, in pills containing one or more openings, in pills having a shell capable of forming one or more openings, or in open-type pills. For example, in these embodiments, the concentration of the methane inhibitor in the core is not reduced due to its absorption into the shell material.

[0129] The shell of the pills disclosed herein can be endowed with further functional characteristics, such as, but not limited to, by incorporating further components into the shell material or by modifying the size and properties of the shell. In one embodiment, the shell material of the pills disclosed herein comprises one or more excipients. In a preferred embodiment, the one or more excipients include plasticizers, hardeners, and / or colorants.

[0130] In one embodiment, the shell further comprises a compound selected from nucleating agents or stabilizers. In one embodiment, the shell does not comprise a nucleating agent and / or stabilizer. The thickness of the shell can be selected to promote the release rate of the methane inhibitor, i.e., a relatively thicker shell will have a relatively slower release rate than a relatively thinner shell. This is especially true if the shell material is permeable to the methane inhibitor. In one embodiment, the shell may have a material thickness of less than about 2 mm, preferably in the range of about 0.3-1.8 mm, and more preferably in the range of about 0.3-1.5 mm. In some embodiments, the shell has a material thickness of less than about 1.5 mm, less than about 1.3 mm, or less than about 1 mm. In some embodiments, the shell has a material thickness of greater than about 0.8 mm, greater than about 1 mm, or greater than about 1.1 mm. In some embodiments, the shell has a material thickness of about 0.9 mm. In some embodiments, the shell has a material thickness of about 1.2 mm. In some embodiments, the shell has a material thickness of about 1.5 mm. For pills containing a shell with one or more openings, a thicker shell can also be applied, for example, a shell wall thickness of up to about 5 mm.

[0131] Optionally, the core and shell have a ratio of about 3 to about 6:1, about 4 to about 5:1, or about 4.6:1 by weight.

[0132] In one embodiment, the shell is configured to degrade over a predetermined time period. The predetermined time period can be adjusted, for example, by means of the shell's material thickness, the selection of the shell material, or the shell's manufacturing process.

[0133] In one embodiment, the housing includes a cavity therein containing at least a portion of a core, wherein the core contains a methane suppressant, such as a methane inhibitor. In another embodiment, the housing does not include any openings and completely surrounds the core. In yet another embodiment, the housing completely covers and surrounds the core. In one embodiment, the housing includes one or more openings as described above.

[0134] The shell of the disclosed pellet can facilitate the controlled release of a methane inhibitor. For example, the shell can withstand rumen conditions for a predetermined period of time. During this time, the shell protects the core from rumen fluids, while still promoting or facilitating the controlled release of the methane inhibitor. However, the shell is designed to allow for disintegration or degradation within the predetermined time period. This can help mitigate the adverse effects of the device on animals and also ensure that animals can be treated with multiple pellets, such as administering a second pellet at the end, near the end, or after the predetermined time period.

[0135] In this respect, when the shell is exposed to a temperature between 28°C and the temperature present in the rumen of a living organism, preferably between 28°C and 42°C, the shell becomes permeable to the methane inhibitor and / or at least a portion of the shell is configured to form one or more openings allowing the methane inhibitor to exit the pellet through said one or more openings. Alternatively, when the shell is exposed to a critical minimum temperature, the permeability of the shell to the methane inhibitor may be increased, or the exit through said formed openings may be increased. In the latter case, the permeability and / or exit of the methane inhibitor is increased compared to the permeability / exit from the pellet (e.g., pellets exposed to temperatures below 28°C) when it is not exposed to at least said temperatures.

[0136] A temperature-responsive release of the methane inhibitor, provided only after exposure to the minimum required temperature, allows for a significant increase in the release of the methane inhibitor or its release rate, accompanied by an effect on the environment of the pill. This means that the pill releases an effective amount of the methane inhibitor only after, and not before, administration to animals. In particular, the pill may be kept at room temperature or at a low temperature prior to application to ensure that no methane inhibitor or a significant amount of methane inhibitor is released from the pill. Preventing premature release of the methane inhibitor from the pill in this way can provide several benefits, including preventing or reducing any loss of the methane inhibitor before actual application, preventing or reducing contamination by potentially invasive methane inhibitors held in the environment / surrounding the pill, and protecting farmers, workers, or others handling the pill from exposure to potentially harmful amounts of the methane inhibitor.

[0137] In one embodiment, the shell includes one or more openings, and the openings are filled and / or covered with a material that melts, dissolves, or disintegrates in the rumen of a live animal. Preferably, the shell is made of a material that does not melt, dissolve, or disintegrate in the rumen of a live animal, and preferably does not melt, dissolve, or disintegrate in the rumen of a live animal during a 1-day period.

[0138] To achieve temperature-dependent release, the pill may contain at least a portion that forms openings or increases the permeability of a methane inhibitor, and may comprise or consist of certain suitable compounds or mixtures of compounds having properties that can be altered upon reaching a certain temperature critical point. In one embodiment, a portion of the shell, and preferably a portion forming one or more openings in the shell, is made of a material that melts, dissolves, or disintegrates in the rumen of a living animal.

[0139] In one embodiment, the material to be melted is selected from the following compounds: hydrogels, oleogels, organic gels, phase change materials (PCMs), fatty acids, alkanes, olefins, gelators, waxes, L-alanine amino acids, L-alanine amino acid derivatives, poly(methyl methacrylate) (PMMA), (1,3:2,4) dibenzyl sorbitol (DBS), hydroxystearic acid, paraffin wax, gelatin, 1-tetradecane alcohol, polyethylene glycol, octadecane, nonadecane, eicosane, Pluronic polymers or mixtures of Pluronic, emulsifiers, sucrose isobutyrate acetate (SAIB), derivatives of the above, and combinations of one or more of the above compounds, wherein said compound or combination of compounds has a melting temperature of 28°C to 42°C, more preferably 28°C to 35°C.

[0140] The melting temperature is the temperature at which a substance changes from a substantially solid state to a liquid state under atmospheric pressure.

[0141] In another embodiment, the dissolved material is preferably selected from the following water-soluble materials: polymers, polyols, sugars, polyamides, salts, cellulose acetate, polyethylene glycol, methylcellulose, CMC, polyvinyl alcohol, alginate, polyacrylic acid or its salts, polyacrylamide, cellulose ethers, carrageenan, guar gum, and pectin. "Water-soluble" means that the substance can dissolve in distilled water at a temperature of 20°C.

[0142] In another embodiment, the disintegrating material is a compound selected from cellulose, polyhydroxyalkanoates (PHA), poly(butylene succinate-adipate) (PBSA), and mixtures of two or more of the above. The rumen environment contains enzymes that can disintegrate or facilitate the disintegration of the above compounds. When the material disintegrates, the release of the active agent from inside the pill to the outside of the pill will increase, which can be tested as outlined above in the context of quantifying the release of the active agent from inside the pill.

[0143] In another aspect, this disclosure relates to pellets for administration to ruminants, said pellets being configured to release a methane inhibitor into the animal, said pellets comprising: a core containing the methane inhibitor; and a shell covering at least a portion of the core, said shell being at least a portion configured to form one or more openings allowing the methane inhibitor to exit the pellet through said one or more openings, said portion of the shell forming the one or more openings comprising or consisting of a compound selected from or composed of: temperature-responsive hydrogels, oleogels, organic gels, phase change materials (PCMs), fatty acids, alkanes, olefins, gelling agents and waxes, L-alanine amino acids or L-alanine amino acid derivatives, poly(methyl methacrylate) (PMMA), (1,3:2,4)dibenzyl sorbitol (DBS), hydroxystearic acid, paraffin wax, gelatin, 1-tetradecanool, polyethylene glycol, octadecane, nonadecane, eicosane, Prönkel polymers or mixtures of Prönkel, emulsifiers, sucrose isobutyrate acetate (SAIB), derivatives of the above, and combinations of one or more of the above compounds. In some implementations, the shell surrounds the core.

[0144] In another aspect, this disclosure relates to pellets for administration to ruminants, said pellets being configured to release a methane inhibitor into the animal, said pellets comprising: a core containing the methane inhibitor; and a shell covering at least a portion of the core, said shell being at least a portion configured to form one or more openings allowing increased release of the methane inhibitor from within the pellet through said one or more openings, said portion of the shell forming the one or more openings comprising or consisting of a compound selected from or composed of: temperature-responsive hydrogels, oleogels, organic gels, phase change materials (PCMs), fatty acids, alkanes, olefins, gelling agents and waxes, L-alanine amino acids or L-alanine amino acid derivatives, poly(methyl methacrylate) (PMMA), (1,3:2,4)dibenzyl sorbitol (DBS), hydroxystearic acid, paraffin wax, gelatin, 1-tetradecanoic alcohol, polyethylene glycol, octadecane, nonadecane, eicosane, Prönkel polymers or mixtures of Prönkel polymers, emulsifiers, sucrose isobutyrate acetate (SAIB), derivatives of the above, and combinations of one or more of the above compounds. In some implementations, the shell surrounds the core.

[0145] In another embodiment, a portion forming one or more openings in the shell comprises or consists of a compound selected from or composed of: temperature-responsive hydrogels, oleogels, organic gels, phase change materials (PCMs), fatty acids, alkanes, olefins, gelling agents, and waxes, preferably wherein the compound has a melting temperature between 28°C and the temperature present in the rumen of an active animal, and more preferably between 28°C and 42°C.

[0146] In another embodiment, a portion forming one or more openings in the housing comprises or consists of a compound selected from or composed of: temperature-responsive hydrogels, oleogels, organic gels, phase change materials (PCMs), fatty acids, alkanes, olefins, gelling agents, and waxes, preferably wherein the compound is solid at 30°C and liquid at 42°C.

[0147] In a preferred embodiment, the compound is selected from L-alanine amino acid derivatives, poly(methyl methacrylate) (PMMA), (1,3:2,4) dibenzyl sorbitol (DBS), hydroxystearic acid, paraffin wax, gelatin, 1-tetradecane alcohol, polyethylene glycol (PEG), octadecane, nonadecane, eicosane, Pluronic polymers or mixtures of Pluronic, emulsifiers, sucrose isobutyrate acetate (SAIB), derivatives thereof, and combinations of one or more of the above compounds.

[0148] The material of the shell portion where the one or more openings are not formed comprises compounds selected from PLA, PCL, PBS, PBAT, PHB, PBSA, wood flour, and combinations thereof. Such materials have the property of having a melting temperature higher than that in the rumen of an animal. This means that the portion where the one or more openings are formed will be allowed to melt in the rumen, while the remaining portion of the shell remains intact and solid when exposed to the same rumen temperature.

[0149] Organic gel In a further aspect, a pellet is provided for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core comprises a methane inhibitor dispersed in one or more of a hydrogel, oleogel, or organic gel, or constituting a part of one or more of a hydrogel, oleogel, or organic gel; and The shell covers at least a portion of the core.

[0150] Hydrogels, oleogels, and organic gels offer favorable release profiles (controlled and / or prolonged) and are relatively easy to handle, simplifying manufacturing. Furthermore, in at least one preferred embodiment, hydrogels, oleogels, and organic gels can provide relatively high release levels at lower loadings of the active ingredient compared to comparable pellets with other carriers (particularly polymer-based carriers), potentially reducing the amount of active agent required per pellet.

[0151] As used herein, a hydrogel can be a temperature-responsive hydrogel. A temperature-responsive hydrogel should be understood as a gel comprising a cross-linked polymer network, wherein the swelling agent is water or an aqueous solution. Hydrogels can be based, for example, on cross-linked polymers, including but not limited to natural polymers, N-isopropylacrylamide polymers, poly(ethylene oxide)-b-(polypropylene oxide)-b-poly(ethylene oxide) polymers, and poly(ethylene glycol)-biodegradable polyester copolymers.

[0152] Organic gels should be understood as formulations comprising an organic liquid and a gelling agent component, said component forming a gel filled with the organic liquid, said organic liquid including but not limited to polar organic solvents and their aqueous mixtures, ionic liquids, fats and oils. The thermal stability of the gel can be adjusted by selecting the solvent according to its boiling point, and generally by selecting the components according to its critical phase transition temperature.

[0153] Olegels, classified as a type of organic gel, should be understood as formulations whose base can consist of paraffin oil, fats, or natural oils, often with the addition of polyethylene, forming so-called isogels. Alternatively, they can consist of oils gelled through various additives, forming so-called heterogels. Gelation agents used in heterogels include zinc stearate, aluminum stearate, highly dispersed silica, and ethyl cellulose.

[0154] In some implementations, the core is a hydrogel. In some implementations, the core is an oleogel. In some implementations, the core is an organic gel.

[0155] In some embodiments where the core is a hydrogel, oleogel, or organic gel, the core comprises a further surfactant. In some embodiments where the core is a hydrogel, oleogel, or organic gel, the core comprises a further methane inhibitor (preferably lecithin). In some embodiments where the core is a hydrogel, oleogel, or organic gel, the combination of the methane inhibitor and the further surfactant (preferably lecithin), optionally further comprising water, forms a hydrogel, oleogel, or organic gel. In some embodiments where the core is a hydrogel, oleogel, or organic gel, the core consists of a methane inhibitor, a further methane inhibitor (preferably lecithin), and optionally water.

[0156] In some embodiments where the core is a hydrogel, oleogel, or organic gel, the core comprises phospholipids (preferably lecithin) and / or an acrylate-based polymer (preferably poly(methyl methacrylate) [PMMA]). In some embodiments where the core is a hydrogel, oleogel, or organic gel, the shell surrounds the core. Optionally, Ploxamethylene, also known as poloxamer, is a class of synthetic block copolymers composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) arranged in an ABA triblock structure, thus giving PEO-PPO-PEO. Concentrated solutions of poloxamethylene can also form hydrogels when mixed with water, which can also be suitable compounds as described. Increasing the temperature to a certain critical level can affect the hydrogen bonding between polyethylene oxide and water molecules and change the cohesiveness of the Ploxamethylene / poloxamer components, likely increasing permeability.

[0157] Sucrose isobutyrate (SAIB), prepared by esterification of sucrose with acetic anhydride and isobutyric anhydride, is known to be an acceptable emulsifier in food preparation and therefore exhibits particularly tolerable properties when used in animals.

[0158] In some embodiments, a portion of the housing forming one or more openings contains or is composed of a compound whose properties are altered to allow increased permeability at a critical temperature (which is the melting point of the compound). This is, for example, when oils and / or waxes are contained in a portion of the housing, in which one or more openings are formed and / or the housing becomes permeable to methane inhibitors.

[0159] Those skilled in the art should know that when a portion forming one or more openings in the shell contains or is composed of polyethylene glycol, the critical temperature allowing for increased permeability depends on the PEG or PEG mixture used. Those skilled in the art can select a suitable PEG component to achieve the desired critical release temperature. PEG can also be suitably used in the form of a PEG gel, which is a gel containing PEG as a functional phase.

[0160] Phase change materials (PCMs) are materials or compounds that can melt or solidify at certain temperatures. They absorb or release heat energy by changing the state of the material. PCMs can be solid at room temperature and soften when they reach a specific temperature, which can encompass materials that become more permeable. Bio-based PCMs include glycols, alcohols, esters, and fatty acids. In particular, fatty acids, and especially saturated fatty acids such as palmitic acid and stearic acid, are suitable PCMs, which can be derived from vegetable oils and animal fats, such as palm oil or coconut oil. Further biomedical and therefore veterinary applications of PCMs are known in the art, including, but not limited to, 1-tridecyl alcohol, 1-tetradecyl alcohol, 1-pentadecanol, decanoic acid, or lauric acid.

[0161] When the shell is exposed to the rumen and / or at least the rumen or physiological temperature of an animal, the largest opening formed in the shell may suitably have a maximum diameter of 1 mm to ensure that the release of the methane inhibitor through the opening remains controlled and continuous.

[0162] In one embodiment, when the shell is exposed to the rumen of a live animal, the largest opening formed in the shell has a maximum diameter of 2 mm. In another embodiment, when the shell is exposed to the rumen of a live animal, the largest opening formed in the shell has a maximum diameter of 1 mm.

[0163] In one embodiment, when the shell is exposed to the temperature present in the rumen of a living animal, preferably 42°C, the largest opening formed in the shell has a maximum diameter of 2 mm. In another embodiment, when the shell is exposed to the temperature present in the rumen of a living animal, preferably 42°C, the largest opening formed in the shell has a maximum diameter of 1 mm.

[0164] In another embodiment, when the housing is exposed to a temperature of at least 38°C, the largest opening formed in the housing has a maximum diameter of 2 mm. In another embodiment, when the housing is exposed to a temperature of at least 38°C, the largest opening formed in the housing has a maximum diameter of 1 mm. The size of the formed pores can determine the release rate of the methane inhibitor from the pellet, wherein the methane inhibitor is released through the formed pores.

[0165] When delayed release is sought, the distribution mechanism provided by the pellet, including the temperature-enhanced or temperature-dependent release of the methane inhibitor contained in the pellet, is useful. As used in this context, delayed release should be understood as a delay or substantially a slowing of the release of the methane inhibitor from the pellet until after the pellet has been administered to the ruminant, i.e., until after the pellet has been placed in the animal's rumen. This can be advantageous in pellet handling, where, when handled externally to the rumen environment, the pellet releases much less or even no methane inhibitor contained in the pellet, and release of the methane inhibitor only begins after administration to the animal's rumen, or at a higher rate, such as an effective rate. Advantages provided by such pellet modification include protection for farmers or other workers handling the pellet from methane inhibitors, such as bromoform, which may, for example, be harmful or irritating to humans upon direct contact.

[0166] When the shell is exposed to a temperature at least physiological temperature or rumen temperature, the release rate of the methane inhibitor from the pill through one or more openings can be increased, allowing the methane inhibitor to leave the pill more rapidly through one or more openings.

[0167] In one embodiment, the pills of this disclosure comprise the methane inhibitor bromoform and are adapted to achieve a maximum release rate of about 0.1–about 0.5 g / day, more preferably about 0.2 g / day. Such a release rate can provide sustained release of haloforms, such as bromoform. Pills having such a release rate are suitable, for example, for cattle and sheep.

[0168] To achieve a preferred release rate, and in small farm animals, the concentration of the methane inhibitor, such as haloform, or the thickness of the shell material can be adjusted, for example. Furthermore, to achieve a preferred release rate, and in small farm animals, the size of the opening formed in the pellet of this disclosure upon administration into the rumen can be adjusted, for example. Additionally, to achieve the desired release rate of the methane inhibitor, the overall polarity of the carrier material that can be mixed with the methane inhibitor can be adjusted to achieve the desired affinity of the methane inhibitor mixed therewith. However, in alternative embodiments, the methane inhibitor can be provided in a substantially pure form, for example, unmixed with the carrier.

[0169] In one embodiment of any pill comprising a shell surrounding a methane inhibitor, the pill is adapted to release the methane inhibitor over a period of at least two months. In a preferred embodiment, the pill is adapted to release the substance over a period of at least six months, such as at least seven, eight, nine months, or at least ten months and longer.

[0170] In one embodiment of any of the pills described herein, the methane inhibitor is selected from haloform.

[0171] In one embodiment, compared to the release rate of a pill exposed to a temperature of 20°C, the release rate of the methane inhibitor from the pill through one or more openings in the shell is increased when the shell is exposed to the rumen of a live animal and / or a temperature between 28°C and the temperature present in the rumen of a live animal, preferably between 28°C and 42°C. In other words, when the pill is located inside the rumen of a live animal, there is an increased release of the methane inhibitor from the pill through said one or more openings. In one embodiment, when the shell is exposed to a temperature of at least 38°C, the release rate of the methane inhibitor from the pill through said one or more openings is increased, allowing the methane inhibitor to leave the pill more significantly through said one or more openings.

[0172] The increase in the release rate of the methane inhibitor from the pellet through one or more openings is affected by the diameter of the formed openings or pores, which, as described above, is, for example, at most 1 mm or less, in order to maintain controlled and sustained release.

[0173] A preferred embodiment of the first aspect of this disclosure relates to a pill of the first aspect that can be produced by performing the following steps: (i) A housing is provided, wherein the housing material comprises PLA and PBAT, preferably in a weight % ratio of about 90:10 PLA:PBAT, and preferably has a wall thickness of about 0.5 to 2 mm; (ii) Fill the shell with at least 20 g of steel balls; (iii) Mix ethyl cellulose with tribromomethane; (iv) The mixture obtained from (iii) is mixed with hydroxypropyl methylcellulose, wherein the weight ratio of the resulting mixture comprising tribromomethane, ethylcellulose and hydroxypropyl methylcellulose is preferably about 3:1:1; (v) to close it by rotating and welding the cover to the housing; and The shell is configured such that its permeability to the methane inhibitor increases when the shell is exposed to the rumen of a living organism; and / or wherein, when the shell is exposed to the rumen of a living organism, at least a portion of the shell is configured to form one or more openings that allow the methane inhibitor to exit the pellet through the one or more openings.

[0174] In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor in the animal, said pellet comprising: a core containing the methane inhibitor in microencapsulated particles, said microencapsulated particles being dispersed in a carrier; and optionally a dispersant and a shell covering at least a portion of the core.

[0175] In a further embodiment, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising: a core containing the methane inhibitor in microencapsulated particles, wherein said microencapsulated particles are dispersed in a carrier; and a dispersant and a shell covering at least a portion of the core.

[0176] Encapsulating methane inhibitors into microcapsule particles offers several benefits, which will become apparent below. Microencapsulation promotes uniform and sustained release of the methane inhibitor from the microcapsules contained within the pills, for example, because the microcapsules can be uniformly dispersed within the pills. Furthermore, encapsulation of the methane inhibitor prevents or reduces its direct contact with other pill components and protects these components from the potentially aggressive activity of the methane inhibitor.

[0177] As used herein, a "dispersant" is a substance added to a mixture or suspension of solid or even liquid particles in a carrier to improve particle separation and prevent their sedimentation or agglomeration. Suitable dispersants include ionic (e.g., anionic) and nonionic surfactants, polyethylene glycol and its derivatives, glycosides, and others, and those skilled in the art should know suitable compounds and polymers to be used as dispersants.

[0178] In one embodiment, microencapsulated particles are produced by microencapsulation in at least one encapsulating agent, preferably said encapsulating agent being selected from polymers, surfactants, emulsifiers, gelatin-sorbitol mixtures, and gelatin-starch syrups and mixtures thereof, more preferably said encapsulating agent being selected from PLA, PBSA, PBS, PHBV, PVA, PBAT, PCL, PDLA, gelatin-sorbitol mixtures, and gelatin-starch syrups. Due to the small size of the microcapsules, a wide range of polymer compounds can be used for microencapsulation, especially because at small microcapsule sizes, a certain degree of brittleness of the encapsulated compound is not detrimental to stability.

[0179] Microencapsulation methods are known in the art and will be apparent to those skilled in the art. For example, methods as described by Aida et al. (1989) can be used to microencapsulate methane inhibitors, such as haloform (Aida et al., “Practical Application of Microcapsulation for Toxicity Studies Using Bromodichloromethane as a Model Compound”, JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY, Vol. 8, No. 6, 1989). In one embodiment, the microencapsulated particles are produced by microencapsulation in a gelatin-starch syrup.

[0180] When the oil phase into which the substance to be encapsulated is mixed is used, the oil phase may suitably contain further stabilizers, such as emulsifiers, to facilitate particle formation. Thus, in one embodiment, the oil phase used in the formation of microencapsulated particles may contain at least one stabilizer, preferably at least one emulsifier, and more preferably, the oil phase contains lecithin.

[0181] In one embodiment, the microencapsulated particles can be microencapsulated using interfacial polymerization. During interfacial polymerization, polymerization occurs at the interface of two immiscible phases, such as two liquids, resulting in a polymer positioned at the interfacial layer. Suitable process modifications for interfacial polymerization used in capsule formation are known in the art, for example as described by Song et al. (2017) (Song et al., "Recent progress in interfacial polymerization." Materials Chemistry Frontiers 1.6 (2017): 1028-1040), and will be clear to those skilled in the art. In one embodiment, the microencapsulated particles can be microencapsulated without the use of interfacial polymerization.

[0182] Porous carrier materials can be suitable for dispersing microcapsules. For example, although bromoform, as an exemplary methane inhibitor, may not be directly compatible with hydrophilic carrier materials, microcapsules containing bromoform can still be dispersed in a hydrophilic carrier, provided that the bromoform, after being released from the microcapsule, can still leave the pellet, for example, through the porous structure of the carrier.

[0183] In a further aspect, this disclosure provides pellets for administration to ruminants, said pellets being configured to release a methane inhibitor into the animal, said pellets comprising: a carrier and microencapsulated particles, said microencapsulated particles containing the methane inhibitor, and said microencapsulated particles being dispersed in the carrier, preferably said carrier having a porous structure. Such porous structures may contain small or minute spaces or pores through which air and liquids, such as rumen fluid, can pass. Thus, microencapsulated particles dispersed in a carrier having a porous structure can come into contact with rumen fluid passing through the pores, facilitating the delivery of the methane inhibitor from the microencapsulated particles to the rumen fluid.

[0184] In one embodiment, the microencapsulated particles are microencapsulated using compounds selected from the following: hydrophilic materials, gelatin, zein, methylcellulose and poly(N-isopropylacrylamide) (PNIPAM) microgels, starch, cyclodextrin, and combinations of two or more of the above compounds.

[0185] For example, cyclodextrins can be used in particular due to their beneficial ability to contain hydrophobic compounds within an encapsulation core. For instance, poly(N-isopropylacrylamide) (PNIPAM) microgels are widely used in biomedical applications and comprise colloidal particles that form the microgels.

[0186] Microencapsulation of methane inhibitors allows the use of a variety of different methane inhibitors, with various pellet carrier components dispersed within the microcapsules, because there is no need for specific compatibility between the carrier and the methane inhibitor to load as much of the methane inhibitor as possible, since the methane inhibitor is not loaded directly into the carrier but rather as the contents of the microcapsule. In one embodiment, the carrier comprises compounds selected from: silica, cellulose and activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, polyalphahydroxy esters, hydroxyalkanoates and dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate, and ethylene-vinyl acetate.

[0187] As with the exemplary shell materials described herein, the microencapsulation compounds and carrier compounds used in the pills of this disclosure may also be biodegradable; however, this is not a necessary condition. More preferably, the ingredients used in the pills as described herein should not be harmful to animal health or the environment, especially when accumulated in larger quantities. Therefore, non-biodegradable pill components are also acceptable for the pills of this disclosure.

[0188] Furthermore, the microparticle production mechanism ensures that all particles have a substantially homogeneous structure; for example, they have approximately the same size and are surrounded by an encapsulant of approximately the same layer thickness. Therefore, the release rate from all microcapsules over a sustained period will be approximately the same. In one embodiment, the microencapsulated particles have an average diameter of 50 nm to 2 mm, preferably 1 to 1000 µm. The diameter of the microencapsulated particles can be determined, for example, by sieving analysis, such as using sieves of different standard aperture sizes. Furthermore, scanning electron microscopy can be applied to examine the particles, which further allows for the determination of particle shape and surface morphology.

[0189] In one embodiment, the pills are configured to release a methane inhibitor over a period of at least 6 months. In another embodiment, the pills are configured to release a methane inhibitor over a period of up to 6 months. In another embodiment, the pills are configured to release a methane inhibitor over a period of at least 4 months. In yet another embodiment, the pills are configured to release a methane inhibitor over a period of at least 2 months.

[0190] No shell In a further aspect, this disclosure provides a pellet for administration to ruminants, said pellet being configured to release a methane inhibitor into the animal, said pellet comprising a core containing the methane inhibitor and a carrier, and said pellet not comprising a shell.

[0191] In some embodiments, it is preferred that the pellets do not contain a shell, and the carrier is hydrophobic. In some embodiments, it is preferred that the pellets do not contain a shell, and the carrier is composed of one or more hydrophobic materials. In some embodiments, it is preferred that the pellets do not contain a shell, and the carrier has a melting point of at least 60°C, preferably at least 75°C.

[0192] In some embodiments, it is preferred that the pellet does not contain a shell, and the pellet does not contain carboxylate glass. In some embodiments, it is preferred that the pellet does not contain a shell, and the pellet does not contain glass.

[0193] In some embodiments, it is preferred that the pills do not contain a shell and that the pills do not contain bromoform-rich seaweed extract.

[0194] In some embodiments where the pellet does not include a shell, the pellet does not contain hydrophobic pyrolytic silica.

[0195] In some embodiments where the pills do not include a shell, the carrier comprises one or more materials selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene adipate succinate (PBSA), polylactic acid (PLA), polylactic acid, poly-d-lactic acid, poly-L-lactic acid, poly-D,L-lactic acid (PDLLA), polylactide-co-glycolic acid, lignin, polybutylene terephthalate (PBAT), styrene-acrylic acid copolymers (e.g., Jonathan). ®Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, waxes, castor wax, paraffin wax, silica, microcrystalline wax, methylcellulose, starch, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, carboxymethyl cellulose, soluplus, poly(acrylic acid), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(2-hydroxypropyl methacrylamide), poly(N,N-dimethylacrylamide) Poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), poly(2-(methacryloyloxy)ethylphosphocholine), poly(carboxybetaine methacrylamide), poly(ethylene glycol), poly(ethyleneimine), poly(sarcosine), poly(2-methyl-2-oxazoline), polyamino esters, polyesteramides, polyphosphate esters, poly(l-lysine), poly(l-proline), polyphosphazenes, dextran, sodium alginate, gelatin, agarose, carrageenan, gellan gum, xanthan gum, urea, sucrose, derivatives thereof, combinations thereof, and copolymers thereof. In some embodiments where the pills do not include a shell, the carrier is composed of one or more materials selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene adipate succinate (PBSA), polylactic acid (PLA), polylactic acid, poly-d-lactic acid, poly-L-lactic acid, poly-D,L-lactic acid (PDLLA), polylactide-co-glycolic acid, lignin, polybutylene terephthalate (PBAT), styrene-acrylic acid copolymers (e.g., Jonathan). ®Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, waxes, castor wax, paraffin wax, silica, microcrystalline wax, methylcellulose, starch, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, carboxymethyl cellulose, soluplus, poly(acrylic acid), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(2-hydroxypropyl methacrylamide), poly(N,N-dimethylacrylamide) Poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), poly(2-(methacryloyloxy)ethylphosphocholine), poly(carboxybetaine methacrylamide), poly(ethylene glycol), poly(ethyleneimine), poly(sarcosine), poly(2-methyl-2-oxazoline), polyurethane, polyesteramide, polyphosphate, poly(L-lysine), poly(L-proline), polyphosphazene, dextran, sodium alginate, gelatin, agarose, carrageenan, gellan gum, xanthan gum, urea, sucrose, derivatives thereof, combinations thereof, and copolymers thereof. In some embodiments where the pills do not include a shell, the carrier comprises PLA, PBSA, PBS, PHBV, PVA, PBAT, PCL, PDLA, an epoxide-based chain extender, magnesium silicate, cellulose material, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, wax, castor wax, paraffin, silica, and combinations thereof. In some embodiments where the pellet does not include a shell, the carrier comprises microcrystalline wax.

[0196] As used herein, a "carrier" is a compound that can be mixed with a methane inhibitor and / or other active agent without altering the chemical structure of the methane inhibitor and / or other active agent. Preferably, when used in the pills of this disclosure, the carrier delays the release of the methane inhibitor and / or other active agent from the pills.

[0197] For example, a carrier may contain at least one polar functional group.

[0198] The functional groups covalently linked to the support can be selected from esters, fatty acids, fatty alcohols, carbonyl groups, and fatty amines. Without being bound by theory, such modified supports can interact with the methane inhibitor via polar functional groups, possibly in part via hydrogen bonds.

[0199] A range of substances may be suitable for use as carriers in the pellets of this disclosure, and the following examples are not limiting. For example, the carrier may be selected from waxes, myristic acid, stearic acid, stearyl alcohol, cetyl alcohol, cetearyl alcohol, or combinations thereof. The carrier may be a waxy substance, for example, selected from beeswax, paraffin wax, PEG4000, carnauba wax, castor wax, candelilla wax, jojoba wax, or lanolin wax, or combinations thereof. The carrier may comprise a mixture of two or more components, such as a mixture of at least one relatively polar substance and a relatively nonpolar substance. Therefore, the overall polarity of the carrier can be adjusted to achieve the desired affinity for the methane inhibitor. This can be used to achieve the desired release rate of the methane inhibitor. For example, in some forms, the carrier may comprise a mixture of paraffin wax (a mixture of alkanes without polar functional groups) and castor wax and / or carnauba wax (which has a relatively high amount of polar functional groups).

[0200] In one embodiment, the pills may be adapted to exhibit a release rate of 0.02 g to 2 g / day into the rumen, preferably about 0.1 to 0.5 g bromoform / day. When the pills exhibit such a release rate for a methane inhibitor (e.g., haloform, such as bromoform), this can reduce methane production. The rate of release of the methane inhibitor into the rumen may increase over time, i.e., the release rate starts from zero when administered to the animal and increases to a maximum due to several factors. However, the foregoing should not be considered limiting, and other release rates are contemplated within the scope of this disclosure.

[0201] The carrier of the pellets described herein can have a melting point lower than the boiling point of the methane inhibitor. This can be useful because the carrier can melt and mix with the methane inhibitor, whereas the methane inhibitor is essentially lost due to evaporation. Furthermore, having a melting point above 37°C, and more preferably above 40°C, can aid the carrier in stabilizing the methane inhibitor in the rumen. This means that in the rumen (which can in some cases have temperatures as high as around 40°C), the pellet core does not melt. This can be beneficial, for example, for controlling the release of the methane inhibitor in pellets containing a shell, including the movement of the methane inhibitor by the material forming the shell.

[0202] Additionally, the carrier may comprise powdered activated carbon, zeolite or bentonite, elemental zinc or zinc oxide. Preferably, the carrier may contain a high-density material, such as metal (preferably steel) sheets. Other components may be used to achieve the desired density regarding the core and / or the pellet.

[0203] Those skilled in the art will understand that, depending on the application, other carriers and / or core components may be selected or used. It is conceivable to select a particular carrier to provide a desired release profile of the methane inhibitor, or alternatively, to provide the desired physical properties of the core material—such as density or volume. In one embodiment, a carrier contained in a pellet that also includes a shell may have a relatively higher affinity for the methane inhibitor than the shell itself. This can be achieved, for example, through the relative polarity of the substances forming the carrier and the shell, and by appropriately matching these materials to the methane inhibitor.

[0204] In one embodiment, the core comprises one or more materials selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene adipate succinate (PBSA), polylactic acid (PLA), polylactic acid, poly-d-lactic acid, poly-L-lactic acid, poly-D,L-lactic acid (PDLLA), polylactide-co-glycolic acid, lignin, polybutylene terephthalate adipate (PBAT), styrene-acrylic acid copolymers (e.g., Joncryl) ®Talc-filled poly(D-lactide) (TALCPDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, wax, castor wax, paraffin wax, silica, hydrophilic silica, microcrystalline wax, methylcellulose, starch, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, carboxymethyl cellulose, soluplus, poly(acrylic acid), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(2-hydroxypropyl methacrylamide), poly(N,N-dimethylacrylamide), poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), poly(2-(methacryloyloxy)ethyl phosphate choline), poly(carboxybetaine methacrylamide), poly(ethylene glycol), poly(ethylene glycol) Enimine), poly(sarcosine), poly(2-methyl-2-oxazoline), polyurethane, polyesteramide, polyphosphate, poly(L-lysine), poly(L-proline), polyphosphazene, dextran, sodium alginate, gelatin, agarose, carrageenan, gellan gum, xanthan gum, urea, sucrose, beeswax, polyethylene glycol (PEG), sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), carrageenan, guar gum, xanthan gum, sodium alginate, locust bean gum, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP / VA), polyacrylic acid and / or its copolymer variants, polyisobutylene, ethylene-vinyl acetate (EVA), functional waxes with melting points below about 120°C, their derivatives, combinations thereof, and their copolymers. In one embodiment, the core comprises one or more materials selected from the following: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene adipate succinate (PBSA), polylactic acid (PLA), polylactic acid, poly-d-lactic acid, poly-L-lactic acid, poly-D,L-lactic acid (PDLLA), polylactide-co-glycolic acid, lignin, polybutylene terephthalate adipate (PBAT), styrene-acrylic acid copolymer (e.g., Joncryl) ®Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, wax, castor wax, paraffin wax, silica, microcrystalline wax, methylcellulose, starch, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, carboxymethyl cellulose, soluplus, poly(acrylic acid), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(2-hydroxypropyl methacrylamide), poly(N,N-dimethylacrylamide), poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), poly(2-(methacryloyloxy)ethyl phosphate choline), poly(carboxybetaine methacrylamide), poly Ethylene glycol, poly(ethyleneimine), poly(sarcosine), poly(2-methyl-2-oxazoline), polyurethane, polyesteramide, polyphosphate, poly(L-lysine), poly(L-proline), polyphosphazene, dextran, sodium alginate, gelatin, agarose, carrageenan, gellan gum, xanthan gum, urea, sucrose, beeswax, polyethylene glycol (PEG), sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), carrageenan, guar gum, xanthan gum, sodium alginate, locust bean gum, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP / VA), polyacrylic acid and / or its copolymer variants, polyisobutylene, ethylene-vinyl acetate (EVA), functional waxes with melting points below about 120°C, their derivatives, combinations thereof, and copolymers thereof.

[0205] In one embodiment, the core comprises a compound selected from the following: polylactic acid (PLA), poly(butylene succinate-co-butylene adipate) (PBSA), polybutylene succinate (PBS), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), polybutylene terephthalate-co-butylene adipate (PBAT), polycaprolactone (PCL), poly(D,L-lactic acid) (PDLA), epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, wax, castor wax, paraffin, silica, and combinations thereof.

[0206] Those skilled in the art should be aware of further compounds, and in particular further polymers, preferably biodegradable polymers, which can be suitably used as core components of the pills of this embodiment.

[0207] In one embodiment, the pellets of this disclosure as described herein comprise hydrophobic pyrolytic silica. Preferably, such pyrolytic silica is amorphous, or consists of or comprises hydrophobic pyrolytic silica particles (HFSP). In a preferred embodiment, the average particle size of the hydrophobic pyrolytic silica is 5 nm to 15 nm. For example, the pellets may contain up to 10% by weight, up to 8% by weight, or up to 5% by weight of the hydrophobic pyrolytic silica. Preferably, the pellets contain up to 5% by weight of the hydrophobic pyrolytic silica, wherein the methane inhibitor is bromoform. In one embodiment, the hydrophobic pyrolytic silica is silica produced by contacting silica with a hydrophobic silane, and preferably the silica is contacted with a compound selected from: dimethyldichlorosilane (DDS), silane methacrylate, octylsilane, octamethylcyclotetrasiloxane, hexadecylsilane, octylsilane, silane methacrylate, polydimethylsiloxane, hexamethyldisilazane (HMDS), silicone oil, silicone oil plus aminosilane, HMDS plus aminosilane, organophosphates, HMDS (hexamethyldisilazane), and combinations of the above compounds.

[0208] In one embodiment, the pills as described in this disclosure comprise hydrophilic silica.

[0209] The core of the pellet, excluding the shell as described herein, may be selected to provide sufficient sustainability of the unshelled pellet in the rumen environment. In one embodiment, the pellet has a Shore D hardness of at least 20. In another embodiment, the pellet may have a Shore D hardness of at least 40. The Shore D hardness may be adjusted, for example, by selecting the core material or the manufacturing process of the core. It will be apparent to those skilled in the art that the pellet hardness can be selected such that the pellet can persist in the rumen environment and withstand physical and chemical effects. In such embodiments, it is believed that pellets (excluding the shell) with a Shore D hardness of less than 20 may result in excessively soft pellets, which may hinder administration of the pellet to animals or cause it to be otherwise damaged or prematurely degraded before the full amount of methane inhibitor is applied.

[0210] Methods for determining Shore D hardness are known in the art and will be clear to those skilled in the art. For example, this can be accomplished by using a hardness tester that determines Shore D hardness by penetrating the sample with its indenter foot under a defined spring force.

[0211] While the pills can function without a shell, the core of the shell-free pellet can be partially or completely coated. Therefore, in a further embodiment, the pellet may comprise a core containing a methane inhibitor (preferably a haloform such as bromoform); and a coating covering at least a portion or preferably the entire core; wherein the pellet is configured to release the methane inhibitor. A coating layer thickness of less than 2 mm is preferred to allow the methane inhibitor, such as haloform, to permeate outward from the core material at an optimal rate.

[0212] In one implementation, the pellet is in the form of a lump, pellet, tablet, or tablet. The size and shape of the lump, pellet, tablet, or tablet can be appropriately selected by a person skilled in the art to match the dosage to be administered, the expected duration of administration, and the size of the test animal. For example, a larger lump, pellet, tablet, or tablet size may be selected for large animals such as cattle, while a smaller lump, pellet, tablet, or tablet size may be appropriate for small ruminants such as sheep.

[0213] Pellets, in the form of lumps, pellets, tablets, or tablets, can be small pellets, for example, pellets with a length of about 1 to 5 cm. Animals may also be given multiple such pellets simultaneously or subsequently. For example, animals may be given multiple such pellets mixed with their feed, i.e., as feed additives.

[0214] In one embodiment, the pellet is formulated to dissolve in the rumen of a ruminant within a time period of less than 48 hours. In a preferred embodiment, the pellet is formulated to dissolve in the rumen of a ruminant within a time period of less than 12 hours, more preferably less than 6 hours, and even more preferably less than 2 hours. Those skilled in the art will know how to select the size of the pellet used in this disclosure and the possible coatings to obtain the aforementioned dissolution time periods.

[0215] Whether and how rapidly the pill dissolves in the rumen of an animal can be tested, for example, by in vitro testing, such as by placing the pill in a solution with conditions simulating the rumen environment and determining whether and when the pill dissolves, i.e., by partially or completely disintegrating over time. For in vitro testing, the pill can be placed, for example, in a container or vessel containing a known volume (e.g., 1 liter) of phosphate buffer (pH: 6.5, 0.02 M) at 40°C. Optionally, the solution containing the pill can be agitated to simulate rumen agitation.

[0216] Further surfactants In a further aspect, a pellet is provided for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: core; A shell covering at least a portion of the core; The core comprises at least one methane inhibitor and at least one further activator.

[0217] In some implementations, the shell surrounds the entire core.

[0218] In some embodiments, the further active agent is selected from methane inhibitors, hydrogen chelators, anti-inflammatory agents, analgesics, anthelmintics, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, growth promoters, lactation promoters, sustainability improvers, antibacterial agents, ketosis preventive agents, mineral / element / vitamin supplements, and combinations thereof. In some embodiments, the further active agent is selected from methane inhibitors, hydrogen chelators, nonsteroidal anti-inflammatory drugs (NSAIDs), anthelmintics, and ketosis preventive agents. In some embodiments, the further active ingredient is selected from methane inhibitors, antibiotics, and ketosis preventive agents.

[0219] In some embodiments, the further methane inhibitor is selected from the following: haloforms (e.g., haloforms other than bromoform if the first methane inhibitor is bromoform), monensin, phospholipids (e.g., lecithin), and fatty acids (e.g., lauric acid, myristic acid, and linoleic acid); plant extracts or derivatives including tannins, oils, and essential oils; fumarates (e.g., fumaric acid and sodium fumarate), acrylates (e.g., sodium acrylate), statins (e.g., atorvastatin and simvastatin), sulfur-containing salts (e.g., sulfates and sodium sulfate), nitrates (e.g., potassium nitrate, calcium nitrate, calcium ammonium nitrate, and sodium nitrate), malates, C 6-14 Fatty acids (preferably C) 6-12Fatty acids, such as aproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecanoic acid, lauric acid), unsaturated fatty acids (such as α-linolenic acid, stearatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, trans-linolenic acid, gamma-linolenic acid, di-homo-gamma-linolenic acid, arachidonic acid, docosahexaenoic acid, palmitoleic acid, isoleic acid, guaranaic acid, oleic acid, trans-oleic acid, gondoic acid, erucic acid, nervonic acid, and mideic acid), and lipids (such as fatty acyl groups, glycerides, glycerophospholipids, sphingolipids, sterols, isopentenol, and glycolipids). In some embodiments, the further methane inhibitor is selected from: haloforms (e.g., haloforms other than bromoform if the first methane inhibitor is bromoform), monensin, phospholipids (e.g., lecithin), and fatty acids (e.g., lauric acid, myristic acid, and linoleic acid). In some embodiments, the further methane inhibitor is not 3-nitrooxypropanol (3-NOP). In some embodiments, the hydrogen chelating agent is selected from the following: fumaric acid, sodium fumarate, phenolic compounds, phloroglucinol, gallic acid, resorcinol, catechol, hydroquinone, and pyroglucinol. In some embodiments, the anti-inflammatory agent / analgesic / NSAID is selected from nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, ketoprofen, carprofen, meloxicam, robecoxib, fenicoxib, malvacoxib, and flunixin), corticosteroids, α-2 antagonists, ketamine, and opioid receptor agonists (e.g., tramadol). In some embodiments, the anti-inflammatory agent / analgesic / NSAID is selected from meloxicam and ketoprofen. In some embodiments, the anthelmintic is selected from benzimidazoles (e.g., mebendazole, flubendiazole, fenbendazole, oxifendazole, oxifendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate-methyl, febantel, netopride, and trichlorobenzazole), imidazothiazides (e.g., levamisole), and tetrahydropyrimidines (e.g., pyrantel tartrate). The anthelmintics include tartarate (or dihydroxynaphthyl salt and octetrate), macrolides (e.g., ivermectin, abamectin, doramectin, epramectin, seramectin, milbemex, and moxicritin), salicylanilines (bromitin, cloisothiazolinone, cloisothiazolinone, cloisothiazolinone, hydroxychlorozadamide, and iodoisothiazolinone), substituted phenols (e.g., thiochlorophenol, diiodonitrophenol, hexachlorophenol, binitrochlorophenol, nitrochlorophenol, and nitroisothiazolinone nitrile), aromatic amides difenitol (e.g., difenitol), praziquantel, esetel, aminoacetonitrile derivatives, octadepsipeptides (e.g., emodepside), spironol (e.g., detrifend), piperazine, closulon, bufenamidin, and nitrothiocyanate. In some embodiments, the anthelmintic is albendazole. In some implementation schemes, the antibiotic is selected from meloxicam, ketoprofen, penicillin, tetracycline, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, and tylosin.In some embodiments, the antimicrobial agent is selected from the following: tetracyclines (e.g., chlortetracycline, oxytetracycline, doxycycline, tetracycline), chloramphenicol (e.g., florfenicol, thiamphenicol), penicillin and clavulanic acid (e.g., amoxicillin, ampicillin, cloxacillin, pennthamate, procaine benzylpenicillin, phenoxymethylpenicillin), cephalosporins (e.g., cefronine, cephalexin, cefepime, cefoperazone, cefquinoxime, and ceftiofur), lincomycin (e.g., lincomycin), sulfonamides, trimethoprim, macrolides (e.g., gamimycin, tilpirocin, tilmicosin, tylosin, and tivalmum), aminoglycosides (e.g., dihydrostreptomycin, apramycin sulfate, neomycin B). Framycetin, neomycin, paromomycin, streptomycin, and spectinomycin; fluoroquinolones (e.g., enrofloxacin, marbofloxacin, and dafloxacin); polymyxins (e.g., colistin); truncated pleuropneumoniae (e.g., tiamulin); and chloramphenicol. In some embodiments, the ketosis preventive agent is monensin. In some embodiments, the mineral / element / vitamin supplement is selected from copper, cobalt, selenium, manganese, magnesium, sodium and chloride, potassium, zinc, iodine, sulfur, chromium, vitamin A, vitamin E, vitamin D3, and combinations thereof. In some embodiments, the further active agent is selected from monensin, phloroglucinol, albendazole, ketoconazole, lecithin, and combinations thereof.

[0220] The inclusion of multiple methane inhibitors can be beneficial, especially if they act on one or more different pathways, enzymes, and organisms of methanogens in the rumen. The inclusion of further active agents that improve the side effects of methane inhibitors can be beneficial; for example, if the methane inhibitor can cause ketosis, including a ketosis preventative agent in the pill can be particularly useful. The inclusion of further active ingredients that improve the release profile of methane inhibitors can be beneficial. Generally, a longer release profile is preferred. For example, the inclusion of further active agents that result in a reduction in the need for administration, such as by administering at least two active agents in a single instance, is desirable.

[0221] In addition to methane, hydrogen can also be produced in the rumen. Although hydrogen is a weaker greenhouse gas than methane, it would be ideal to reduce at least a portion of hydrogen emissions as well. For this purpose, it is desirable to combine or remove at least a portion of the hydrogen produced in the rumen. It has been found that the degradation of phloroglucinol in the rumen promotes the chelation 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). Additionally, other compounds can be used to promote the growth of hydrogen-utilizing microorganisms in the rumen, and thus reduce the partial pressure of hydrogen in the rumen and the amount of this gas expelled by the animal through belching. Therefore, in one embodiment, the pills of this disclosure contain a hydrogen chelating agent, preferably selected from the group consisting of fumaric acid, sodium fumarate, phenolic compounds, phloroglucinol, gallic acid, resorcinol, catechol, hydroquinone, and pyroglucinol.

[0222] The pellets described herein, and particularly those containing hydrogen chelating compounds, may in some embodiments also be pellets, such as granules, tablets, or clumps. Such pellets can be administered in this manner, or by adding pellets, for example in tablet, granule, or clump form, to an animal's feed, whereby the pellets are consumed by the animal. For example, such pellets can be added in a quantity to the feed of consuming animals such that the amount of feed consumed contains about 20 g of hydrogen chelating compound per kg of dry matter, wherein said compound is contained in the mixed pellets. For example, an animal, such as a cow, consuming about 15 kg to about 25 kg of dry matter per day of feed may consume about 300-500 g of hydrogen chelating compound per day contained in pellets as described herein, for example as part of said granules, tablets, or clumps.

[0223] In one embodiment of any of the pills described herein, the methane inhibitor is selected from bromoform, monensin, nisin, lecithin, lauric acid, myristic acid, linoleic acid, and phospholipids, and combinations thereof. Preferably, the phospholipid comprises one or more polyunsaturated fatty acids, more preferably wherein the phospholipid comprises one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18PUFA), palmitic acid, stearic acid, and oleic acid. In one embodiment, the methane inhibitor is mixed with a carrier and contained in the pill.

[0224] It should be understood that the controlled release of the methane inhibitor through the shell of the pellet can be influenced by a variety of factors. For example, controlled release can be affected by the affinity of the methane inhibitor for a carrier contained in the pellet of this disclosure, wherein the carrier can play a role in the diffusion of the methane inhibitor through the shell of the pellet comprising the shell. It should be understood that more polar carriers or carriers containing a high degree of polar functional groups have a higher affinity for polar inhibitors than less polar carriers or carriers containing a lower degree of functional groups.

[0225] The relative affinity of the compounds forming the shell (in the pellet containing the shell) and the core compounds of the pellet described herein for the methane inhibitor can also affect the controlled release of the methane inhibitor from the core. For example, a shell having a relatively low affinity for the methane inhibitor compared to the affinity of the carrier for the methane inhibitor can be a factor in controlling the release rate of the methane inhibitor from the core.

[0226] In one embodiment, the methane inhibitor contained in the core of the pill is haloform, preferably selected from bromoform, chloroform, iodoform, and combinations thereof. In a particularly preferred form, the haloform may be bromoform (CHBr3). Bromoform is reactive and has a short half-life in animals (0.8 hours in rats and 1.2 hours in mice, US Dept of Health, 2003). It is a liquid at room temperature and has a density greater than water. Previous trials have confirmed that, after a 48-hour withdrawal period, no residues were found in meat and tissues from slaughtered bulls (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 there was no significant increase in milk levels (Roque et al. Inclusion of Asparagopsis armata in lactating dairycows' diet reduces enteric methane emission by over 50 percent; Journal of Cleaner Production 234 (2019) 132-138).

[0227] The use of bromoform offers several advantages. For example, it is highly effective for relatively small doses, allowing a device to deliver sufficient amounts of methane inhibitors over extended periods. Additionally, bromoform has a relatively high density, which increases the overall weight of the pill and allows it to remain in the rumen—that is, it sinks to the ventral portion of the rumen rather than floating, reducing reflux. In one embodiment, the pill may contain 10% to 80% (by weight), preferably 20% to 50% (by weight), of haloform, preferably bromoform.

[0228] Methane inhibitors can be synthetic or derived from naturally occurring sources, such as plants like algae. In one embodiment, the methane inhibitor is *Asparagopsis* or a derivative thereof. The methane inhibitor can be obtained, for example, by extraction from *Asparagopsis*. For instance, algal lysis can be achieved by disrupting the algal cell wall or membrane to separate the methane inhibitor from the remaining algal biomass. Algae such as *Asparagopsis* or parts and derivatives thereof can also be directly included in the pellet as a source of methane inhibitors such as bromoform.

[0229] In another embodiment, the methane inhibitor is monensin. Monensin is a carboxylic acid polyether ionoporter that can alter rumen fermentation kinetics by selectively inhibiting the growth of Gram-positive bacteria that produce a large proportion of acetate, lactate, and hydrogen in the rumen, which can promote methane formation. Advantageously, monensin is also known to prevent ketosis in ruminants. The administration of a ketosis preventative agent can be beneficial when a methane inhibitor, such as haloform, is applied. Another methane inhibitor that can be used in conjunction with or as an alternative to monensin is the bacteriocin lactisin. Both lactisin and monensin inhibit methanogenic bacteria primarily by increasing the permeability of their cell membranes.

[0230] Lecithin is known to play a role in rumen fermentation and digestion, and therefore can contribute to methane inhibition. Soy lecithin, for example, could be suitable in this context.

[0231] Certain saturated and unsaturated fatty acids can also be used because of their ability to influence rumen fermentation and the composition of the rumen microbiota, thus affecting the methanogenic potential in the rumen. In one embodiment, the methane inhibitor is selected from lauric acid, myristic acid, and linoleic acid.

[0232] Phospholipids are known to typically comprise glycerol molecules, the carbon atoms of which are linked to two fatty acids and a phosphate group, wherein the fatty acids and the phosphate group are attached to the glycerol molecule via ester bonds. In one embodiment, the pills described herein comprise a methane-inhibiting agent selected from the group consisting of phospholipids comprising glycerol molecules linked to a phosphate group and two fatty acids via ester bonds, preferably wherein the phospholipid comprises one or more polyunsaturated fatty acids, more preferably wherein the phospholipid comprises one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFA), palmitic acid, stearic acid, and oleic acid.

[0233] Given the potential use of phospholipids, phospholipids containing one or more fatty acids with methane-mitigating effects are preferred. For example, saturated fatty acids (SFAs) are known to inhibit rumen methanogenesis, including, for example, lauric acid (C12), myristic acid (C14), or palmitic acid (C16) and stearic acid (C18). Furthermore, polyunsaturated fatty acids (PUFAs), such as C12 and C18 PUFAs, are potent against methanogenesis. Not wishing to be limited by this hypothetical effect of these fatty acids, it is currently believed that the presence of these fatty acids in the rumen affects the gut microbiome of ruminants. In particular, such fatty acids are thought to act against rumen-colonizing methanogens, which otherwise eliminate H2 and CO2 produced by other fermenting members of the rumen microbiome and produce methane (CH4). In a preferred embodiment, the phospholipid is selected from lecithin, phosphatidylcholine, and derivatives of the above compounds.

[0234] In one embodiment, at least 50% by weight of the pills disclosed herein contains a methane inhibitor. In another embodiment, at least 60% by weight and at least 70% by weight of the pills disclosed herein contain a methane inhibitor.

[0235] It should be understood that the ratio of the methane inhibitor to the carrier or the total weight of the pellet can be selected to optimize the function of the pellet, such as to accommodate the desired release profile of the respective inhibitors. In one embodiment, haloform, preferably bromoform, is included in the core of the pellet of this disclosure in an amount of 10% to 80% by weight, and preferably 15% to 70% by weight. As used herein in the context of methane inhibitors (e.g., haloform or bromoform) contained in pellets as described herein, the term "% by weight" refers to the weight percentage of the methane inhibitor based on the total weight of the pellet. In conjunction with the above-described methane inhibitors, suitable carrier materials can be advantageously used in the pellets of this disclosure, having a high capacity to accommodate the methane inhibitor. Due to the volatility of some methane inhibitors, such as bromoform, and their reactivity with a variety of compounds, including organic compounds, it is inherently difficult to contain such methane inhibitory compounds in a stable manner and at high concentrations (to reduce the size of the formulation) in a delivery device such as a pellet. One example of a particularly suitable carrier material is pyrolytic silica, preferably hydrophobic pyrolytic silica, which can consist of particles of amorphous silica that can fuse into branched particles. For example, pyrolytic silica, which can be obtained as a powder, offers low bulk density and high surface area. Using pyrolytic silica as a carrier in pills stabilizes the formulation, improves stability, and increases the loading capacity of pharmaceutical formulations for methane-inhibiting compounds, particularly halogenated compounds such as bromoform. Therefore, when bromoform is used as a methane inhibitor, it can be suitable for pills containing pyrolytic silica.

[0236] For some methane inhibitors, it may be suitable to incorporate one or more openings in the shell of the pellet to facilitate the release of the methane inhibitor from the pellet. In a further aspect, this disclosure relates to pellets for administration to ruminants, said pellets being configured to release a methane inhibitor into the animal, said pellets comprising: a core containing a methane inhibitor and a carrier; and a shell containing said core; wherein said methane inhibitor is selected from monensin, lauric acid, myristic acid, and linoleic acid; and wherein said shell includes at least one opening exposing the core to the environment surrounding the pellet. Preferably, the shell material comprises PLA and PBAT.

[0237] This implementation can be particularly useful when other compounds besides haloform are used as methane suppressors.

[0238] In one embodiment, the pill according to any aspect or embodiment comprises a shell, wherein the shell contains a stabilizer. In a preferred embodiment, the stabilizer is selected from surfactants, plasticizers, phthalates, and triglycerides. In a more preferred embodiment, the stabilizer is selected from lecithin, nitriles, and triacetin.

[0239] Stabilizers can contribute to the stability of the shell by, for example, introducing more flexibility into the shell material or blend, or by reducing the brittleness or tendency of said shell material or blend to become brittle. In the case of shells containing blends of different materials, stabilizers can also be beneficial by promoting the mixing efficiency of the blend components, thereby producing a more homogeneous shell, which can therefore be more stable against forces acting through the digestive system of ruminants. For example, lecithin is known to be a suitable surfactant and stabilizer for use in food and pharmaceuticals. Those skilled in the art will recognize further compounds that can be suitably used as stabilizers, forming parts of the shell.

[0240] In one embodiment, the core contained in the pill includes at least one filler. This embodiment relates to any pill described herein. The use of a filler can provide additional internal material to the pill, providing sufficient stability from within the pill to counteract forces acting on the pill from the outside. Additionally, the filler can provide additional filling material to ensure uniform distribution of the methane-inhibiting agent (within the pill's interior) without promoting any significant undesirable interactions, and simultaneously be well tolerated by ruminants.

[0241] In one preferred embodiment, at least one filler is a stabilizer. In another preferred embodiment, at least one filler is selected from gelatin, milk, milk derivatives, infant formula, milk powder, triglycerides, medium-chain triglycerides and their oils, ethanol, lecithin, tween, xanthan gum, cellulose derivatives, alkyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), zein, and surfactants.

[0242] In another preferred embodiment, the core of any pill described herein comprises gelatin. In yet another preferred embodiment, the core of any pill described herein comprises milk, milk derivatives, infant formula, or milk powder. In yet another preferred embodiment, the core of any pill described herein comprises milk powder. In yet another preferred embodiment, the core of any pill described herein comprises at least one stable protein and / or filling protein. In yet another preferred embodiment, the core of any pill described herein comprises casein and / or zein. In yet another preferred embodiment, the core of any pill described herein comprises a cellulose derivative, preferably alkyl cellulose, ethyl cellulose, and / or hydroxypropyl methylcellulose (HPMC). In yet another preferred embodiment, the core of any pill described herein comprises a cellulose derivative, preferably alkyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), combinations thereof, and copolymers thereof.

[0243] In one embodiment, the core of the pills according to any aspect or embodiment comprises at least one PEG glyceride consisting of monoglycerides, diglycerides and triglycerides, as well as monoesters and diesters of PEG, and preferably comprises PEG esters of palmitic acid, stearic acid and / or lauric acid.

[0244] In one embodiment, the core of the pills contained according to any aspect or embodiment described herein comprises at least one surfactant, preferably a nonionic, water-dispersible surfactant. In a preferred embodiment, the surfactant comprises a mixture of glycerides and fatty acid esters, preferably a mixture of monoglycerides, diglycerides, triglycerides, and PEG.

[0245] In another embodiment, the surfactant comprises polyoxyethylene glycerol ester, more preferably oleoyl polyoxyethylene-6 glycerol ester. In one embodiment, the surfactant comprises monoglycerides, diglycerides, and triglycerides of glycerol, as well as PEG-6 (MW 300) and monoesters and diesters of oleic acid (C18:1).

[0246] In another embodiment, the surfactant comprises monoesters and diesters of octanoic acid (C8) and decanoic acid (C10).

[0247] In another embodiment, the surfactant comprises monoglycerides, diglycerides, and triglycerides, as well as PEG-6 (MW 300) monoesters and diesters of lauric acid (C12) and stearic acid (C18).

[0248] In another embodiment, the surfactant comprises monoglycerides, diglycerides, and triglycerides of glycerol, as well as PEG-32 (MW 1500) monoglycerides and diesters of lauric acid (C12).

[0249] In one embodiment, the core of the pellet comprises zein. Zein is a composition comprising at least one protein and gliadin, which is typically found, for example, in protein bodies in the endosperm of corn kernels. Due to the amphiphilic nature of proteins, zein can also be used to form protective coatings. The product can be encapsulated based on the binding or self-assembly capabilities of zein when the solution polarity changes towards a more hydrophilic environment. Therefore, zein can be used not only as a core component of the pellets of this disclosure, but also suitably as a coating application for pellets.

[0250] The pellets of this disclosure can also be used as a delivery platform, for example, to allow sustained local release of other methane-inhibiting molecules and non-methane-generating molecules. In one embodiment, in addition to or instead of the methane-inhibiting agent, the pellets of this disclosure comprise an active agent, wherein said active agent is not a methane-inhibiting agent. In one embodiment, in addition to the methane-inhibiting agent, the pellets of this disclosure further comprise an active agent, wherein said active agent is not a methane-inhibiting agent. In one embodiment, instead of the methane-inhibiting agent, the pellets of this disclosure comprise an active agent, wherein said active agent is not a methane-inhibiting agent.

[0251] In one embodiment, in addition to or instead of the methane inhibitor, the pills of this disclosure comprise an active agent, wherein the active agent is not a methane inhibitor, and wherein the release of the active agent is local and / or sustained in the ruminant intestinal system. Preferably, the release of the active agent is local and sustained in the ruminant intestinal system.

[0252] In one embodiment, the active agent, which is not a methane inhibitor, is selected from anti-inflammatory agents, analgesics, and anthelmintics. However, the active agent can be any health and / or growth promoting and / or sustainability improving agent or combination of such agents known in the art. For example, anti-inflammatory agents and / or analgesics can be selected from nonsteroidal anti-inflammatory drugs (NSAIDs). In one embodiment, the active agent is selected from meloxicam and ketoprofen. For example, an anthelmintic can be albendazole. Thus, in one embodiment, the active agent is albendazole. Further active agents can also be antibiotics, preferably selected from penicillin, tetracycline, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, and tylosin. Therefore, in a preferred embodiment, the active agent is selected from anti-inflammatory agents, analgesics, antibiotics, and anthelmintics. In a more preferred embodiment, the active agent is selected from meloxicam, ketoprofen, penicillin, tetracycline, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, tylosin, and albendazole. Other compounds conventionally and commonly administered to ruminants, as well as substances having one or more beneficial effects on ruminants, are known in the art, and those skilled in the art should know how to properly administer such substances in the pills disclosed herein. Such compounds also include, but are not limited to, growth promoters, lactation promoters, and sustainability improvers. Sustainability improvers are agents that improve the sustainability of ruminant husbandry. Such improvement can be a reduction in pollution, such as a reduction in greenhouse gas emissions.

[0253] In one embodiment, the core of the pill described herein may comprise one or more metal particles (preferably steel particles), wherein the particles are preferably spherical. For example, the total number of all particles in each pill may have a mass of at least 100 g. Incorporating metal particles into the pill increases its weight and allows it to be inserted into the rumen of an animal for more efficient retention, preventing reflux of the pill after administration.

[0254] The pills disclosed herein can be used for the treatment of animals. In one aspect, this disclosure relates to the pills of this disclosure for the treatment of ruminants. In a preferred embodiment, this disclosure relates to the pills of this disclosure for the treatment of cattle or sheep.

[0255] In another aspect, this disclosure relates to the pills of this disclosure for reducing methane emissions in ruminants. In a preferred embodiment, the ruminant is a cow or a sheep. In a further embodiment, this disclosure provides a method for administering a methane inhibitor to an animal, the method comprising the step of administering the pills of this disclosure to the animal. In a further embodiment, this disclosure provides a method for reducing methane production in the rumen of a ruminant, the method comprising the step of administering the pills of this disclosure to the ruminant.

[0256] In a preferred embodiment, the pill can be configured for administration to ruminants, which may include beef or dairy cattle, sheep, goats, buffalo, deer, elk, giraffes, or camels.

[0257] In one embodiment, the pellet may be adapted to reduce the release of one or more greenhouse gases (“GHG”) from ruminants.

[0258] In one implementation, the ruminant could also be a goat or a deer.

[0259] A reduction in methane emissions and / or greenhouse gas emissions from ruminants is considered a reduction compared to ruminants not treated with the pills or methane inhibitors of this disclosure. In one embodiment, methane emissions in ruminants can be reduced by at least 30%, preferably at least 50%, more preferably at least 70%, 80%, and most preferably at least 90%. In another embodiment, methane emissions in ruminants can be reduced by at least 99%. In a preferred embodiment, the pills are administered orally. In another preferred embodiment, the pills are configured to remain in the rumen after administration.

[0260] The pill is delivered orally into the rumen of the ruminant to be treated, entering the rumen via the esophagus. In the rumen, gastric juices (and other substances such as plant fibers) can act to erode or dissolve the core, releasing methane inhibitors or pill contents over time. For example, methane inhibitors can diffuse or seep from the pill into the rumen.

[0261] If the pill contains a shell, the shell is substantially intact for the duration of the treatment period. In cases where the pill shell includes one or more openings, these openings allow gastric juices and, possibly fibrous material, to come into contact with the core.

[0262] The core and shell can be designed to facilitate the release of the methane inhibitor during the treatment period in the animal. The pellet can be adapted to release the methane inhibitor over a period of at least three months, preferably at least six months, more preferably 12 months, and potentially up to two years. Preferably, the release rate of the methane inhibitor can be calculated based on the weight of the ruminant being treated and the type of inhibitor used. Therefore, it should be understood that the required release rate can vary from animal to animal. Typically, the required release rate can be calculated based on the amount of inhibitor per animal's weight. Alternatively, the required release rate can also be calculated based on the amount of feed consumed by the animal. A particularly preferred release rate for bromoform, as an exemplary methane inhibitor, includes about 0.1 – about 0.5 g / day, and more preferably about 0.2 g / day.

[0263] Ruminants can also be treated with multiple pills according to this disclosure to achieve a preferred dose of the methane inhibitor. This allows for the manufacture of pills with a specific concentration and total load of the methane inhibitor. Multiple such pills can be administered to animals simultaneously or sequentially. This allows for the delivery of the desired dose to the animal. This can be particularly advantageous to allow the pills to be used in animals requiring different doses of inhibitor, such as large or small animals, or to compensate for natural growth over time.

[0264] Ruminants can also be treated with multiple pills according to this disclosure to achieve preferred combinations of substances, wherein different substances can be administered simultaneously. For example, the pill combination may be suitable in which one pill provides a methane inhibitor and further pills provide different active agents, such as antibiotics or other compounds that improve the health of ruminants.

[0265] Pellet formulations can be used to deliver a dose of inhibitor directly into the rumen of an animal. For example, bromoform can be used to effectively reduce or eliminate the rate of methane release during digestion. This reduces greenhouse gas emissions, especially methane, through animals, and thus reduces the environmental impact of agriculture.

[0266] Those skilled in the art will understand that, depending on the dosage of the inhibitor to be delivered to the ruminant, the size, thickness, and / or dimensions of the provided pellet, including the core and shell, can be adjusted without departing from the spirit and scope of this disclosure. For example, smaller pellets may be suitable for small ruminants such as sheep or goats, while larger pellets may be suitable for large ruminants such as cattle. Preferably, the pellets have a weight of less than 180 g. For example, two pellets may be administered to each cow, each having a dimension of about 75 mm in length and about 34 mm in width, thereby each pellet may have a weight of about 80 g.

[0267] Furthermore, reducing methane production can provide benefits to animal production, and pellets can improve feed conversion in ruminants for animal production. For example, by reducing methane production during digestion, this is thought to lead to more efficient utilization of ingested feed and improved growth and weight gain, or other production such as milk or meat production. Therefore, farmers may be able to improve efficiency by ensuring greater productivity for a given feed volume or by correspondingly reducing feed intake. Additionally, the composition of the core and the synergistic effects arising from the combination of carrier and inhibitor may allow for the provision of slow-release, long-term delivery devices to improve animal productivity and / or reduce greenhouse gas emissions.

[0268] In a further aspect, this disclosure relates to a method of manufacturing a pellet as defined herein. The manufacturing method may include the steps of: (1) providing a shell, preferably made of a polymeric material, more preferably a biodegradable polymer, or preferably a material as disclosed herein; and (2) filling the shell with a core, preferably comprising a material as disclosed herein; wherein the pellet comprises: a core, wherein the core comprises a methane inhibitor that inhibits methane production in the rumen of a ruminant, and a carrier and a shell containing the core. Providing the shell in step (1) may be performed, for example and not limited to, by 3D printing or injection molding. Filling the shell with the core in step (2) may be performed, for example and not limited to, by melting or crushing and mixing the core material, and filling the shell with the core material component or mixture while the components are flowable or at least flexible or plastic.

[0269] Preferably, the method of manufacturing the pellet may further include step (3) sealing the shell containing the core with a cap. The shell may be sealed by friction welding the cap to the shell. This is advantageous compared to screw caps or glued caps, which can become loose or be pushed out of the shell when the pellet is exposed to chemical and mechanical stresses and turbulence in the rumen of an animal.

[0270] The provision of the housing in step (1) can be achieved using any technique known to those skilled in the art. For example, a suitable material can be extruded into the desired shape defining the cavity. Alternatively, additive manufacturing processes can also be used to construct the housing shape defining the cavity, or molding processes such as injection molding, 3D printing, or hot melt extrusion can be used.

[0271] The core filling step (2) may include, for example, one or more of the following steps: melting and / or crushing the carrier material to provide a melted and / or crushed carrier material, adding a methane inhibitor to the melted and / or crushed carrier material, mixing the methane inhibitor with the melted and / or crushed carrier material to produce a substantially homogeneous mixture, and filling the substantially homogeneous mixture into the prepared shell.

[0272] For pellets without a shell, step (1) of forming the shell can be omitted, and step (2) can be a core-forming step, which may include, for example, one or more of the following steps: melting and / or crushing a carrier material to provide a melted and / or crushed carrier material, adding a methane inhibitor to the melted and / or crushed carrier material, mixing the methane inhibitor with the melted and / or crushed carrier material to produce a substantially homogeneous mixture, and forming the substantially homogeneous mixture into a desired shape. It should be understood that the step of forming the substantially homogeneous mixture into a desired shape may involve providing the mixture to a mold.

[0273] It should be understood that the essentially homogeneous mixture contains a methane inhibitor at a concentration sufficient to achieve the desired release profile of the methane inhibitor when the device is applied to a ruminant. The concentration can vary depending on the type of ruminant to be treated, the shape and size of the device, or the desired release profile to be achieved.

[0274] The method also includes a step that allows the substantially homogeneous mixture to cool, especially if it has been previously heated and melted. As it cools, the carrier material hardens and takes on a shape according to the mold or shell into which it has been provided.

[0275] This disclosure also provides pills that can be obtained or acquired by performing the method of manufacturing pills disclosed herein.

[0276] In another aspect, this disclosure relates to a methane inhibitor for reducing methane emissions from ruminants, wherein the methane inhibitor is selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid, and phospholipids, preferably wherein the phospholipid comprises one or more polyunsaturated fatty acids, more preferably wherein the phospholipid comprises one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFA), palmitic acid, stearic acid, and oleic acid. In a preferred embodiment, the ruminant is a cow.

[0277] In another aspect, this disclosure relates to a method of treating ruminants to reduce methane emissions from said ruminants, comprising administering to said animal a methane inhibitor selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid, and phospholipids, preferably wherein said phospholipids comprise one or more polyunsaturated fatty acids, more preferably wherein said phospholipids comprise one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFA), palmitic acid, stearic acid, and oleic acid. In a preferred embodiment, the ruminant is a cow. The inventors believe that the techniques described herein can provide numerous benefits. These benefits may be the result of unique synergies between different aspects and embodiments of the techniques. The techniques of this disclosure are therefore described based on the inventors’ current understanding of such possible interactions. It should be understood that any aspect or embodiment described herein, or the interaction of two or more aspects / implementations, may form different disclosures.

[0278] Modified release formulation Modified release formulations are those that alter the timing, rate, or site of release of the active ingredient to achieve clinical outcomes that cannot be achieved with unmodified release formulations.

[0279] Modified release takes the form of temperature-dependent release, where the release of the active ingredient changes in response to temperature variations. This can result in release only at suitable temperatures, potentially controlling the site of release. Temperature-dependent release offers advantages in both application and storage, potentially allowing storage at more demanding temperatures, which is particularly beneficial in the more severe storage conditions often encountered when handling livestock.

[0280] Another form of release modification is sustained, delayed, or extended release, which slows the release of the active ingredient, allowing a dosage form to deliver the active ingredient over a longer period. This has the advantage of reducing dosing frequency. In humans, reduced dosing frequency is typically around several hours, as once-daily oral administration is generally considered acceptable. The benefits of extended-release dosage forms are even more pronounced in the treatment of livestock. Once-daily or even weekly dosing may be impractical for many animals, especially those requiring herding and gathering for treatment. Treatment may only become feasible with weekly, bi-weekly, monthly, six-weekly, eight-weekly, two-monthly, or ten-weekly dosing. This is difficult to achieve with extended-release dosage forms.

[0281] The extended release can be primarily due to the core. The extended release can also be primarily due to the shell. The amount of extension can vary greatly, from a day to several months or a year, depending on the composition of the core and shell.

[0282] Extended release can be a release profile in which, 24 hours after reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate. Extended release can be a release profile in which, one week after reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate. Extended release can be a release profile in which, one month after reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate. Extended release can be a release profile in which, six months after reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate.

[0283] Extended release can be a release profile in which, 24 hours before reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate. Extended release can be a release profile in which, one week before reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate. Extended release can be a release profile in which, one month before reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate. Extended release can be a release profile in which, six months before reaching the maximum rate, the pills release the methane inhibitor at at least 20%, at least 30%, at least 40%, and at least 50% of the maximum rate.

[0284] Matrix systems, extended-release coatings, and other systems, such as extended-release particles within a matrix, can be used to prolong the release of the active ingredient. The shell of this disclosure acts as an extended-release coating. The core of this disclosure also has extended-release properties. In a preferred embodiment, the core of this disclosure is a matrix system in which the active ingredient (as particles or particulate matter, optionally accompanied by a non-extended-release carrier) is uniformly mixed into the core excipient. Alternatives considered by this disclosure include extended-release particles containing an active ingredient dispersed within a binder, wherein the binder may or may not have additional extended-release properties. Preferably, the active ingredient is excipient-free and is directly and uniformly dispersed within the other components of the core.

[0285] In a preferred embodiment, the matrix system in the core is hydrophobic (or insoluble in water with minimal swelling). Optionally, the core is a blend of hydrophobic and hydrophilic components; however, the release characteristics are largely controlled by the hydrophobic component.

[0286] In a preferred embodiment, the shell is hydrophobic. In some embodiments, the core is hydrophobic. Optionally, both the core and the shell are hydrophobic.

[0287] In any embodiment of any aspect of this disclosure, the core comprises a methane inhibitor and a support, and the methane inhibitor is optionally dispersed in the support.

[0288] Zero-level release Zero-order release of the active ingredient, which is the consistent release of the active ingredient over the duration of release, is the objective of the preferred embodiments of the dosage forms disclosed herein.

[0289] Active ingredients In some embodiments, the methane suppressant is haloform, including mixed haloforms. Preferably, the haloform is selected from chloroform, bromoform, iodoform, or combinations thereof; more preferably, bromoform.

[0290] Optionally, the active ingredient or haloform is at the core of approximately 20% to approximately 90%, approximately 30% to approximately 80%, approximately 40% to approximately 80%, approximately 50% to approximately 70%, or approximately 60% w / w.

[0291] hydrophobic In some embodiments, one or more of the housing and the core are hydrophobic. Those skilled in the art will understand that hydrophobicity can be measured by analyzing the water contact angle using a goniometer. In some embodiments, the difference in static water contact angle between one or more of the housing and the core is at least about 60°, at least about 50°, at least about 40°, at least about 30°, at least about 20°, at least about 15°, at least about 10°, or at least about 5° at 20°C.

[0292] Ruminants In some embodiments, the pills are intended for or suitable for administration to the rumen of ruminants. In some embodiments, the ruminants are cattle, sheep, goats, or deer. In some embodiments, the ruminants are cattle. In some embodiments, the ruminants are sheep.

[0293] pill In a broad sense, a pellet is a dosage form of a substance, such as a drug, supplement, or metabolic regulator, having a discrete dosage. In the context of this disclosure, a pellet can be solid, semi-solid, or a combination thereof. A pellet can also be a combination of a liquid and a solid, semi-solid, or a combination thereof, provided that the liquid is encapsulated within the solid, semi-solid, or combination thereof. A semi-solid can be a blend of liquid and solid or semi-solid substances. Pellets are typically administered orally to the gastrointestinal tract of animals, preferably the rumen of ruminants. Pellets are swallowed, but can also be administered using a pellet gun or balling gun, several of which are commercially available. The shape of a pellet can vary, but round, oval, or capsule shapes are common. The size of a pellet can vary depending on its suitability for the animal to which it is administered. A pellet can be hard or have a softer, more malleable consistency. A pellet can be in the form of a bullet, capsule, or tablet, provided that the bullet, capsule, or tablet can be administered using a pellet gun or balling gun, in contrast to smaller bullets, capsules, or tablets sized to be included in the animal's feed.

[0294] In such Figure 22 In a preferred embodiment depicted herein, the pill (100) of this disclosure includes a shell (101) that encapsulates or substantially encapsulates a core (102). The shell further includes an enclosed region (103). The shell thickness is optionally about 0.5 to about 2.0 mm, about 0.8 to about 2.0 mm, about 0.8 to about 1.8 mm, about 0.9 to about 1.8 mm, about 1.0 to about 1.8 mm, about 0.8 to about 1.5 mm, about 0.9 to about 1.5 mm, about 1.0 to about 1.5 mm, or about 1.2 mm. The shell is optionally about 5 to about 15%, about 6 to about 12%, about 6 to about 10%, about 7 to about 15%, about 7 to about 12%, about 7 to about 10%, or about 8% w / w of the pill. The core is optionally about 20 to about 55%, about 25 to about 50%, about 30 to about 45%, about 35 to about 40% w / w, or about 37% w / w of the pill. The pill further comprises a densifying agent (104) that separates the enclosed area of ​​the shell from the core. The densifying agent is optionally about 30 to about 75%, about 40 to about 70%, about 45 to about 65%, about 50 to about 60%, or about 55% w / w of the pill.

[0295] In some implementations, the pill contains a therapeutically effective amount of a methane inhibitor, as well as: • Approximately 5% to approximately 15% (w / w) of the shell; • A core of approximately 20 to approximately 55 (w / w); and • Densifying agent of approximately 30 to approximately 75 (w / w).

[0296] Release and duration In some embodiments, the pills of this disclosure contain the methane inhibitor bromoform and are adapted to achieve a maximum release rate of about 0.1–about 0.5 g / day, more preferably about 0.2 g / day. Such a release rate can provide sustained release of haloforms, such as bromoform. Pills having such a release rate are suitable, for example, for cattle and sheep.

[0297] In some embodiments, the pills may be adapted to exhibit a release rate of 0.02 g to 2 g / day into the rumen, preferably about 0.1 to 0.5 g bromoform / day. When the pills exhibit such a release rate for a methane inhibitor (e.g., haloform, such as bromoform), this can reduce methane production. The rate of release of the methane inhibitor into the rumen may increase over time, i.e., the release rate starts from zero when administered to the animal and increases to a maximum due to several factors. However, the foregoing should not be considered limiting, and other release rates are contemplated within the scope of this disclosure.

[0298] In some embodiments, the pills are formulated for at least about 8 weeks after halogenated formaldehyde is administered to the rumen of ruminants. In some embodiments, the pills are formulated for at least about 20 weeks after halogenated formaldehyde is administered to the rumen of ruminants.

[0299] Retention in the rumen By formulating pills with a density greater than that of the fluid in the rumen, the length of time the pills remain in the rumen can be increased. One way to achieve this is by including a densifying agent in the pills. In some embodiments, the pills further contain a densifying agent. A densifying agent is a component that increases the density of the pills. The densifying agent can be a metal powder such as ZnO, metal spheres such as steel balls, or other dense materials suitable for inclusion in the pills. Preferably, the densifying agent increases the density of the pills to greater than 1.0 g / cm³. 3 The density. In some embodiments, the thickener is a thickener matrix comprising a thickener and at least one veterinary-acceptable excipient. Optionally, the thickener matrix comprises a matrix material that is more hydrophobic than at least one carrier. Optionally, the thickener matrix comprises wax. Optionally, the thickener is dispersed in the core, within the shell, or on the shell, or separate from the core and shell (preferably within the shell). Optionally, the thickener is about 30 to about 75% w / w for pellets, preferably about 45 to about 65%, or about 55% w / w for pellets.

[0300] An alternative method to increase the duration of time the pill remains in the rumen is to ensure that the pill is too large to pass through the rumen while in the rumen. Such devices are known to those skilled in the art and often involve components that are close to the pill during administration and expand after administration to increase the size of the pill. These may include attaching further components to the pill, which increases the cross-sectional area of ​​the pill at at least one point to at least 4 cm².2 At least 5 cm 2 At least 6 cm 2 The center of the cross-section does not need to be solid.

[0301] diffusion test Diffusion testing is a common technique used to evaluate the properties of dosage forms in vitro. Diffusion test results are often correlated with the in vivo performance of the dosage form and are used in quality control testing to ensure consistent manufacturing of the dosage form.

[0302] Halogenated tribromoform diffuses from the pills of this disclosure into the surrounding solution and is tested over a period of several months in 1 L of 0.02 M phosphate buffer at pH 6.5 (simulated rumen pH) and 39°C (simulated rumen temperature) without agitation. Samples of the buffer are obtained daily, and tribromoform is analyzed by GC-FID.

[0303] Dispersion testing is similar to dissolution testing. Dissolution testing involves placing the dosage form in a liquid at a specific pH and temperature, accompanied by specific agitation, and determining the time it takes for the active ingredient to be released from the dosage form. Standardized dissolution tests exist in the United States Pharmacopeia (USP) and the European Pharmacopeia (EU). See, for example, a section in the USP. <711> However, these dissolution tests are not suitable for measuring the diffusion of the dosage forms disclosed herein, at least due to the extension of the size and length of the pills.

[0304] Application method In another aspect, this disclosure provides a method for applying a methane inhibitor to a ruminant, the method comprising administering a pellet according to this disclosure into the rumen of the ruminant.

[0305] In another aspect, this disclosure provides a method for reducing methane production in the rumen of a ruminant, the method comprising administering a pill according to this disclosure into the rumen of the ruminant.

[0306] In embodiments of the application method disclosed herein, the pills are administered to the rumen of ruminants for at least approximately 8 weeks after co-administration of haloform. Optionally, the pills are administered to the rumen of ruminants for at least approximately 20 weeks after co-administration of haloform.

[0307] In any embodiment of the present invention, the animal is preferably a ruminant, and the pill is preferably used to release the methane inhibitor into the rumen of the animal.

[0308] In an embodiment of the application method disclosed herein, after the pill is administered, the pill sinks below the liquid surface or to the bottom of the rumen.

[0309] In embodiments of the administration method disclosed herein, the pills are retained in the rumen for at least about 8 weeks or at least about 20 weeks after administration.

[0310] In embodiments of the administration method disclosed herein, after the release of the active ingredient, the pill is degraded in the rumen. Optionally, degradation continues until the residue of the pill is of a size that can be safely passed through a ruminant.

[0311] In embodiments of the administration method of this disclosure, following administration of the pills, methane excreted by ruminants is reduced by approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, or approximately 80% in g / day. Optionally, this reduction occurs approximately 5 days, approximately 10 days, or approximately 15 days after pill administration. Optionally, the reduction persists for approximately 4 weeks, approximately 6 weeks, approximately 8 weeks, approximately 12 weeks, approximately 16 weeks, or approximately 20 weeks. Optionally, within approximately 4 weeks, approximately 6 weeks, approximately 8 weeks, approximately 12 weeks, approximately 16 weeks, or approximately 20 weeks, the reduction persists at approximately 40% to approximately 90%, approximately 40% to approximately 70%, approximately 40% to approximately 50%, approximately 60% to approximately 90%, or approximately 70% to approximately 90% in g / day.

[0312] In embodiments of the administration method disclosed herein, a second pellet is administered to the ruminant at approximately 8 to 20 weeks, approximately 12 to 20 weeks, approximately 8 to 16 weeks, or approximately 12 to 16 weeks after the initial administration. Optionally, further pellet administrations occur periodically at these intervals. Optionally, this dosage regimen results in an ongoing methane reduction of approximately 40 to 90%, approximately 40 to 70%, approximately 40 to 50%, approximately 60 to 90%, or approximately 70 to 90% per g / day.

[0313] In some embodiments of the methods disclosed herein, the pills of this disclosure contain the methane inhibitor bromoform and achieve a maximum release rate of about 0.1 to about 0.5 g / day, and more preferably about 0.2 g / day.

[0314] In some embodiments, the pills exhibit a release rate of 0.02 g to 2 g / day into the rumen, preferably about 0.1 to 0.5 g bromoform / day. The foregoing should not be considered limiting, and other release rates are contemplated within the scope of this disclosure.

[0315] In some embodiments, the pills exhibit near-zero order release kinetics. In some embodiments, the pills exhibit near-zero order release kinetics at 2 months, 4 months, and / or 6 months after administration.

[0316] Production methods In another aspect, this disclosure provides a method for preparing pills, the method comprising: Choose the core and shell Insert the core into the casing. Optionally, the shell is closed to surround or substantially surround the core within the shell; The core contains a methane suppressor. Optionally, the core and shell are prepared prior to their selection.

[0317] In some embodiments, the shell is configured such that its permeability to the methane inhibitor is increased when the shell is exposed to the rumen of a living organism. Optionally, the pellet further includes a densifying agent dispersed in the core, within the shell, on the shell, or separately from the core and shell (preferably within the shell).

[0318] In another aspect, this disclosure provides a method for preparing pills, wherein the pills do not contain a shell, the method comprising: The core is formed by a methane inhibitor and a support.

[0319] Optionally, core formation includes the use of a mold. Optionally, core formation includes the use of a shell and subsequent removal of the shell.

[0320] These methods can be used to prepare pill dosage forms according to this disclosure.

[0321] In some embodiments, core insertion into the housing occurs before the densifier is inserted into the housing. In some embodiments, densifier insertion into the housing occurs before the closed area of ​​the housing is sealed.

[0322] In some embodiments, closing the enclosure area includes sealing two segments of the housing together. Alternatively, closure includes sealing the cap. For example, closing the enclosure area includes attaching a cap to the enclosure area of ​​the housing, or sealing a cap already attached to the housing to the core (optionally attached to another portion of the enclosure area of ​​the housing). In some embodiments, closure is achieved by sealing or stitching. Optionally, closure includes brazing and / or rotational welding.

[0323] In some implementations, the enclosed area includes means for enclosing the housing, and the housing is enclosed using enclosing means. Optionally, the means for enclosing the housing is a cover.

[0324] In some implementations, after the enclosure is closed, the enclosure is formed by the previously separate shell parts that have been melted and / or soft-welded together.

[0325] In some embodiments, the densifier is at a temperature above room temperature when it is inserted into the housing. In some embodiments, the densifier and / or at least one component of the densifier matrix is ​​a liquid when it is inserted into the housing.

[0326] In some implementations, the housing is prepared by injection molding.

[0327] In some embodiments, the densifier and / or densifier matrix are in direct contact with the core. In some embodiments, the densifier and / or densifier matrix are in direct contact with the sealing area. Preferably, the densifier is in direct contact with both the core and the sealing area. In some embodiments, the densifier and / or densifier matrix are not in direct contact with one or both of the core and / or the sealing area (e.g., there may be a further spacer component to prevent direct contact).

[0328] In some embodiments, the enclosed area includes means of enclosing the housing. In some embodiments, the means of enclosing the housing is a cover. In some embodiments, the enclosed area includes previously separate housing portions melted and / or soft-welded together.

[0329] Packaging materials In a further aspect, materials comprising acrylate-based polymers are provided when used for packaging the pills of this disclosure.

[0330] In some implementations, the polymer of the acrylate is PMMA.

[0331] In some embodiments, PMMA is the only polymer in contact with the pills when the pills are packaged in a package.

[0332] Unless otherwise stated herein, any of the embodiments disclosed herein may be freely combined with any other embodiments disclosed herein.

[0333] It should be understood that this disclosure, as disclosed and defined herein, extends to all alternative combinations of two or more of the various features mentioned or apparent in the text or drawings. All these different combinations constitute various alternative aspects of this disclosure. Example

[0334] Pellets for administration to ruminants are known. They can therefore be prepared as known in the art and, for example, as described by reference to WO2022124914 incorporated herein by reference. In the following, the production of improved pellets of this disclosure is depicted in non-limiting examples. From these examples, how to prepare alternative pellets of this disclosure will be readily apparent.

[0335] Example 1 The following provides a general description of how to prepare a pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor in the animal, wherein the pellet comprises: a core containing the methane inhibitor; and a shell covering the outer surface of the pellet, wherein the shell becomes permeable to the methane inhibitor when exposed to a temperature between 28°C and the temperature present in the rumen of the animal, preferably between 28°C and 42°C; and / or wherein when the shell is exposed to a temperature between 28°C and the temperature present in the rumen of the animal, preferably between 28°C and 42°C, at least a portion of the shell is configured to form one or more openings allowing the methane inhibitor to exit the pellet through the one or more openings.

[0336] In the first step, the shell is fabricated by 3D printing or injection molding. The shell can have various bottle-like shapes, and is preferably shaped like a cylinder. The shell is typically made of a biodegradable polymer, and the shell material includes, for example, PLA and PBAT. The shell can have a wall thickness of about 1.2 mm and dimensions of, for example, about 35 mm (diameter) x about 73 mm (length). The shell is then perforated, for example, by drilling openings or holes within it. The holes can have an average diameter of, for example, from about 0.1 mm to about 1 mm. The diameter of the holes / openings can vary within a given shell.

[0337] Next, the hole / opening is sealed by filling it with a compound that melts between 28°C and the temperature present in the rumen of a living organism. Exemplary compounds and mixtures of compounds that can be used for this purpose are disclosed herein. Alternatively, the perforated pellet may be encapsulated in a foil having the mentioned melting temperature.

[0338] Optionally, a portion of the volume inside the shell can be filled by a densifying agent composition containing, for example, steel balls.

[0339] In the next step, tribromomethane is added to ethyl cellulose and mixed until a homogeneous paste is obtained. HPMC is added to the paste and mixed until a homogeneous dough is obtained. The dough (e.g., 60 grams) is then pressed into a prepared shell (which optionally contains a densifying agent composition).

[0340] In a further step, the shell is closed by adding a cap, which is rotate-welded to the shell to seal it. The steps of producing the pellet can also be performed in any alternative order, for example by perforating the shell after filling it with the core material, and / or by sealing the openings in the shell in a final step.

[0341] This document also provides pills of the present disclosure that can be produced by performing the method steps outlined above.

[0342] Example 2 The following provides a general description of how to prepare pellets for administration to ruminants, wherein the pellets are configured to release a methane inhibitor in the animal, and wherein the pellets comprise: The core comprises a methane inhibitor in microencapsulated particles and the microencapsulated particles are dispersed in a composition comprising a carrier and optionally also comprising a dispersant; and a shell covering at least a portion of the core.

[0343] Methods for producing microencapsulated substances are known, for example, according to US6458118B1 or US7105158B1, both of which are incorporated herein by reference. In such systems, a small amount of drug, such as 1 microgram, is encapsulated in an inert material, such as a stable polymer. Such methods can be applied to encapsulating methane inhibitors, such as bromoform. After encapsulation, the encapsulated bromoform is then filled into pellets of this disclosure. This embodiment can also be manufactured by including a porous carrier, such as mesoporous silica, in the pellet.

[0344] Example 3 For example, shell-less pellets can be prepared by following the steps in Example 1 but without using a shell. Instead, the core material can be further densified by adding additional fillers such as pyrolytic silica. The core is then compressed into, for example, clumps or the like.

[0345] Example 4 The following provides a general description of how to prepare pellets for administration to ruminants, wherein the pellets are configured to release a methane inhibitor in the animal, and wherein the pellets comprise: The core, wherein the core comprises a methane inhibitor and a support; and A housing containing the core; The methane inhibitor is selected from monensin, lauric acid, myristic acid, and linoleic acid; and the shell includes at least one opening that exposes the core to the environment surrounding the pill.

[0346] For example, such pills containing alternative methane inhibitory compounds can be produced by following the steps outlined in Example 1 above and by replacing bromoform with one or more alternative methane inhibitory compounds.

[0347] In such implementations, it is also possible not to fill the holes / openings of the perforated pellet.

[0348] Example 5 The following provides a general description of how to prepare pills, wherein the methane inhibitor is added or replaced, and the pills further contain an active agent, wherein the active agent is selected from anti-inflammatory agents, analgesics, antibiotics and anthelmintics; more preferably, wherein the active agent is selected from meloxicam, ketoprofen, penicillin, tetracycline, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, tylosin and albendazole.

[0349] Such pills can be prepared by replacing the methane inhibitor with an alternative activator, following the steps outlined in any of Examples 1 to 4 above.

[0350] Example 6 The following provides a general description of how to use pills as described herein in a method of treating animals, the method comprising administering the pills as described herein to the animal, wherein the animal is preferably a ruminant such as a cow.

[0351] The pills described herein, such as any of the pills in Examples 1 to 5, can be administered orally (esophageally) into the rumen of ruminants such as cattle. After administration of the pills, the animals can be allowed to graze freely while the pills remain in the rumen. The application of an active agent, such as a methane inhibitor, to a pill that provides a sustained release of the active agent has the advantage of not requiring very frequent reapplication of the active agent.

[0352] To determine the effectiveness of the active agent released from the pill and the tolerability of the administered pill and active agent, such as a methane inhibitor, certain parameters can be evaluated. This allows, for example, improvements to dosing regimens regarding the specific active agent and pill type used. For instance, animal feed intake, such as dry matter intake, and live weight can be recorded as indicators of animal health.

[0353] If the pills release methane or greenhouse gas inhibitors, the reduction in these emissions can be quantified by measuring the animal’s gas emissions (e.g., methane, hydrogen, and / or carbon dioxide) in the breathing chamber, for example, using a 4900C ContinuousEmission Analyser and measuring emissions every 3 minutes over a 48-hour period.

[0354] If the pill will release antibiotics or anthelmintics, its effect on the gut microbiome or parasites can be evaluated by obtaining samples from the animal's intestines and assessing their presence in relation to the microbiota or parasites. Methods for evaluating and quantifying the microbiota and parasites include microscopy and cell culture, antibiotic challenge assays for bacteria, and molecular methods such as polymerase chain reaction (PCR).

[0355] The evaluation of the animals can be repeated periodically during the evaluation period to verify the effectiveness over time. When haloform (e.g., bromoform) is used as a methane inhibitor, the pills can be formulated to release 0.4 mg haloform / kg ruminant / day. In one embodiment, haloform (e.g., bromoform) at a dose of 200 mg / day can be administered to large ruminants of average size (i.e., with a weight of approximately 350-400 kg).

[0356] Example 7 The effect of temperature on the release behavior of pills was tested by preparing pills and placing them in 1L Schott bottles containing 0.02M phosphate buffer, as described below. These bottles were stored at room temperature (RT, 25°C), 30°C (±2°C), and 40°C (±2°C) for comparison.

[0357] Preparation of pills Two pellets (1 and 2) with different bromoform loadings were prepared, having carrier / matrix compositions as shown in Table 2. Briefly, in each case, bromoform (purity >95%, ethanol as stabilizer: 1-3%) was added to ethyl cellulose (EC) (ethoxy: 48-49.5; chloride: <0.05%; apparent viscosity: 41-49 mPa·s) to form a viscous paste in a mortar and pestle. Those skilled in the art will understand that other mixing apparatus, particularly on an industrial scale, can also be used. Hydroxypropyl methylcellulose (HPMC) (methoxy content: 19-24%; hydroxypropyl content: 7-12%; apparent viscosity: 75000-140000 mPa·s) was added to this pellet in small aliquots, followed by thorough mixing to form a homogeneous mixture. This process was repeated until all HPMC was added and a homogeneous dough / matrix was formed.

[0358] Once the bromoform / EC / HPMC matrix is ​​prepared, ~60 g (accurate measurement ±1 g) of it is loaded into the body of the shell. A densifying agent (~100 g, accurate measurement ±5 g) is added on top of the matrix. The densifying agent is free stainless steel (SS) particles (0.1–0.5 mm diameter) at a ratio of approximately 15:1 (w / w) to paraffin. The densifying agent matrix is ​​introduced as a mixture of molten paraffin / stainless steel particles poured directly onto the bromoform / EC / HPMC matrix. The shell is filled to ensure minimal to no air gaps. As an alternative densifying agent option, the densifying agent matrix can be a pre-manufactured tablet of stainless steel particles / paraffin or any other suitable densifying material. The method described for the densifying agent should not be considered a limiting factor regarding the range of densifying agents, as the purpose of the densifying agent is to ensure that the pellet has sufficient density so that it sinks in a buffer solution without floating. From a ruminant application perspective, the technician should understand that sufficient density is required to achieve an effective pellet that, once administered to a ruminant, can retain itself in the rumen. After both the carrier / matrix and the thickener are incorporated into the pellet's body, the cap is attached to the body via spin welding. Alternatively, a welding torch can also be used for attachment.

[0359] In this case, injection molding is used to prepare the shell from a blend of 90% polylactic acid (PLA) (average molecular weight - ~145000 g / mol; D-lactic acid - 1.2%) and 10% polybutylene terephthalate (PBAT) (average molecular weight - ~80000 g / mol). Each pill shell is 73 mm long, 35 mm in diameter, and 1.2 mm thick. Those skilled in the art should understand that other techniques besides injection molding are also suitable.

[0360] Table 2. Composition of the carrier / matrix in each pill. TBM = tribromomethane (bromoform); EC = ethyl cellulose; and HPMC = hydroxypropyl methyl cellulose.

[0361] The DSC data on the EC suggests that it works amorphously.

[0362] Release test Once the pellets were prepared, they were kept in 1L Schott flasks containing 0.02 M phosphate buffer (pH = 6.5) and stored without agitation at room temperature (RT, 25°C), 30°C (±2°C), and 40°C (±2°C). The buffer was changed daily except at weekends. However, at least four daily release data points were collected weekly in all cases. Bromoform (TBM) was quantified using GC-FID (Shimadzu, Nexus GC-2030). Briefly, in each case, 10 mL of sample was collected into 15 mL Falcon tubes using a 10 mL autopilot. For this purpose, 1 mL of ethyl acetate (analytical grade, Merck) was added to each Falcon tube as the extraction solvent for TBM. The Falcon tubes were capped, thoroughly mixed using a Vortex, and centrifuged at 4000 rpm for 15 minutes. 0.5 mL of ethyl acetate was recovered and loaded into GC vials. 200 µL of sample was injected using an autosampler in splitless mode with nitrogen flow at 5 mL / min, using a temperature gradient of 30–300 °C over 20 minutes, and analyzed using a ZB5HT 30 m capillary column. TBM had a retention time of ~5 minutes. Peak areas were compared with calibration standards prepared in ethyl acetate to determine the mass (mg) of TBM in solution, and correlation analysis was performed to quantify daily TBM release from 1 L of buffer solution.

[0363] result Figure 1 and 2 The release profiles of the pills (types 1 and 2; Table 2) when placed in buffer solutions at different temperatures are shown. Temperature-dependent release was observed. In both cases, TBM release from the pills began earlier and at a higher rate when placed at higher temperatures compared to lower temperatures. However, surprisingly, pills releasing ~150 mg of TBM per day at 40°C ( Figure 1 Significant release was observed starting on day 14 at 30°C. However, for pills releasing ~80 mg TBM / day at 40°C... Figure 2 The study observed that this pellet did not significantly release TBM over 35 days. This suggests that multiple factors, besides temperature itself, are at play. It is well-established that increasing system temperature leads to higher thermal energy, which can often promote increased diffusion. Further increases in temperature can also make the polymer more permeable, promoting an increased release rate. The permeability of the polymer can be influenced by its composition and further factors such as crystallinity.

[0364] Not wanting to be bound by theory, it is surprising to note that the plasticizing effect of TBM (in addition to its role as an active ingredient, it also acts as a solvent) on the polymer of the shell appears to play a significant role in the release behavior. The inventors have observed that the solvent content of the shell material increases upon exposure to bromoform / water. For example, when the shell was exposed to a ~100 mg / L bromoform solution for ~10 days, the solvent content of the PLA / PBAT shell of Example 7 increased by at least 3-fold. The solvent content was assessed using a thermogravimetric analyzer (TA Instruments; model - TGA55). Briefly, ~5 mg (accurately measured) of the sample was heated from room temperature to 200°C at a heating rate of 20°C / min under an inert nitrogen atmosphere, and the weight change was recorded. Furthermore, the inventors have observed that the glass transition temperature of the shell can decrease with increasing solvent content. A ~10% decrease in the glass transition temperature of the PLA / PBAT shell of Example 7 was observed from ~55°C to ~50°C. The glass transition temperature was evaluated using a differential scanning calorimeter (TA Instruments, model - DSC250). Briefly, ~5 mg (accurately measured) of shell material was loaded into a Tzero aluminum pot and heated under modulated conditions. The sample was heated from 0 °C to 195 °C at a heating rate of 1 °C / min, an amplitude of 0.16, and a modulated period of 60 seconds. Solvent adsorption further potentially leads to expansion and increased permeability. The expansion of PLA in the presence of organic solvents and water was well determined (Udayakumar M et al. (2020)). Polymers (Basel) May 6; 12(5):1065).

[0365] Such changes in release behavior can also potentially be achieved through other changes, such as the crystallinity of the carrier and / or shell matrix. For example, the inventors used amorphous EC in Example 7. Temperature changes and the plasticizing effect of TBM as a solvent can contribute to changes in crystallinity, which can disrupt the bonding interactions between TBM and EC in the matrix, leading to an increase in free TBM in the matrix, which can diffuse into the shell. Furthermore, the solid state of the shell itself can be altered to a high degree of crystallinity by using dry heat annealing or by using a solvent. Such changes in crystallinity can also be used to modulate the permeation or diffusion coefficient. For example, TBM release from pellets having shells that have crystallized (as measured by DSC) by exposure to high temperatures (~80°C) over several hours showed lower TBM release over a week compared to pellets with shells that were not heat-treated and therefore had a higher amorphous content.

[0366] Example 8 The effect of shell thickness on release profiles was investigated using three different shell thicknesses – 0.90 mm, 1.2 mm, and 1.5 mm. The shell composition was the same as the 90% polylactic acid (PLA) and 10% polybutylene terephthalate (PBAT) blend described in Example 7.

[0367] Preparation of pills As described in Example 7, the pills are assembled by loading them with a matrix (pill 2 matrix - Table 2) and a densifying agent matrix, and then covering them.

[0368] Release test As described in Example 7, each pill was placed in 1 L of 0.02 M phosphate buffer, and the amount of TBM released from the pill daily was quantified.

[0369] result The pills with a shell thickness of 0.9 mm began to release significantly from day 10. Figure 3 The pills with a 1.2 mm shell thickness began to release TBM significantly from day 29, and those with a 1.2 mm shell thickness began to release TBM significantly from day 35. The release rate was greater for thinner shells. This suggests an inverse relationship between shell thickness and release rate, and a direct relationship between shell thickness and TBM release hysteresis. Here, hysteresis refers to the period during which the pill does not significantly release TBM.

[0370] Example 9 The effects of buffer solution (water) or TBM on the shell material were tested. The pellet shell was the same as described in Example 7. The shell, along with the pellet, was kept in a 1 L buffer solution at 40°C. At the end of 25 days, the changes in volatile content and glass transition temperature of the shell were evaluated. Volatile content was analyzed by heating ~5 mg (accurately measured) of sample from room temperature to 200°C in a thermogravimetric analyzer at 20°C / min. Weight loss during the process was considered as volatile content and expressed as a percentage of the initial mass.

[0371] The glass transition of the material was evaluated using modulated differential scanning calorimetry (MDSC). Briefly, approximately 5 mg (accurately measured) of sample was loaded into a Tzero aluminum pot and heated from 0 to 195 °C at a heating rate of 1 °C / min with an amplitude of ±0.16 and a modulation period of 60 seconds. The glass transition temperatures were obtained from reversible heat flow profiles and analyzed using TRIOS software from TA instruments.

[0372] The test results are shown in Table 3. Exposure of PLA / PBAT to water / bromoform increased the total volatile content of the shell and decreased its glass transition temperature. The data suggest that the shell material has the ability to contain solvents and likely acts as a reservoir for bromoform, regulating its release. This also suggests that the presence of bromoform and water plasticizes the shell. Plasticization likely promotes further bromoform release over time.

[0373] Table 3. Effects of buffer solution (water) or TBM on shell material. TBM = tribromomethane.

[0374] Example 10 Surprisingly, TBM forms an organic gel with lecithin (refined, acetone-insoluble - 98%, residual water <1%) and polymethyl methacrylate (PMMA) (molecular weight - 450-550 kDa). For lecithin, a concentration of >40% is preferred. w / w A TBM concentration of >10% w / w is used to form a gel. Here, by employing water, gel formation is possible even at lower concentrations. Water potentially contributes to increased hydrogen bonding in the matrix and stabilizes the 3D gel structure. For PMMA, a TBM concentration of >10% w / w is preferred for gel formation.

[0375] Different pellets were prepared by loading lecithin and PMMA with gels of different TBM concentrations, and their release profiles were evaluated.

[0376] Preparation of pills Lecithin / TBM gels were prepared by adding TBM to lecithin in a beaker and mixing. The lecithin may dissolve and form pale yellow, translucent, viscous clumps at the beginning of mixing, which later begin to gel. Those skilled in the art will understand that heating can be used. Three different gels with different bromoform loadings—45%, 60%, and 70%—were prepared as outlined in Table 4.

[0377] PMMA / TBM gels were prepared by adding TBM to PMMA in a beaker. Those skilled in the art will understand that heating can be used. The mixture may dissolve and form translucent, viscous clumps, which gel upon prolonged standing. Two different gels with TBM loadings of 45% and 70% were prepared (Table 4).

[0378] Table 4. Composition of the carrier / matrix in each pill. TBM = tribromomethane; PMMA = polymethyl methacrylate.

[0379] The pellet casing is the same as described in Example 7. The carrier matrix, along with the densifying agent, is loaded into the casing and sealed as described in Example 7. Due to its lower density and tendency to occupy more space, the pellets with lecithin-based gels are loaded in slightly lower quantities. Those skilled in the art will understand that a larger diffusion surface area can affect the quality of diffusion within the pellet. Here, attempts are made to minimize variations in the pellet in terms of the surface area in contact with the matrix of the TBM loaded inside the casing.

[0380] Release test As described in Example 7, each pill was placed in 1 L of 0.02 M phosphate buffer, and the amount of TBM released from the pill daily was quantified.

[0381] result For pills with lecithin-based gels ( Figure 4 The release rate is directly proportional to the TBM loading in the gel. Figure 5 However, for gels loaded with 60% or 70% TBM, the release profile was order one. For gels loaded with 45% TBM, a release profile close to order zero was observed. This behavior was observed over a longer period of 4 months. Figure 6 ).

[0382] Similarly, PMMA gel ( Figure 7 It also exhibits TBM concentration-dependent release ( Figure 8 Interestingly, PMMA gels with 45% TBM loading were observed to release minimal TBM (<10 mg / day) over 3 months. Figure 9 This suggests that PMMA could be an excellent packaging material for loading TBM pellets. However, PMMA can also be used as a stabilizer to modulate release from other matrices, such as stearic acid-based matrices, which, as discussed later, provide limited control over release in the absence of a stabilizer.

[0383] Example 11 Pellets containing waxes with different melting points (MP) loaded with TBM were also prepared. Microcrystalline wax (MCW) with a melting point of ~80°C (supplier: Alchemy agency, specific gravity: 0.92 at 20°C, melting point: 80°C) was used; stearic acid with a melting point of ~70°C (purity: 95%); and eicosane with a relatively low melting point of ~40°C (purity: >95%). For the eicosane system, the primary objective was to achieve temperature-dependent release.

[0384] Preparation of pills Different pellets with a wax / TBM matrix were prepared as described in Table 5. Briefly, for the MCW system, the wax was first melted and maintained at ~100°C, and pre-melted TBM (held at room temperature) was added, which lowered the temperature to ~70°C. Here, especially when multiple pellets are prepared from the same melt, care should be taken to pour the mixture into the shell body in a clear liquid state before any solidification to avoid non-homogeneity in matrix loading. Those skilled in the art will understand that the pouring temperature or agitation / sedimentation prior to pouring in such systems can affect the release profile by influencing its solid state. Stearic acid was melted and maintained at ~90°C, and TBM was added. As discussed earlier for the MCW system, it was carefully poured in a clear liquid state. Eicosane was melted and maintained at ~60°C, and TBM was added. Here, the mixture was also above 40°C and in a clear liquid state when poured into the shell. The pellet shell was the same as described in Example 7. In all cases, the wax / TBM system is allowed to solidify before the densifier is added and the system is sealed with a cap, as described in Example 7.

[0385] Table 5. Composition of the carrier / matrix in each pill. TBM = tribromomethane; MCW = microcrystalline wax.

[0386] Release test As described in Example 7, each pellet was placed in 1 L of 0.02 M phosphate buffer, and the amount of TBM released from the pellet daily was quantified. Unique to the pellets containing eicosane, the pellets were held at room temperature for approximately 2 weeks before being transferred to a 40°C incubator. TBM release from the pellets during this time period was recorded, including changes in release patterns during the transition.

[0387] result Although both MCW systems demonstrated release, the observation of <70% TBM load provided more desirable control over TBM release. Figure 10 The MCW system with 65% TBM loading showed consistent release of ~150 mg daily over 80 days. Figure 11 Furthermore, it was observed that for MCW-35% in the pills... w / w / TBM-65% w / w The system release can also be adjusted based on the mass load of the MCW / TBM. Figure 12 This is a desirable characteristic of such systems. Here, by simply changing the matrix loading in the pellet, the pellet can be designed to deliver the desired dose to the animal based on its weight.

[0388] For the stearic acid system, the release rate is much higher than that of the MCW system at the same loading, with releases in the range of ~500 mg / day. Figure 13 In some applications, a higher release rate may be desirable. However, at 65% TBM loading, stearic acid systems offer less control over release compared to MCW systems. Figure 10 and 13 ).

[0389] For the eicosane system ( Figure 14 No significant TBM release was observed at room temperature; however, extensive release occurred when the pellets were heated to 40°C. It is not desirable to be bound by theory and assume that the melting of the carrier is responsible for the temperature-dependent release. Those skilled in the art will understand that such systems can be advantageous because they do not release significant amounts of the active ingredient during storage, but only after administration to animals. Furthermore, the release from such systems can be modulated by including excipients (e.g., EC, lecithin, MCW, or SAIB), which can further control the release of the active ingredient, such as TBM.

[0390] Interestingly, it was also noted that TBM release from wax systems with the same TBM loading increased as the melting point of the carrier wax decreased. At a TBM loading of 65% within the wax system, MCW (MP = ~80°C) provided better control over release than stearic acid (MP = ~70°C), which in turn provided better control over release from eicosane (MP = ~80°C) as the carrier.

[0391] Example 12 MCW was also used as a carrier to prepare shell-less pellets.

[0392] Preparation of pills The pellet shell (when used) is the same as described in Example 7. Here, MCW matrix loaded with 65% or 45% TBM loading was prepared and loaded into pellets or shell-less pellets were prepared (Table 6). Briefly, pellets with shells were prepared as described in Example 11. For shell-less pellets, 3D-printed molds were used. Alternatively, the shell can be cut off and removed once the matrix has solidified. Because the pellets are dense enough to sink in water, densifying agents were not included in these tests. However, if needed, it is readily possible for a technician to further include densifying agents in equivalent pellets for animal administration.

[0393] Table 6. Composition of the carrier / matrix in each pill. TBM = tribromomethane; MCW = microcrystalline wax.

[0394] Release test As described in Example 7, each pellet was placed in 1 L of 0.02 M phosphate buffer, and the amount of TBM released from the pellet daily was quantified. All shell-less pellets also sank into the dissolution medium, potentially occupying a more significant proportion of the pellet in the absence of a shell due to the high density of TBM.

[0395] result The shell-less pellets appear to release TBM at a rate of approximately 2-3 times that of the shell-containing equivalent pellets. Figure 15 and 16 Nevertheless, shell-less pellets are stable in the dissolving medium and did not break during testing, suggesting that they possess satisfactory mechanical properties, at least when using MCW. Based on this result, other waxes with melting points higher than MCW can also be used in shell-less pellets. Shell-less pellets can offer advantages in terms of material reduction using potentially simpler production methods. Shell-less pellets can also be advantageous when high release rates are required. When greater adjustment of the release rate is needed, the shell can be advantageous.

[0396] Example 13 The inventors have observed that different excipients / carriers provide varying levels of control over TBM release. In particular, EC, lecithin, SAIB, and MCW have been observed to provide significant control over TBM release; a desirable property in prolonged-release formulations. Therefore, EC, lecithin, SAIB, and MCW act as stabilizers regarding TBM release. Here, lecithin is used as an example of a stabilizer for a system to improve control over TBM release relative to a stearic acid system.

[0397] Preparation of pills A stearic acid matrix loaded with 65% TBM was prepared, with or without 5% lecithin (Table 7). The inclusion of lecithin was compensated by reducing the concentration of stearic acid. The pellet shell was the same as described in Example 7. Here, the pellets were assembled as described in Example 11. In the case of a matrix containing lecithin, lecithin was first dissolved in TBM, and then the solution was added to molten stearic acid.

[0398] Table 7. Composition of the carrier / matrix in each pill. TBM = tribromomethane.

[0399] Release test As described in Example 7, each pill was placed in 1 L of 0.02 M phosphate buffer, and the amount of TBM released from the pill daily was quantified.

[0400] result It was observed that the inclusion of only 5% lecithin was able to stabilize the release profile of the stearic acid system loaded with 65% TBM. Figure 17 This suggests that similar control can be achieved when using other stabilizer excipients such as SAIB, EC, lecithin, MCW, etc.

[0401] Example 14 Pills can contain more than one active ingredient. The inclusion of more than one active agent provides advantages, at least in terms of reducing the application of the active agent. Furthermore, they can potentially have advantages from a formulation perspective. Here, pills were prepared comprising the following further active agents: monensin (sodium salt, purity ≥90%), phloroglucinol (dihydrate, purity ≥98%), ketoprofen (purity ≥98%), and albendazole (purity ≥98%). Monensin is known to exhibit anti-methane formation activity (Cooke RF et al. (2024)). Transl Anim Sci , Mar 9; 8:txae032). Phloroglucinol is a hydrogen chelator that potentially helps redirect excess hydrogen in the rumen to acetate, where anti-methanogenic agents such as haloform have inhibited methanogenesis (which uses hydrogen), and is also known to reduce methane production (Sarwono KA et al. (2019)). Tropical Animal Science Journal , 42(2):121-127). Ketoprofen is a common anti-inflammatory drug used in cattle. Albendazole is a common anthelmintic used in cattle.

[0402] Preparation of pills As detailed in Table 8, an EC / HPMC / TBM matrix loaded with 60% TBM was prepared, including or excluding 2 or 5% monensin, phloroglucinol, albendazole, and ketoconazole. The inclusion of further active agents in the formulation is compensated for by the reduction of HPMC. Here, the EC to TBM ratio remains constant because EC has been determined to provide stability for the release profile. These active ingredients are first added to the TBM. The matrix and shell are prepared as described in Example 7.

[0403] Table 8. Composition of the carrier / matrix in each pill. TBM = tribromomethane; EC = ethyl cellulose; and HPMC = hydroxypropyl methyl cellulose.

[0404] Release test As described in Example 7, each pill was placed in 1 L of 0.02 M phosphate buffer, and the amount of TBM released from the pill daily was quantified.

[0405] result The inclusion of additional active agents resulted in only minor changes in the release profile. Figures 18 to 21 ).

[0406] Example 15 The effect of shell crystallinity on release rate was evaluated.

[0407] Preparation of pills The pellet shell is the same as that described in Example 7, except that a pellet shell with a high content of crystalline PLA and a high content of amorphous crystals was prepared. Those skilled in the art should be familiar with techniques that affect the content of crystalline polymers, such as annealing. Here, as described in Example 11, an MCW matrix loaded with a total mass of 65% TBM up to 60 g was prepared.

[0408] Release test As described in Example 7, each pill was placed in 1 L of 0.02 M phosphate buffer (pH = 6.5), and the amount of TBM released from the pill daily was quantified.

[0409] result Pills with high crystalline PLA content exhibited a greater release rate than pills with low crystalline PLA content. This suggests that the crystallinity of the outer shell affects the release rate.

[0410] Invention Statement 1. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core, wherein the core comprises a methane inhibitor; and The shell surrounding the core, The shell is configured such that its permeability to the methane inhibitor is increased when the shell is exposed to the rumen of a living organism; and / or When the shell is exposed to the rumen of a living organism, at least a portion of the shell is configured to form one or more openings that allow for increased release of a methane inhibitor from within the pellet through the one or more openings.

[0411] 2. The pill according to statement 1, wherein the shell includes one or more openings, and wherein the openings are filled with and / or covered with a material that melts, dissolves or disintegrates in the rumen of a living animal.

[0412] 3. The pill according to statement 1, wherein a portion of the shell, and preferably a portion of the shell forming one or more openings, is made of a material that melts, dissolves, or disintegrates in the rumen of a living animal.

[0413] 4. The pills of statement 2 or 3, wherein the molten material is selected from the following compounds: hydrogels, oleogels, organic gels, phase change materials (PCMs), fatty acids, alkanes, olefins, gelling agents, waxes, L-alanine amino acids, L-alanine amino acid derivatives, poly(methyl methacrylate) (PMMA), (1,3:2,4) dibenzyl sorbitol (DBS), hydroxystearic acid, paraffin wax, gelatin, 1-tetradecanoic acid, polyethylene glycol, octadecane, nonadecane, eicosane, Pluronic polymers or mixtures of Pluronic, emulsifiers, sucrose isobutyrate acetate (SAIB), derivatives of the above, and one or more combinations of the above compounds, and wherein the compound or combination of the compound has a melting temperature of 28°C to 42°C, more preferably 28°C to 35°C.

[0414] 5. The pills of statement 2 or 3, wherein the dissolved material is preferably a water-soluble material selected from polymers, polyols, sugars, polyamides, salts and cellulose acetate.

[0415] 6. The pill of statement 2 or 3, wherein the disintegrating material is a compound selected from cellulose, polyhydroxyalkanoates (PHA), poly(butylene adipate) (PBSA), and mixtures of two or more of the above.

[0416] 7. A pill according to any one of statements 1 to 6, wherein when the shell is exposed to the rumen of a living animal, the largest opening formed in the shell has a diameter of a maximum of 2 mm.

[0417] 8. The pill according to any one of statements 1 to 7, wherein the methane inhibitor is selected from haloform.

[0418] 9. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core comprises a methane inhibitor in microencapsulated particles, and the microencapsulated particles are dispersed in a composition comprising a carrier and optionally also comprising a dispersant. And the shell covering at least part of the core.

[0419] 10. The pellet of statement 9, wherein the microencapsulated particles are produced by microencapsulation of the particles in at least one encapsulating agent, preferably wherein the encapsulating agent is selected from polymers, surfactants, emulsifiers, gelatin-sorbitol mixtures, gelatin-starch syrups and mixtures thereof, more preferably wherein the encapsulating agent is selected from PLA, PBSA, PBS, PHBV, PVA, PBAT, PCL, PDLA, gelatin-sorbitol mixtures, gelatin-starch syrups and mixtures comprising two or more of the above compounds.

[0420] 11. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: A carrier and microencapsulated particles, wherein the microencapsulated particles contain a methane inhibitor, and wherein the microencapsulated particles are dispersed in the carrier. Preferably, the carrier has a porous structure, such as mesoporous silica.

[0421] 12. The pill according to any one of statements 9 or 11, wherein the microencapsulated particles are microencapsulated using a compound selected from: hydrophilic materials, gelatin, zein, methylcellulose and poly(N-isopropylacrylamide) (PNIPAM) microgels, starch, cyclodextrin, and combinations of two or more of the above compounds.

[0422] 13. The pill according to any one of statements 9 to 12, wherein the carrier comprises a compound selected from: silica, cellulose and activated carbon, gelatin, chitosan, poly(lactic-co-glycolic acid) (PLGA), cyclodextrin, collagen, polyalphahydroxy esters, hydroxyalkyl esters and dioxane, starch, gluten, zein, polyethylene, polypropylene, polyamide, polyethylene terephthalate and ethylene-vinyl acetate.

[0423] 14. The pill according to any one of statements 9 to 13, wherein the microencapsulated particles have an average diameter of 50 nm to 2 mm, preferably 1 µm to 1000 µm.

[0424] 15. A pill according to any one of statements 9 to 14, wherein the pill is configured to release a methane inhibitor over a period of at least 3 months.

[0425] 16. A pellet for administration to ruminants, wherein the pellet is formulated to release a methane inhibitor into the animal. The pill comprises a core, wherein the core contains a methane inhibitor and a carrier, and The pills mentioned above do not include the shell.

[0426] 17. The pill according to statement 16, wherein the core comprises a compound selected from the group consisting of PLA, PBSA, PBS, PHBV, PVA, PBAT, PCL, PDLA, epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, wax, castor wax, paraffin, silica, and combinations thereof.

[0427] 18. A pill according to any one of statements 16 or 17, wherein the pill has a Shore D hardness of at least 20.

[0428] 19. The pill according to any one of statements 16 to 18, wherein the pill is in the form of a lump, pellet, lozenge, or tablet.

[0429] 20. A pill according to any one of statements 16 to 19, wherein the pill is formulated to dissolve in the rumen of a ruminant over a period of less than 48 hours.

[0430] 21. Any of the pills stated above, wherein the pills contain a hydrogen chelating agent, preferably selected from the group consisting of fumaric acid, sodium fumarate, phenolic compounds, phloroglucinol, gallic acid, resorcinol, catechol, hydroquinone, and pyroglucinol.

[0431] 22. The pill according to any of the preceding statements, wherein the methane inhibitor is selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid and phospholipids, preferably wherein the phospholipids comprise one or more polyunsaturated fatty acids, more preferably wherein the phospholipids comprise one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFA), palmitic acid, stearic acid and oleic acid.

[0432] 23. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core, wherein the core comprises a methane inhibitor and a support; and A housing containing the core; The methane inhibitor is selected from monensin, lauric acid, myristic acid, and linoleic acid; and the shell includes at least one opening that exposes the core to the environment surrounding the pill.

[0433] 24. A pill according to any of the preceding statements, wherein the pill comprises a shell, wherein the shell comprises a stabilizer, preferably selected from surfactants, plasticizers, phthalates and triglycerides, more preferably wherein the stabilizer is selected from lecithin, nitriles and triacetin.

[0434] 25. The pill according to any of the preceding statements, wherein the core of said pill comprises at least one filler. Preferably, the at least one filler is a stabilizer, and preferably, the at least one filler is selected from gelatin, milk, milk derivatives, infant formula, milk powder, triglycerides, medium-chain triglycerides and their oils, ethanol, lecithin, tween, xanthan gum, cellulose derivatives, alkyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), zein, and surfactants.

[0435] 26. A pill as defined in any of the preceding statements, wherein the methane inhibitor is added or replaced, and the pill further comprises an active agent, wherein the active agent is selected from anti-inflammatory agents, analgesics, antibiotics and anthelmintics; more preferably, wherein the active agent is selected from meloxicam, ketoprofen, penicillin, tetracycline, macrolides, monensin, ceftiofur, florfenicol, tilmicosin, enrofloxacin, tylosin and albendazole.

[0436] 27. A pill according to any one of statements 1 to 26, used to treat ruminants.

[0437] 28. A pill according to any one of statements 1 to 26, used to reduce methane emissions in ruminants.

[0438] 29. A method of treating an animal, comprising administering to the animal a pill as defined in any of the preceding claims; wherein the animal is preferably a ruminant, such as a cow.

[0439] 30. A method for manufacturing a pill according to any one of statements 1 to 28, comprising the following steps: (a) Provide a housing; (b) Multiple openings are formed in the wall of the housing, wherein each opening has a maximum diameter of 3 mm; (c) Seal the opening of the shell with the material, the material melting, dissolving, and / or disintegrating in the rumen of a living animal; and (d) Fill the shell with the inhibitor.

[0440] 31. A methane inhibitor for reducing methane emissions from ruminants, wherein the methane inhibitor is selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid, and phospholipids, preferably wherein the phospholipids comprise one or more polyunsaturated fatty acids, more preferably wherein the phospholipids comprise one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18PUFA), palmitic acid, stearic acid, and oleic acid.

[0441] 32. A method for treating ruminants to reduce methane emissions from said ruminants, comprising administering to said animal a methane inhibitor selected from bromoform, monensin, lecithin, lauric acid, myristic acid, linoleic acid and phospholipids, preferably wherein said phospholipids comprise one or more polyunsaturated fatty acids, more preferably wherein said phospholipids comprise one or more fatty acids selected from 18-carbon polyunsaturated fatty acids (C18 PUFA), palmitic acid, stearic acid and oleic acid.

Claims

1. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: core; A shell covering at least a portion of the core; The core comprises at least one methane inhibitor and at least one further activator.

2. The pill according to claim 1, wherein the further active agent is selected from methane inhibitors, hydrogen chelators, anti-inflammatory agents, analgesics, anthelmintics, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, growth promoters, lactation promoters, sustainability improvers, antibacterial agents, ketosis preventive agents, and combinations thereof.

3. The pill according to claim 1 or 2, wherein the further active agent is selected from monensin, phloroglucinol, albendazole, ketoconazole, lecithin, and combinations thereof.

4. The pill according to any one of the preceding claims, wherein the further active agent is monensin.

5. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core, wherein the core contains a methane inhibitor; and a shell covering at least a portion of the core, The shell is configured such that, relative to its permeability on the same day after being exposed to phosphate buffer (pH: 6.5, 0.02 M) without agitation at a reference temperature for the same duration, its permeability to the methane inhibitor is increased by at least 50% when the shell is exposed to phosphate buffer (pH: 6.5, 0.02 M) without agitation at 40°C. The permeability was evaluated based on the release rate of the methane inhibitor at day fourteen; and The reference temperature is 20°C.

6. The pill according to claim 5, wherein the reference temperature is 25°C.

7. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core comprises a methane inhibitory agent dispersed in one or more of a hydrogel, oleogel, or organic gel, or forming part of one or more of a hydrogel, oleogel, or organic gel. as well as A shell covering at least a portion of the core.

8. The pill of claim 7, wherein the core comprises phospholipids and / or an acrylate-based polymer.

9. The pill according to claim 7 or 8, wherein the core comprises lecithin and / or poly(methyl methacrylate) (PMMA).

10. The pill according to any of the preceding claims, wherein the shell surrounds the core.

11. The pill according to any one of the preceding claims, wherein the shell comprises one or more polymers selected from: high-density polyethylene (HDPE), polypropylene (PP), polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene succinate-adipate (PBSA), polylactic acid (PLA), poly-D,L-lactic acid (PDLLA), polybutylene terephthalate-adipate (PBAT), styrene-acrylic acid copolymers (e.g., Jonathan). ® Talc-filled poly(D-lactide) (TALCPDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), combinations thereof, and copolymers thereof.

12. The pill according to any of the preceding claims, wherein the shell comprises one or more biodegradable polymers.

13. The pill according to any of the preceding claims, wherein the shell comprises one or more polymers selected from polylactic acid, polybutylene terephthalate, combinations thereof, and copolymers thereof.

14. The pill according to any one of claims 1 to 13, wherein the shell completely surrounds the core.

15. The pill according to any one of claims 1 to 14, wherein the shell is 5 to 100% or 10 to 100% PLA w / w.

16. The pill according to any one of claims 1 to 15, wherein the shell is 20 to 100% or 30 to 90% PBAT w / w.

17. The pill according to any one of claims 1 to 16, wherein the shell has a material thickness of less than about 2 mm, preferably in the range of about 0.3-1.8 mm, and more preferably in the range of about 0.3-1.5 mm.

18. The pill according to any one of claims 1 to 17, wherein the core and shell have a ratio of about 3 to about 6:1, about 4 to about 5:1 or about 4.6:1 by weight.

19. The pill according to any one of claims 1 to 18, wherein the pill has a Shore D hardness of at least 20.

20. A pellet for administration to ruminants, wherein the pellet is configured to release a methane inhibitor into the animal, wherein the pellet comprises: The core comprises the methane inhibitor and the carrier, and the pellet does not include a shell.

21. The pill according to any one of the preceding claims, wherein the core comprises one or more materials selected from: polycaprolactone (PCL), polybutylene succinate (PBS), polybutylene adipate succinate (PBSA), polylactic acid (PLA), poly-lactic acid, poly-d-lactic acid, poly-L-lactic acid, poly-D,L-lactic acid (PDLLA), polylactide-co-glycolic acid, lignin, polybutylene terephthalate (PBAT), styrene-acrylic acid copolymer (e.g., Joncryl) ® Talc-filled poly(D-lactide) (TALC PDLA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyvinyl alcohol (PVA), epoxide-based chain extenders, magnesium silicate, cellulose materials, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), pyrolytic silica, gelatin, wax, castor wax, paraffin wax, silica, hydrophilic silica, microcrystalline wax, methylcellulose, starch, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, carboxymethyl cellulose, soluplus, poly(acrylic acid), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(2-hydroxypropyl methacrylamide), poly(N,N-dimethylacrylamide), poly([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide), poly(2-(methacryloyloxy)ethyl phosphate choline), poly(carboxybetaine methacrylamide), poly(ethylene glycol), poly(ethylene glycol) Enimine), poly(sarcosine), poly(2-methyl-2-oxazoline), polyurethane, polyesteramide, polyphosphate, poly(l-lysine), poly(l-proline), polyphosphazene, dextran, sodium alginate, gelatin, agarose, carrageenan, gellan gum, xanthan gum, urea, sucrose, beeswax, polyethylene glycol (PEG), sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), carrageenan, guar gum, xanthan gum, sodium alginate, locust bean gum, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP / VA), polyacrylic acid and / or its copolymer variants, polyisobutylene, ethylene-vinyl acetate (EVA), functional waxes with melting points below about 120°C, their derivatives, combinations thereof, and their copolymers.

22. The pill according to any one of the preceding claims, wherein the core comprises one or more materials selected from ethyl cellulose, hydroxypropyl methylcellulose (HPMC), combinations thereof, and copolymers thereof.

23. The pill according to any one of claims 1-22, wherein the core comprises microcrystalline wax.

24. The pill according to any one of the preceding claims, wherein the methane inhibitor is haloform, preferably bromoform.

25. The pills according to claim 24, wherein the haloform, preferably bromoform, is contained in the core of the pills disclosed herein in an amount of 10% to 80% by weight and preferably in an amount of 15% to 70% by weight.

26. The pill according to claim 25, wherein the bromoform is not a bromoform-rich seaweed extract.

27. The pill according to any one of the preceding claims, wherein the pill further comprises a densifying agent.

28. The pill according to any one of the preceding claims, wherein the pill comprises the methane inhibitor bromoform and is adapted to achieve a maximum release rate of about 0.1 – about 0.5 g / day, and more preferably about 0.2 g / day.

29. The pill according to any one of the preceding claims, wherein the pill comprises a therapeutically effective amount of a methane inhibitor and: • Approximately 5% to approximately 15% (w / w) of the shell; • A core of approximately 20 to approximately 55 (w / w); and • Densifying agent of approximately 30 to approximately 75 (w / w).

30. A method of applying a methane inhibitor to a ruminant, the method comprising administering a pellet according to any one of the preceding claims into the rumen of the ruminant.

31. A method for reducing methane production in the rumen of a ruminant, the method comprising administering a pill according to any one of claims 1 to 29 into the rumen of the ruminant.

32. A method for preparing pills, the method comprising: Choose the core and shell Insert the core into the casing. Optionally, the shell is closed to surround or substantially surround the core within the shell; The core contains a methane inhibitor.

33. The method of claim 32, wherein the molten core is poured into the shell and solidifies within the shell.

34. The method of claim 33, wherein after the core solidifies, the shell is sealed around the core.

35. A packaged pill according to any one of claims 1 to 29, or a pill prepared according to claims 32 and 33, wherein the pill is packaged in a material comprising an acrylate-based polymer.

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