NZ785890A - Improvements to devices and methods for delivery of substances to animals - Google Patents

Improvements to devices and methods for delivery of substances to animals

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Publication number
NZ785890A
NZ785890A NZ785890A NZ78589020A NZ785890A NZ 785890 A NZ785890 A NZ 785890A NZ 785890 A NZ785890 A NZ 785890A NZ 78589020 A NZ78589020 A NZ 78589020A NZ 785890 A NZ785890 A NZ 785890A
Authority
NZ
New Zealand
Prior art keywords
bolus
core
housing
dosage form
carrier
Prior art date
Application number
NZ785890A
Inventor
Geoffrey Earle Corbett
Leslie Hayman David
Peter Thomas Hayden
Christopher Lay Mark
Richard Gladden Neil
Bhusal Prabhat
Original Assignee
Ruminant Biotech Corp Entitlement Physical
Ruminant Biotech Corp Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ruminant Biotech Corp Entitlement Physical, Ruminant Biotech Corp Limited filed Critical Ruminant Biotech Corp Entitlement Physical
Publication of NZ785890A publication Critical patent/NZ785890A/en

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Abstract

The invention provides a delayed release dosage form and a bolus configured for administration to an animal, wherein said dosage form and said bolus is configured to release a hydrophobic substance to the animal over a period of time. Preferably the hydrophobic substance is a haloform. Also provided is the use of the delayed release dosage form or bolus of the invention to reduce methane production in a ruminant animal. Also provided is the method of manufacturing a bolus of the invention. is the use of the delayed release dosage form or bolus of the invention to reduce methane production in a ruminant animal. Also provided is the method of manufacturing a bolus of the invention.

Description

James & Wells Ref: 316642NZ IMPROVEMENTS TO DEVICES AND METHODS FOR DELIVERY OF SUBSTANCES TO ANIMALS Field of Invention The present invention relates to improvements in devices and methods for animal production and delivery of substances to animals, and in particular to devices and methods for administering at least one advantageous substance to an animal, and methods of manufacturing the devices.
Background to the Invention In g it is often necessary to deliver substances to animals. This can be for any of various purposes, ing but not limited to ent or prevention of disease and to increase animal production.
There are various s and methods to deliver substances such as medicament to animals. However, one class of compounds that are difficult to deliver to s are hydrophobic compounds. The properties of these compounds present challenges to developing technology for the controlled release of these hobic substances, particularly via an animal’s h.
One specific purpose to administer substances to s is to reduce the e effects of agriculture. For instance, various methane and nitrification inhibitors are known to be administered to s to reduce or mitigate the adverse effects of the methane and nitrate containing compounds produced by the animals.
However, despite current efforts, climate change is creating a wide range of environmental and social impacts globally. It is widely understood that these impacts will only ue to increase over time. As a result, there has been a global push to reduce harmful greenhouse gas (GHG) emissions in an effort to avoid the worst effects of climate change.
James & Wells Ref: The agricultural sector is considered to be a major source of GHG emissions. Total emissions of e from global livestock accounts for an estimated 7.1 gigatons of CO2- equivalent per year, enting 14.5% of all anthropogenic GHG emissions. Therefore, this sector will play a key role in ng overall GHG emissions.
The main GHGs released by agriculture are methane (CH4) and nitrous oxide (N2O), with the main source of methane emission attributed to livestock. Most methane is emitted when cattle burp. The amount of methane produced for each farm is directly related to the total animal feed intake.
Countries which have a strong agricultural sector such as New Zealand, face challenging goals of reducing ltural emissions. For instance, the New Zealand government has introduced policies aimed to reduce methane emission by 24-50% before 2050. In New Zealand livestock methane production is estimated to comprise as much as half of the country's total GHG emissions. The reduction of methane is a al component of g targets for emissions of GHGs and reducing the effects of global warming.
Release of GHGs by animals also has adverse effects on animal productivity. Any feed that is converted to a compound which is subsequently d or released by the animal is an energy source that has not been converted to a productive use. Accordingly, for efficiency, it is important to optimise sion of feeds into animal productivity in the form of weight gain or milk production.
Object of the Invention It is an object of the present invention to provide improved devices and methods to deliver nces to an animal, e.g. hydrophobic substances and / or methane inhibitors.
It is an object of the invention to provide devices and methods to reduce emission of GHGs.
It is an object of the invention to provide devices and methods to e or optimise animal productivity.
James & Wells Ref: 316642NZ Alternatively, it is an object of the invention to provide devices and methods to improve animal tion gains e.g. through reduction of methane production.
It is an object of the invention to provide a formulation to reduce emission of GHGs by one or more s e.g. a nt animal.
It is an object of the invention to e devices and methods that can release substances at different rates over a period of time. atively, it is an object of the invention to provide methods of manufacturing devices to deliver substances to an animal e.g. substances to reduce emission of GHGs.
Alternatively, it is an object of the invention to overcome some of the disadvantages of the prior art.
Alternatively, it is an object of the present invention to e the public with a useful choice.
Summary of the Invention According to one aspect of the invention, there is provided a bolus configured for administration to an animal, wherein said bolus is configured to release a hydrophobic substance to the animal over a period of time.
According to one aspect of the invention, there is provided a bolus for administration to a ruminant animal, wherein said bolus is ured to release an effective amount of the substance, wherein the substance is preferably at least one inhibiting agent.
According to a further aspect of the invention, there is provided a method for reducing on of gas (preferably methane) from a ruminant animal, the method comprising the step of administering to said ruminant animal a bolus comprising at least one inhibiting agent.
James & Wells Ref: According to another aspect of the invention, there is provided a use of a methane inhibitor and a carrier in a bolus for reducing methane production in a ruminant animal. ing to another aspect of the invention, there is provided a use of a methane tor and a carrier in a bolus for reducing methane on from a ruminant animal.
According to another aspect of the ion, there is provided a use of a haloform in the manufacture of a bolus for reducing the emission of one or more greenhouse gases ("GHGs") from a ruminant animal.
In a preferred embodiment, the bolus may be configured to be administered to a ruminant, the ruminant may include beef or dairy cows, sheep, goats, buffalo, deer, elk, giraffes or camels.
In one embodiment, the bolus may be adapted to reduce the release of one or more greenhouse gases ("GHGs") from the ruminant.
In r embodiment, the bolus may be a slow-release bolus, configured to release the at least one inhibiting agent in the ruminant animal over a period of time e.g. in the ’s rumen.
According to a further aspect, there is provided a bolus for administration to a ruminant animal, wherein the bolus comprises: a core, wherein the core includes at least one substance to be administered to the ruminant animal mixed with a carrier; and a housing which covers at least a portion of the core; wherein, the bolus is configured to e the nce through the housing over a period of time.
In another aspect of the invention, there is provided a bolus comprising a core which contains a substance to be administered to an animal, and a housing which at least partially covers a portion of the core; James & Wells Ref: 316642NZ wherein the housing is formed from at least one polylactic acid (PLA).
In a r aspect of the invention, there is provided a bolus comprising a core, wherein the core comprises a mixture of at least one wax and a haloform.
The inventors have surprisingly found that the technology bed herein may provide a number of benefits. These benefits may be the result of the unique synergistic interactions between ent aspects of the technology. The technology of the present invention is therefore described based on the or’s current understanding of these interactions. It should be appreciated any aspect described herein, or the interaction of two or more aspects, may form a distinct ion.
Throughout the t specification reference will be made to the term "substance" or "substance to be administered to an animal". This should be understood as meaning any substance which provides benefits to the animal e.g. a drug for treatment or prevention of disease, which improves animal productivity, or mitigates at least one adverse effect of agriculture.
In preferred embodiments, the substance may be hydrophobic substance.
In particularly preferred embodiments the hydrophobic nce may be an inhibiting agent. Reference will be made herein to the substance as an inhibiting agent. However, this should not be seen as limiting on the scope of the present invention and alternatives are envisaged for the e.g. it may be a hydrophilic substance.
In an embodiment, the at least one inhibiting agent may be a methane inhibitor.
The use of a methane inhibitor may e a number of advantages. For instance, a methane inhibitor will , or eliminate, production of e by the ruminant e.g. in the rumen. As a result, there is less methane in the rumen which could be emitted by the ruminant and therefore emission of GHGs are effectively reduced.
In addition, reducing production of methane may provide animal tion benefits. For instance, reduction of methane ensures that relatively more of the feed ingested is James & Wells Ref: 316642NZ available for digestion and sion into n (either milk or meat). As a result, farmers may be able to improve efficiency by either securing r productivity for a given feed volume or reduce feed accordingly.
In an embodiment, the methane inhibitor may be a haloform.
In a preferred embodiment, the methane inhibitor may be selected from the list of chloroform, bromoform, iodoform, or combinations thereof.
In a particularly preferred form, the haloform may be bromoform (CHBr3). The use of bromoform may provide a number of advantages. For instance, it has a high efficacy for a relatively small dose, which enables one device to deliver ient amounts of the inhibiting agent over an extended period of time. In addition, bromoform also has a relatively high density which adds to the overall weight of the bolus and allows for the bolus to be retained in the rumen i.e. it sinks to the ventral part of the rumen rather than floats reducing regurgitation.
However, e these advantages the ors have faced a number of challenges and problems to developing a bolus for the controlled release of a haloform, particularly bromoform, to a ruminant.
In a further embodiment, the bolus may comprise a core.
The core may be formed by the inhibiting agent mixed with a carrier. r, in alternative embodiments, the inhibiting agent may be provided in a substantially pure form e.g. is not mixed with a carrier.
In embodiments, the carrier may have a structure which promotes or facilitates ty for the carrier by the inhibiting agent. For instance, the carrier may have polar onal groups.
In embodiments, the carrier may be a vely polar substance e.g. it has a relatively high % w/w of polar functional groups. The inventors have surprisingly found that the James & Wells Ref: 316642NZ carrier and the inhibiting agent can interact with each other, and the interaction can affect the release rate of the inhibiting agent from the bolus. This aspect of the invention should become clearer from the following description.
Examples of suitable functional groups for the carrier to include are ester, fatty acids, fatty alcohols, yls and fatty amines. Without being limited to a specific mechanism, the inventors believe that the inhibiting agents may interact with polar functional groups in waxes, potentially via creation of hydrogen bonds. The amount of polar functional groups present in the carrier will affect the affinity of the carrier and the inhibiting agent for each other.
The inventors have found that a range of substances may be suitable for use as a carrier in the present ion. For instance, the carrier may be selected from the list of waxes, myristic acid, stearic acid, steryl alcohol, cetyl alcohol, cetosteryl alcohol or a combination thereof.
In a particularly preferred embodiment, the carrier may be a waxy substance. For e, the carrier may be selected from the list of bee’s wax, paraffin wax, 0, Carnauba, castor wax, Candellila, Jojoba, or Lanolin or a combination thereof.
In a ularly preferred embodiment, the carrier may comprise paraffin wax and castor wax.
In a particularly preferred ment, the carrier may comprise paraffin wax and castor wax in a ratio of about 50:50 (parts by weight).
In r embodiment, the carrier may se a mixture of two or more components. For example, the carrier may comprise a mixture of at least one relatively polar substance with a relatively non-polar substance. For instance, in some forms the carrier may include a mixture of paraffin wax (a mixture of s with no polar onal groups) and castor wax and / or carnauba wax (which have a relatively high amount of polar functional groups). As a result, the overall polarity of the carrier may be adjusted to achieve the desired ty for the inhibiting agent. This can be used to achieve a d release rate for the inhibiting agent.
James & Wells Ref: 316642NZ Additionally, to the above, solid carriers such as powdered activated carbon, zeolite or bentonite may also be used as a carrier. Accordingly, the discussion herein should not be seen as limiting on the scope of the present ion.
In a further embodiment, the carrier may also include one or more additional components. For example, additional ents such as elemental zinc or zinc oxide may be incorporated. Preferably, a high density material, such as a piece of metal (preferably steel) may be sed in the carrier. The additional components may be used to achieve a desired density for the core and / or bolus.
It should also be understood that additional components may be added to a cavity of the bolus separate to, and not mixed with, the carrier. This may be ularly beneficial to form a core having a desired release profile, where the density of the bolus can be adjusted to a desired amount by including the additional components.
Other suitable additives for incorporation into the carrier may also include colloidal silicon dioxide, charcoal, ite and zeolite(s).
Further s of the carrier and its effect on the release of the inhibiting agent from the bolus, together with the interaction of the carrier and housing, should become clearer from the following description.
In a preferred ment, the carrier may have a melting point between substantially 50-90°C.
In a particularly red embodiment, the carrier has a g point which is less than the boiling point of the inhibiting agent. This may be useful as the carrier can be melted and mixed with the inhibiting agent without substantial loss of the inhibiting agent due to evaporation.
In a preferred embodiment, the core may have a melting point greater than 37oC.
James & Wells Ref: 316642NZ In a particularly preferred ment, the core may have a g point greater than 40°C.
The melting point of the core may be beneficial to the function of the present technology in several ways. For instance, having a melting point above 37oC, and more preferably 40oC, can assist the carrier in stabilising the inhibiting agent when the bolus is in the rumen. This could be beneficial to control e of the inhibiting agent e.g. nt of the inhibiting agent through the material g the housing.
In an embodiment, the bolus may be adapted to reach a maximum release rate of approximately 0.05g to 2g of bromoform per day into the rumen.
In an embodiment, the bolus may be adapted to release bromoform in an amount of between 0.02g and 0.5g per day into the rumen.
In a particularly preferred embodiment, the bolus may be adapted to reach a maximum release rate of approximately 0.1 to 0.5g of bromoform per day into the rumen.
In a preferred embodiment, the bolus is configured to release bromoform in the amount of between 0.02g and 0.3 g per day into the rumen.
In an embodiment of the invention, the core of the bolus may comprise the rm, preferably bromoform, in an amount of 30% (by weight) to 80% (by weight), preferably in an amount of 55% (by weight) to 75% (by weight), more preferably in an amount of 50% (by ).
In a particularly preferred embodiment, the core comprises the haloform, preferably bromoform, in a concentration of no more than 55% (by weight).
The inventors have found that the rate of release of the inhibiting agent into the rumen increases me. This may be the result of several factors. Therefore, the rate of release starts from zero on administration of the animal and increases to a maximum. However, the James & Wells Ref: 316642NZ foregoing should not be seen as limiting, and other release rates are ged as within the scope of the present invention.
In a further embodiment, the bolus may include a housing.
Throughout the present specification, reference to the term "housing" should be understood as meaning a structure which can receive and hold a core ning the at least one ting agent.
In preferred embodiments, the housing comprises a body which has a cavity in which a core is located.
However, it should also be understood that the housing may take other forms. For instance, the g may include two or more cavities which can each receive and hold a separate core.
In one embodiment, the housing may include an open end.
The bolus may be used with an open end e.g. administered to an animal with the end open. As a , in these embodiments the open end provides an opening to in use expose the contents of the core to fluids in the rumen.
In yet a further and preferred embodiment, the housing may tely cover and surround the core e.g. it has a sealed cavity in which the core is located.
For instance, the bolus may include a g with a cavity in which at least a portion of the core can be located, and an open end to facilitate insertion of the core into the cavity. A cap can be used to cover the open end.
The cap may be formed separately of the housing and releasably or permanently secured thereto. Alternatively, the cap may be formed integrally to the housing.
In yet a further embodiment, the housing may be provided in at least two-parts, each of which has a cavity to receive a respective portion of the core. Together the at least two James & Wells Ref: 316642NZ parts tely nd the core and define a closed and sealed cavity in which the core is located.
In yet further embodiments, the housing may be formed around the core e.g. by moulding. Alternatively, the g and cap may together define a substantially closed and sealed cavity in which the core is d.
The inventors believe that the provision of a substantially or tely closed and sealed cavity is preferred because it can assist in achieving a desired controlled e of the inhibiting agent from the bolus of the present invention. For instance, in such an embodiment, the ting agent can pass through the material forming the housing e.g. by mass diffusion.
In embodiments, the housing may be configured to have sufficient structural integrity to remain intact for a predetermined period of time.
In a preferred embodiment, the housing may be configured to degrade over a predetermined period of time.
Throughout the present specification, reference to the term "predetermined period of time" should be understood as meaning the period of time over which the inhibiting agent is to be released to the animal.
In a particularly preferred embodiment, the predetermined period of time may be at least two months, preferably six months, and more preferably 12 months.
The inventors have surprisingly found that housings of the present invention may assist with the controlled release of the inhibiting agent. For instance, the housing is able to withstand the conditions in the rumen for the predetermined period of time. During this time, the housing protects the core from fluid in the rumen, yet can facilitate or contribute to the controlled release of the inhibiting agent. However, the design of the housing may allow the housing to disintegrate or degrade over the ermined period of time. This can contribute to mitigating adverse effects of device administration to an animal, and could also ensure that an animal can be treated with le bolus e.g. a second bolus is administered at or towards, or after, the end of the predetermined period of time.
James & Wells Ref: 316642NZ In embodiments of the invention, the ess of the housing may be selected to contribute to the rate of release of the inhibiting agent. For instance, the inventors have fied that thickness of the housing can affect the rate of release of the inhibiting agent from the bolus.
In these embodiments, a relatively thicker housing will have a relatively slower release rate than a relatively r housing.
In a preferred embodiment, the housing may have a thickness of at least 1mm.
In yet a further red embodiment, the housing may have a thickness of less than 3 mm.
In yet another preferred embodiment, the housing may have a thickness of between 1.5 to 2 mm, or between 0.5 to 2 mm.
In a particularly red embodiment, the housing has a thickness of 1 mm.
The thickness of the housing may be particularly important for achieving a desired controlled release for the inhibiting agent in embodiments such as those where the core is entirely ulated by the housing. This should become clearer from the ing discussion.
In an embodiment, the dimensions of the cavity may vary along the length of the housing.
In a preferred embodiment, the cavity includes at least two regions which have a different cross-sectional area to each other e.g. a first region having a first cross-sectional area and a second area having a second cross-sectional area.
In a particularly preferred embodiment, the first region has a relatively smaller cross-sectional area and the second region has a relatively larger cross-sectional area.
In yet a further preferred embodiment, the first region may be d closer to the open end than the second region.
James & Wells Ref: 316642NZ Having a cavity with regions having different cross-sectional areas to each other may facilitate more controlled release of the inhibiting agent(s) to better meet an animal’s requirements. For instance, a relatively smaller across-sectional area can be provided closer to the open end to deliver a relatively r dose of the inhibiting agent(s), whereas the relatively larger cross-sectional area may be provided closer to the distal end; this may be useful where the dose of the inhibiting agent needs to increase over time e.g. due to animal growth.
It should also be understood that the reverse ement may be ed e.g. the relatively larger cross-sectional area is provided closer to the open end and the relatively smaller cross -sectional area may be provided closer to the distal end. This arrangement may be useful where an initially higher dose of the inhibiting agent(s) is d, to be followed by a subsequently smaller dose at a subsequent time. For instance, this arrangement may be used where an animal has a high demand for the inhibiting agent e.g. at periods of relatively high feed intake and energy requirements such as during milking but to be followed by a period of relatively low feed intake e.g. during the dry-period.
Furthermore, it should be understood that the cross-sectional area of the cavity may increase gradually and continuously from the first region to the second region e.g. there is no defined "step" between the first region and the second region.
In other embodiments, the housing may include a third region having a third-cross sectional area. This may be further used to control the dose of the inhibiting s) to the animal. Accordingly, the ing should not be seen as limiting on the scope of the present technology.
In an embodiment, the thickness of a wall of the housing may vary along the length of the g. In such an embodiment, the wall thickness at or towards one end of the housing may be thicker than at the distal end. For example, the thickness of the wall at or towards the open end may be thinner in size than that of the distal end.
This arrangement may be particularly beneficial in assisting to control release of the inhibiting agent(s) over time. For instance, the relatively r wall(s) will e relatively quicker than the relatively thicker ). This structure can be used to control the rate James & Wells Ref: 316642NZ of ation of the housing along its length. For instance, it may be used to ensure that the open end is the only site at which fluids in the rumen are able to come into contact with, and erode, the core.
In preferred embodiments, the housing made be made from a material through which the inhibiting agent can migrate in use e.g. by a mass diffusion process.
In a preferred embodiment, the housing may be made from at least one plastic material. For instance, the housing may be made from a degradable c or material that degrades over time in the rumen.
In a particularly red embodiment the housing may be made from a material selected from the list of one or more of poly lactic acid (PLA), poly glycolic acid (PGA), poly lactic glycolic acid (PLGA), polypropylene, Polycaprolactone (PCL), poly(d-lactic acid) (PDLA), Polybutylene succinate (PBS), Polybutylene adipate thalate (PBAT), SLA polymer, ABS, or a combination thereof. In a particularly red embodiment, the housing ses PLA and PBS.
The material for the housing may comprise PLA, PBAT and/or PBS in different ratios as shown in examples 1 through 7 in the table below (% by weight): PLA (w%) PBS (w%) PBAT (w%) 1 100 2 70 30 3 40 60 4 20 80 70 30 6 40 60 7 20 80 In a particularly preferred embodiment, the material for the housing comprises PLA and PBS in a weight ratio ranging from 100:0 to 40:60 PLA:PBS.
In a particularly preferred embodiment, the housing comprises PLA and PBS in a weight ratio ranging from 100:0 to 40:60 PLA:PBS, wherein the housing has a ess of between 0,4 and 1,5 mm.
James & Wells Ref: 316642NZ In a further embodiment the core of the bolus of the invention is d by le housings which are arranged concentrically (e.g. akin to an onion). Such multiple gs (e.g. 2 or 3 or even more gs) have the advantage that the bolus will be degraded (e.g. by on) in the rumen less quickly. As a consequence, the haloform in the core will last longer in the rumen and methane production is reduced for a longer time. In embodiments comprising multiple housings the material and thickness of the housing can be as bed herein for other embodiments. In preferred embodiments a bolus of the invention comprises at least two housing layers, one outer housing and one inner g, the material of each housing comprising a biodegradable polymer and preferably a biodegradable polymer selected from the group ting of polylactic acid (PLA), polybutylene succinate (PBS), polybutylene adipate terephthalate (PBAT) and combinations thereof.
In addition, the housing may also be made from a non-biodegradable material, such as EVA, silicons, acrylates etc. As a result, the discussion herein should not be seen as limiting on the scope of the present invention.
In addition, the material from which the housing is made may include one or more other compounds e.g. plasticisers, hardeners, colourants etc.
However, in alternate embodiments, the housing may be made from one or more non-adsorbent materials i.e. a material into which, or through which, the inhibiting agent does not migrate. Using a non-absorbent material for the housing can assist with controlling the rate of release of the inhibiting agent(s) in certain ments such as an nded bolus. For instance, in these embodiments, the concentration of the inhibiting agent(s) in the core is not decreased by their absorption into the housing material.
In some embodiments, the bolus may include a r layer. In these embodiments, the r layer may be positioned between at least a portion of the core and the housing. For instance, the barrier layer can minimise, or completely prevent, contact between the portion of the core and the g. This can be useful to prevent dissolution of the inhibiting agent (or other compounds) to better control the release of the inhibiting agent(s) and improve the stability of the device. This could be particularly useful where the inhibiting agent(s) has a high solubility in the material(s) from which the housing is made.
James & Wells Ref: 316642NZ atively, in an embodiment where the barrier layer is provided between only a portion of the core and the housing, it may reduce but not tely prevent, migration of the inhibiting agent into the g. In effect, the barrier layer reduces the contact area between the core and the housing and so therefore may reduce the release rate of inhibiting agent than were the barrier layer not ed.
Alternatively, the bolus may not include a barrier layer. This configuration may be useful where the inhibiting agent(s) has a relatively low solubility in the material from which the housing is constructed. It may also be useful where the composition of the housing and / or carrier are selected to control the release rate e.g. the rate of diffusion of the inhibiting agent through the housing.
In another embodiment, the bolus may be adapted to have rates of dissolution of the core and the housing which provide substantially uniform dissolution of both ents in the rumen over time.
In one embodiment, the cavity in the housing may provide a reservoir configured to receive an amount of the inhibiting agent(s). For instance, the reservoir may be a closed cavity in the housing which can receive and hold the amount of the inhibiting agent.
In one ment, the bolus may include a dispensing mechanism.
In one embodiment, the carrier may have a relatively higher affinity for the inhibiting agent compared to the affinity of the g for the inhibiting agent. As discussed ere in this document, this may be achieved by the ve polarity of the substances forming the carrier and the g, and matching these materials appropriately to the inhibiting agent.
In another embodiment, the housing may be formed from a substance having a Shore D hardness of at least 40. In such an embodiment, it is believed that having a housing with a lower Shore D hardness of 40 to result in a bolus that is too soft, which could hinder James & Wells Ref: administration of the bolus to an animal or lead to it being otherwise damaged or prematurely ed before the full amount of inhibiting agent is administered.
In a r embodiment, the housing may be formed from a substance having a Shore D hardness of less than 80.
In r embodiment, the housing may be configured to facilitate the controlled release the inhibiting agent from the core. Without being d to a specific mechanism, the inventors postulate that the inhibiting agent may be released through the housing by the mechanism of mass diffusion.
In a further embodiment, the invention provides a bolus for administration to a ruminant animal, wherein said bolus comprises: a core, wherein the core comprises a haloform (preferably orm) mixed with a carrier; and a housing which covers at least a portion of the core or preferably the entire core; wherein, the bolus is ured to e the haloform.
In a further embodiment, the invention provides a bolus for administration to a ruminant animal, wherein said bolus comprises: a core, wherein the core comprises a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or the entire core; wherein, the bolus is configured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof.
In a further embodiment, the invention provides a bolus for administration to a ruminant , wherein said bolus comprises: a core, wherein the core comprises a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or preferably the entire core; wherein, the bolus is configured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the housing comprises a biodegradable polymer and ably a biodegradable polymer selected from the group consisting of polylactic acid (PLA), polybutylene succinate (PBS), polybutylene adipate thalate (PBAT) and combinations thereof.
James & Wells Ref: 316642NZ In a further embodiment, the invention provides a bolus for administration to a ruminant , wherein said bolus comprises: a core, wherein the core comprises a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or preferably the entire core; wherein, the bolus is configured to release the haloform; and wherein the carrier comprises wax, ably castor wax, paraffin wax or a mixture thereof; and wherein the housing has a layer thickness of between 0,4 and 1.5 mm.
In a further embodiment, the invention provides a bolus for administration to a nt animal, wherein said bolus comprises: a core, wherein the core ses a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or preferably the entire core; wherein, the bolus is configured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the housing comprises a radable polymer and preferably a radable polymer selected from the group consisting of polylactic acid (PLA), polybutylene succinate (PBS), polybutylene e terephthalate (PBAT) and combinations thereof; and wherein the housing has a layer ess of between 0,4 and 1.5 mm.
In a further embodiment, the invention provides a bolus for administration to a ruminant animal, wherein said bolus comprises: a core, n the core comprises a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or ably the entire core; wherein, the bolus is configured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, in wax or a mixture thereof; and wherein the housing comprises a biodegradable polymer and preferably a biodegradable polymer selected from the group consisting of polylactic acid (PLA), tylene succinate (PBS), polybutylene adipate terephthalate (PBAT) and combinations f; and wherein the housing has a layer thickness of less than 2 mm.
In a further embodiment, the invention provides a bolus for administration to a ruminant animal, wherein said bolus comprises: James & Wells Ref: 316642NZ a core, wherein the core ses a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or the entire core; wherein, the bolus is configured to release the haloform; and wherein the core further comprises at least one metal piece (such as metal pellets and/or a metal rod), preferably the metal being steel or zinc. The advantage of this embodiment is that the bolus density is increased, and the bolus is less likely of being regurgitated by the animal.
Preferably the bolus of the invention r comprises a ier, and preferably said densifier ses at least one piece of metal, preferably the densifier is provided in the core.
In a further embodiment, the ion provides a bolus for administration to a ruminant animal, wherein said bolus comprises: a core, wherein the core comprises a haloform (preferably bromoform) mixed with a carrier; and a housing which covers at least a portion of the core or preferably the entire core; wherein, the bolus is ured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the housing comprises polylactic acid (PLA); and wherein the housing preferably has a layer thickness of less than 2 mm.
In a further aspect, the invention provides a delayed release dosage form for administration to a nt animal, wherein said delayed release dosage form ses: a core, wherein the core comprises a haloform (preferably bromoform); and a coating which covers at least a portion of the core or preferably the entire core; wherein the delayed e dosage form is configured to release the haloform.
In a further embodiment, the invention provides a delayed release dosage form for administration to a ruminant animal, wherein said delayed release dosage form ses: a core, wherein the core comprises a haloform (preferably bromoform); and a coating which covers art least a portion of the core or preferably the entire core; wherein the delayed release dosage form is configured to release the rm; and wherein the core r comprises wax, preferably castor wax, paraffin wax or a mixture thereof.
In a further embodiment, the invention provides a delayed release dosage form for stration to a ruminant animal, wherein said delayed release dosage form comprises: a core, wherein the core ses a haloform (preferably bromoform) mixed with a carrier; and a James & Wells Ref: 316642NZ coating which covers at least a portion of the core or preferably the entire core; n the delayed release dosage form is configured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the coating comprises a biodegradable polymer and preferably a biodegradable polymer selected from the group ting of polylactic acid (PLA), polybutylene succinate (PBS), polybutylene adipate terephthalate (PBAT) and combinations thereof.
In a further embodiment, the invention provides a delayed release dosage form for administration to a nt animal, wherein said delayed release dosage form comprises: a core, wherein the core comprises a haloform (preferably orm) mixed with a carrier; and a coating which covers at least a portion of the core or preferably the entire core; wherein the delayed release dosage form is configured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the coating has a layer ess of between 0,4 and 1.5 mm.
In a further embodiment, the ion provides a delayed release dosage form for administration to a ruminant animal, wherein said delayed release dosage form comprises: a core, wherein the core comprises a haloform (preferably bromoform) mixed with a carrier; and a coating which covers at least a portion of the core or preferably the entire core; wherein the delayed release dosage form is ured to release the haloform; and wherein the carrier comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the g comprises a biodegradable polymer and preferably a biodegradable polymer selected from the group consisting of polylactic acid (PLA), tylene succinate (PBS), polybutylene adipate terephthalate (PBAT) and combinations thereof; and wherein the coating has a layer thickness of n 0,4 and 1.5 mm.
In a further embodiment, the invention provides a delayed release dosage form for administration to a ruminant animal, wherein said delayed release dosage form ses: a core, wherein the core comprises a haloform (preferably bromoform) mixed with a carrier; and a coating which covers at least a portion of the core or preferably the entire core; wherein the delayed release dosage form is configured to release the haloform; and wherein the r comprises wax, preferably castor wax, paraffin wax or a mixture thereof; and wherein the g comprises a biodegradable polymer and preferably a radable polymer selected James & Wells Ref: 316642NZ from the group consisting of polylactic acid (PLA), polybutylene succinate (PBS), tylene e thalate (PBAT) and ations thereof; and wherein the coating has a layer thickness of less than 2 mm.
In a further embodiment, the invention es a delayed release dosage form for administration to a ruminant animal, wherein said delayed release dosage form comprises: a core, n the core comprises a haloform (preferably bromoform) mixed with a carrier; and a coating which covers the core; wherein the delayed release dosage form is configured to release the haloform; and wherein the core further comprises at least one metal piece (such as metal pellets and/or a metal rod), preferably the metal being steel or zinc. An advantage of this embodiment is that the delayed release dosage form density is increased, and the delayed release dosage form is less likely of being regurgitated by the animal.
In a further embodiment, the invention provides a delayed release dosage form for administration to a ruminant animal, wherein said d release dosage form comprises: a core, n the core comprises a haloform (preferably bromoform) mixed with a carrier; and a coating which covers a portion of the core or the entire core; wherein the delayed release dosage form is ured to release the haloform; and wherein the carrier comprises wax, ably castor wax, paraffin wax or a mixture thereof; and wherein the coating comprises polylactic acid (PLA); and wherein the coating preferably has a layer ess of less than 2 mm. Experiments have shown that coating layer thickness less than 2 mm are preferably because this thickness lets the haloform permeate from the core material outwardly in an optimal rate.
In a delayed release dosage form or a bolus of the invention preferably less than 50% of the haloform comprised in the core is released over a time of three months. In a preferred embodiment of the delayed release dosage form or a bolus of the invention the core comprises at least 100 grams of haloform. The core of the bolus or of the delayed release dosage form of the invention preferably comprises between 30 wt% and 70 wt% of haloform (preferably bromoform).
At present, it is understood that controlled release of the ting agent through the housing may be influenced by a number of factors. For example, the affinity of the inhibiting agent for the carrier may play a role in the diffusion of the inhibiting agent through the housing.
It is understood that more polar carriers or rs containing a high degree of polar functional James & Wells Ref: 316642NZ groups will have a higher affinity with the inhibiting agent than less polar carriers or carriers with a lower degree of functional groups.
The relative affinity of the materials forming the g and the core for the inhibiting agent may also affect controlled e of the inhibiting agent from the core. For example, having a housing with a vely lower affinity for the inhibiting agent ed to the affinity of the carrier for the inhibiting agent, could be a factor in controlling the rate of release of the inhibiting agent from the core. These aspects of the invention should become clearer from the description herein.
Throughout the present specification, reference to the term "release mechanism" should be understood as meaning an arrangement to release a predetermined amount of the inhibiting agent (s) over time. For instance, the e mechanism may comprise a valve arrangement which can release an amount of the inhibiting agent(s) via an outlet. Alternatively, the release mechanism may be a e-type mechanism having a plunger and actuator; over time, the actuator moves the plunger in the reservoir to drive the inhibiting agent(s) out of the reservoir.
Also, the ing items are ing to the ion: Item 1 provides a bolus for administration to a ruminant animal, wherein said bolus is configured to release an effective amount of at least one inhibiting agent.
Item 2 provides the bolus of any one of item 1, wherein the at least one inhibiting agent is a methane inhibitor.
Item 3 provides the bolus of items 1 or 2, wherein the at least one inhibiting agent is a haloform selected from chloroform, bromoform, iodoform, or combinations thereof.
Item 4 relates to the bolus of any one of items 1-3, wherein the at least one inhibiting agent is Item 5 relates to the bolus of any one of items 1-4, wherein the bolus includes a core which comprises an amount of the inhibiting agent.
Item 6 provides the bolus of item 5, wherein the core includes a carrier mixed with the inhibiting agent.
James & Wells Ref: 316642NZ Item 7 relates to the bolus of item 6, wherein the carrier is a waxy substance, selected from the bee’s wax, paraffin wax, PEG4000, Carnauba, Candellila, Jojoba, or Lanolin or a combination Item 8 relates to the bolus of any one of items 5-7, wherein the core has a melting point greater than 37°C.
Item 9 relates to the bolus of any one of items 5-8, wherein the bolus includes a housing to receive and hold the core.
Item 10 relates to the bolus of item 9, wherein the housing includes a cavity which can receive and hold the core.
Item 11 s to the bolus of item 9 or 10, wherein the housing includes an opening to facilitate, in use, exposure of the core to fluid in the rumen of the ruminant.
Item 12 relates to the bolus of item 10 or 11, wherein the cavity includes a first region which has a first cross-sectional area and a second region which has a second cross-sectional area, and n the first cross-sectional area and the second sectional area are different to each other to facilitate controlled release of the inhibiting agent from the core.
Item 13 relates to the bolus of any one of items 9-12, wherein the g is configured to degrade over a predetermined period of time.
Item 14 relates to the bolus of any one of items 9-13, wherein housing is made from one or more non-adsorbent als selected from the following: poly lactic acid (PLA), poly glycolic acid (PGA), poly lactic ic acid (PLGA), polypropylene, SLA polymer, PBS, or a combination thereof.
Item 15 relates to the bolus of any one of items 9-14, further comprising a barrier layer between at least a portion of the housing and the core to isolate the portion of the housing and the core from contact with each other.
Item 16 relates to the bolus of any one of items 1 to 15, wherein the bolus is adapted to release a dose of approximately 0.1g to 0.5g of the ting agent per day into the nt animal’s rumen.
Item 17 relates to the bolus of any one of items 1 to 16, wherein the bolus is adapted to release the inhibiting agent over a period of at least six months.
Item 18 relates to the bolus of any one of items 1 to 17, wherein the bolus is d to release the inhibiting agent within two years.
Item 19 provides a method for reducing emission of gas from a ruminant animal, the method comprising the step of administering to said ruminant animal the bolus of any one of items 1-18.
James & Wells Ref: 316642NZ Item 20 es a method for reducing methane production in a ruminant animal, the method comprising the step of administering to said ruminant animal the bolus as item in any one of items 1-18.
Item 21 provides the use of a methane inhibitor and a carrier in a bolus for reducing methane production in a ruminant animal.
Item 22 provides the use of a methane inhibitor and a r in a bolus for reducing methane on from a ruminant animal.
Item 23 provides the use of a rm in the cture of a bolus for reducing the emission of one or more greenhouse gases ("GHGs") from a ruminant animal.
Item 24 provides a method of manufacture of a bolus of any one of items 1 to 18, comprising: a. forming a housing which has a cavity; b. forming a core which includes the inhibiting agent; c. transferring the core to the .
Item 25 s to the method of item 24, wherein the step of forming the core involves mixing a carrier material with the inhibiting agent.
Item 26 provides the method of item 25, wherein the step of forming the core involves g the carrier material to melt the carrier material prior to mixing the carrier material with the inhibiting agent to create a e.
Item 27 relates to the method of any one of items 24 to 26, wherein the step of transferring the core to the cavity involves pouring the mixture into the cavity.
Further s of the invention, which should be considered in all its novel aspects, will become apparent to those skilled in the art upon reading of the following description which provides at least one example of a practical application of the invention.
Brief Description of the Drawings One or more embodiments of the invention will be described below by way of example only, and without intending to be limiting, with reference to the following drawings, in which: Figure 1A is a front view of a bolus in accordance with one aspect of the invention.
James & Wells Ref: 316642NZ Figure 1B is a perspective cross sectional view of the bolus of Figure 1A.
Figure 2A is a front view of an alternative embodiment of a bolus in ance with a further aspect of the ion.
Figure 2B is a perspective cross sectional view of the bolus of Figure 2A.
Figure 3A is a front view of an ative embodiment of a bolus in accordance with a further aspect of the invention.
Figure 3B is a perspective cross sectional view of the bolus of figure 3A.
Figure 4A is a front view of an alternative ment of a bolus in accordance with a further aspect of the invention.
Figure 4B is a perspective cross sectional view of the bolus of Figure 4A.
Figure 5 is a front view of an alternative embodiment of a bolus in accordance with a further aspect of the invention.
Figure 6A is a front cross sectional-view of an alternative embodiment of a bolus in accordance with a further aspect of the invention.
Figure 6B is a perspective cross-sectional view of the bolus of Figure 6A.
Figure 7 is a flow diagram showing representative steps in a method of cturing a bolus in according with an aspect of the invention.
Figure 8 is a graph showing the daily diffusion/release rate of bromoform from bolus in the media.
Figure 9 is a graph showing variability in the diffusion results.
James & Wells Ref: 316642NZ Figure 10 is a graph showing the concentration of Bromoform in a diffusion media over time.
Figure 11 is a graph showing the mass of Bromoform ed (%) over time.
Figure 12 is a graph showing the release rates of bromoform from ent carriers in open top falcon tubes.
Figure 13A is a graph showing the release rate of bromoform from paraffin wax as a carrier.
Figure 13B is a graph showing the release rate of bromoform from carnauba wax as a carrier.
Figure 13C is a graph showing the release rate of bromoform from Beeswax as a carrier.
Figure 14 is a graph showing the average release rate of bromoform for a reinforced bolus in accordance with an embodiment of the present invention.
Figure 15A is a side view showing a reinforced bolus design in accordance with an alternative embodiment of the present ion.
Figure 15B is a side cross section view of a reinforced bolus design in ance with an alternative embodiment of the present invention.
Figure 15C is a side cross section view of a reinforced bolus design in ance with an alternative embodiment of the present invention.
Figure 15D is a cross n view of the internal structure of a reinforced bolus design in accordance with an alternative embodiment of the present invention.
James & Wells Ref: 316642NZ Figure 16A shows e specimen shrinkage from injection ng.
Figure 16B shows bromoform absorbed vs bromoform composition in beeswax for different itions of PLA blended with PBS and PBAT.
Figure 16C shows bromoform absorbed vs bromoform composition in beeswax for 3D d PLA and injection moulded 2003D PLA.
Figure 16D shows bromoform absorption rate vs bromoform composition in beeswax for different compositions of PLA blended with PBS and PBAT.
Figure 16E shows bromoform absorption rate vs PLA composition in beeswax with different concentrations of bromoform.
Figure 17 shows hardness analysis of PLA blends before and after exposure to Figure 18A shows the release of Bromoform from 67% (by weight) and 55% (by weight) Bromoform loaded 1 mm thick boluses.
Figure 18B shows cumulative release of Bromoform from boluses.
Figure 18C shows cumulative plot of 7, 8 and 9 days for 57-1 mm bolus.
Figure 18D shows release rate from ent boluses.
The term "bromet" as used in the s refers to a bromoform containing bolus.
Brief Description of Preferred Embodiments of the Invention The present invention relates to devices and methods to deliver substances to animals, ularly hydrophobic substances to animals. In preferred forms, the substance is an inhibiting agent such as a methane inhibitor. The present invention is exemplified with reference James & Wells Ref: 316642NZ to a preferred embodiment. However, this should not be seen as limiting on the scope of the invention. One skilled in the art would understand how to apply the teachings herein to devices for delivery of other substances to animals.
Referring first to Figures 1A and 1B, there is provided a bolus (100). The bolus (100) is configured to reduce or ate release of one or more greenhouse gases ("GHGs") from a ruminant animal. For ce, the bolus (100) may reduce or eliminate production of GHGs by the ruminant , and therefore reduce the gases which are released by the animal.
In on, or in the alternative, the bolus (100) may improve animal production by preventing the conversion of feed into one or more GHGs from a ruminant animal.
The bolus (100) includes a core (110) and a housing (120).
In some embodiments, the bolus (100) also es a barrier layer (130). The barrier layer (130) is configured to separate the core (110) from the housing (120).
The housing (120) is generally cylindrical and has an open end indicated generally as (60), and a rounded, closed end (170). The open end (160) can allow fluids in the ruminant animal’s rumen to contact the core (110).
Further aspects of the bolus (100) should become clearer from the following discussion.
The core (110) includes at least one ting agent, which can be optionally mixed with a suitable carrier(s). Particularly preferred carriers include PEG4000, PEG400, natural and synthetic waxes, fatty acids, fatty alcohols, fatty amines, phospholipids-lecithin, and adsorbents, and combinations thereof.
Suitable waxes include x, paraffin, castor wax, ba wax, Candellila wax, Jojoba wax, and Lanolin.
James & Wells Ref: In addition, minerals such as zeolite, bentonite, kaolin, activated carbon or a combination f may also be suitably mixed with the ting agent. It is also possible to include other compounds such a zinc (i.e. in powdered form) or zinc oxide.
Alternatively, the core (110) may include a trated antially pure) form of the inhibiting agent.
In a preferred embodiment, the inhibiting agent is a methane inhibiting agent. ularly preferred forms e haloforms e.g. halomethanes such as bromoform (CHBr3) - as is discussed in more detail below.
It should be appreciated by a person skilled in the art that other carriers may be selected or used depending on the application. It is envisioned that certain carriers can be selected in order to provide a desired release profile for the inhibiting agent, or alternatively provide the desired physical properties of the core material –density or volume etc.
In preferred ments the carrier used in the present invention is a natural waxy substance, with a preferred melting point between 50-90°C, or more preferably 60-80°C.
It was found by the inventors that having a carrier with this melting point range allowed for melting of the carrier and mixing with the ting agent(s) to form a nous core (110), and to subsequently solidify at room temperature.
A particularly preferred carrier is a mixture containing castor wax with one or more of paraffin wax, beeswax, and carnauba wax. Further preferred, the carrier is a mixture containing castor wax and paraffin wax.
It should be appreciated that the ratio of carrier to inhibiting agent may be chosen to optimise the function of the bolus (100) e.g. to suit the desired release profile for the inhibiting agent(s).
James & Wells Ref: 316642NZ When formed, the core (comprising both the r and inhibiting s)) preferably has a melting point of at least 45oC. Having this minimum melting point will assist with ensuring that the core (110) does not melt when the bolus (100) has been administered to the ruminant animal. In addition, it will assist to ensure that the bolus (100) is unlikely to melt on inadvertent exposure to elevated temperatures e.g. those temperatures that could reasonably be enced during transport and/or storage.
It should be appreciated that the range of melting points for the core (110) may be adapted by varying the ratio of inhibiting agent(s) to carrier forming the core (110).
A preferred ratio of inhibiting agent to carrier may include substantially 80:20 w/w% to substantially 50:50 w/w%, or preferably substantially 70:30 w/w% to ntially 60:40 w/w %, or more preferably ntially 66:33 w/w%.
Inhibiting agent(s) In a preferred embodiment, the inhibiting agent is one or more methane inhibiting compounds.
Suitable methane inhibitors include haloforms such as bromoform, chloroform, iodoform and ations thereof. It is envisioned that any methane inhibitor that is suitable for internal administration to a ruminant animal may be used with the present ion.
The inventors have surprisingly found that bromoform is a particularly well suited for use in a bolus (100) according to the present ion. Accordingly, reference herein will be made to the inhibiting agent(s) as bromoform. However, this should not be seen as limiting on the scope of the t invention as alternatives are also envisaged as being within the scope of the present invention.
Bromoform is reactive and has a short half-life in animals (0.8 hrs in rats, 1.2 hours in mice, US Dept of Health, 2003). It is a liquid at room temperature and is denser than water. Previous trials demonstrated no residues in meat and tissue from slaughtered steers, after 48 hour with holding period (Kinley et al. Mitigating the carbon footprint and improving James & Wells Ref: 316642NZ productivity of nt livestock agriculture using a red seaweed, Journal of Cleaner Production 259 (2020) 120836), and no significant increase in the level in milk (Roque et al.
Inclusion of Asparagopsis armata in lactating dairy cows’ diet reduces enteric methane emission by over 50 percent; Journal of Cleaner tion 234 (2019) 132-138).
Bromoform has a relatively high efficacy e.g. effect per administered dose. This enables sufficient quantities to be provided in a core (110) to manufacture a bolus (100) which can deliver controlled release of the inhibiting agent over an extended term.
Additionally, bromoform also has a relatively high y. This can assist with achieving a higher retention of the bolus (100) in the rumen, as the density of the bolus can be optimised to promote the bolus (100) sinking to the ventral part of the rumen, rather than floating.
The above points notwithstanding, there is a prevailing concern about using bromoform in animals. The compound is thought to have e s such as being carcinogenic at certain exposure .
In addition, there are technical challenges which exist when bromoform is administered to animals. These include the lity of the substance, and its ability to dissolve substances which could be used for its delivery. Furthermore, achieving a precise (and relatively low) dose rate over a period of time is a challenge.
Housing The housing (120) includes a cavity (not numbered in the Figures) which is sized and dimensioned to receive the core (110). The housing (120) forms the external structure of the bolus (100).
The housing (120) is configured to provide structural integrity for the bolus (100) but yet is also adapted to degrade over time. Degradation of the housing (120) can tate e of the inhibiting agent over the predetermined period of time.
James & Wells Ref: 316642NZ The housing (120) is preferably non-toxic and resists erosion in the rumen of the ruminant for a sufficient period of time to facilitate release of inhibiting agent from the core (110) at the desired rate. It should be appreciated by the person skilled in the art that the dissolution rate of the housing (120) and the core (110) can be configured to allow the lled release of the inhibiting agent in the ruminant animal’s rumen.
Preferably, the housing (120) is composed of a biodegradable, non-absorbent material, or a material which is otherwise compatible with waste al in slaughter facilities.
It should be appreciated that any material that is suitable for internal administration to a nt animal with the desired dissolution rates can be used with the t ion.
In a preferred embodiment, the housing (120) is preferably selected from a radable material, particularly preferred biodegradable materials include polymers such as polylactic acid (PLA), polyglycolic acid (PGA), polylactic glycolic acid (PLGA), polypropylene, SLA polymer, PBS and combinations f. In a particularly preferred embodiment, the housing (120) is made of a material comprising PLA and PBAT.
In a preferred embodiment the housing (120) is composed of PLA. PLA is available in three forms, D-, L- and a racemic mixture of both D and L. All three types of PLA may be used in the housing (120) of the present invention.
In a preferred form, PLA is preferred as it degrades into lactic acid and is commonly used as medical implants. Depending on the type of PLA used, PLA breaks down inside the body within six months to two years.
It should be appreciated by the person skilled in the art that other suitable biodegradable materials can be used as the g (120).
In an optional ment, further fillers, binders, surfactants, active agents and/or absorbents may be included in the bolus of the present invention.
James & Wells Ref: 316642NZ As can be seen in Figures 1A and 1B, the bolus (100) has a substantially cylindrical form. The housing (120) includes a smooth external surface to assist with ingestion of the bolus (100) by the ruminant animal.
It should be appreciated by the person skilled in the art that the size, thickness and/or dimensions of the bolus (100), including the core (110), barrier layer (130) if provided, and the housing (120) can be adjusted depending on the dose of inhibiting agent to be red to the ruminant, without departing from the spirit and scope of the invention. For example, a smaller size bolus (100) can be adapted for use in smaller ruminant animals such as sheep or goats, while a larger sized bolus (100) can be used in larger ruminant s such as cattle. A bolus for a large animal, such as cattle, may have the dimensions of 13cm , 3.4cm diameter and 257gm in weight (Throughout the application "gm" refers to gram). A bolus for a relatively small animal, such as a sheep, may have the dimensions of 8.5cm length, 2cm er and 60gms in weight. Alternatively, a smaller bolus may be administered to a vely larger nt animal, such as cattle; such a relatively smaller bolus may have the dimensions of 3.4- 3.8cm length and 2.6-3.0cm diameter.
In it also envisaged that multiple smaller s may be used in combination. In preferred embodiments, the bolus and the delayed dosage form of the invention has a length of at least 5 cm and most preferably a length of at least 10 cm, preferably 10.3 cm. In preferred embodiments, the bolus and the delayed dosage form of the invention has a diameter of at least 2 cm, preferably 3.4 cm and a length of at least 10 cm, preferably 10.3 cm. Preferably, the bolus and the delayed dosage form of the invention has a weight of at between 100 and 300 grams.
Additionally, the g (120) may also be configured to control the release rates of the core (110) and/or degradation of the bolus (100). For example, the internal cross-sectional area of the cavity may be adapted to control the amount of the core (110) t in the bolus (100). In such an embodiment, the al volume of the cavity may be adapted to increase in size from the open end (160) to the closed end (170). This may be useful for increasing the amount of inhibiting agent(s) over time. This may account for animal growth where feed intake of the animal increases.
James & Wells Ref: 316642NZ Additionally, or alternatively, the sectional thickness of the wall(s) forming the housing (120) may increase along the length of the housing (120). For instance, the wall(s) may be a thicker at one end of the housing (120) than the other. In such an embodiment, the thickness of the wall at the open end (160) may be r in size than towards closed end (170).
This can assist with ing lled dissolution of the core formulation from the bolus.
Barrier layer The barrier layer (130) is an al component of the bolus (100) of the present invention and may be included to provide onal stability to the bolus (100). The barrier layer (130) can be configured to partially or completely prevent contact between the core (110) and the housing (120). The barrier layer (130) is ably selected from a waxy material, epoxy or a silicon material.
It should be appreciated by the person skilled in the art, the barrier (130) layer may be selected dependent on the desired application and/or release e. For example, where further control of the release rate of the inhibiting agent is desired, choosing a barrier layer (130) material, shape and configuration can facilitate obtaining the desired release profile.
Exemplified composition As an ified embodiment, the bolus may comprise a core enclosed by a housing. The bolus may be about 13 cm in length and about 3,4cm in diameter with an approximate weight of 257gm.
The housing may be made of PLA (3052D, 3001D, 3251D, L130, etc), e.g. by injection moulding, and have a thickness of 1mm.
The matrix of the core may be made of a blend of castor wax and paraffin wax in a ratio of 50:50 (by weight). This matrix may contain bromoform as an inhibiting agent in a concentration of about 50% (by weight).
James & Wells Ref: 316642NZ Method of Treatment The bolus (100) is delivered orally into the rumen of the ruminant animal to be treated, entering the rumen via the oesophagus. In the rumen, stomach fluids (and other matter such as plant fibre mat) act to ally erode or dissolve the core (110) to release the inhibiting agent over time. However, for the duration of the treatment period, the housing is substantially intact.
The open end (160) allows stomach fluids and fibrous matter to come into t with the core (110). In on, it assists to control release of the core (110) therefrom to the rumen.
The core (110) and the housing (120) are designed to facilitate release of the inhibiting agent over a period of time for which an animal is to be treated according to a method disclosed .
The bolus (100) is adapted to release the inhibiting agent over a period of at least six months, ably 12 months, and potentially up to two years.
Preferably, the release rates of the inhibiting agent may be calculated based on the weight of the ruminant animal to be treated and the type of inhibiting agent used. As such, it will be appreciated that the desired release rates may vary from animal to . Typically, the desired release rates may be calculated on an amount of inhibiting agent/weight of animal.
Alternatively, the d release rates may also be ated based on the amount of feed consumed by the animal. ularly preferred release rates for bromoform include from approximately 0.1 – approximately 0.5 g/day, and more preferably approximately 0.2 g/day.
Additionally, it should be appreciated by a person skilled in the art that a ruminant animal can be treated by multiple boluses (100) according to the present invention in order to achieve a preferred dosage of the inhibiting agent. This can allow a bolus (100) to be manufactured which has a concentration and total load of the inhibiting agent. Multiple of those bolus (100) can be administered to an animal concurrently or sequentially. This will allow the desired dosage to be provided to the animal. This can be particularly beneficial to allow the bolus James & Wells Ref: 316642NZ (100) to be used with animals ing different doses of inhibiting agent e.g. larger or smaller animals, or to compensate for natural growth over time.
The bolus (100) is adapted to deliver a dose of inhibiting agent directly into the rumen of the animal. For instance, bromoform may be ed at a rate at which it can effectively reduce or eliminate methane production during ion. That will reduce the on of greenhouse gases by the animal and therefore reduce the environmental s of agriculture.
In addition, the bolus (100) may improve the ruminant’s conversion of feed for animal production. For example, by reducing methane production during digestion, it is believed that this may lead to more efficient utilization of ed feed, and result in improved growth and weight gain, or other production such as milk production. In addition, the compositions for the core and synergistic effects arising from the combination of carrier and inhibiting agent(s) may enable the provision of a slow-release, long term delivery device to improve animal productivity and / or reduce emission of greenhouse gases.
First Alternate Housing Embodiment Referring now to Figure 2A-2B which shows an alternative ment of a bolus (200) according to an embodiment of the invention.
Aspects of the bolus (200) are similar to those of the bolus (100), and therefore like references refer to like components.
A series of ribs (240) are provided along an external e of the g (120).
The ribs (240) may provide additional structural strength to the bolus (200), and can assist to prevent it rupturing if the core (110) were to swell. Additionally, or alternatively, the (240) ribs may also assist the administration of the bolus (200) to the ruminant animal.
As illustrated, the ribs (240) are provided as a series of concentric "hoops".
However, the ribs (240) could be a series of parallel or non-parallel ribs (not illustrated) which extend along the length of the bolus (200) James & Wells Ref: 316642NZ Second Alternate g ment Referring now to Figures 3A-3B which show an alternative embodiment of a bolus (300) according to an embodiment of the invention.
Aspects of the bolus (300) are similar to those of the bolus (100) described above, and therefore like references refer to like components.
The bolus (300) includes additional features on the external surface of the housing (120), including depressions or grooves (350).
The grooves (350) may promote ns of the housing (120) ng away as it degrades. This can be used to further l the release profile for the inhibiting agent.
Third Alternate Housing Embodiment Referring now to s 4A-4B which show an alternative embodiment of a bolus (400) according to an embodiment of the invention.
Aspects of the bolus (400) are similar to those of the bolus (100) described above, and therefore like references refer to like ents.
The bolus (400) includes a housing (120) which has a cavity (not illustrated in the Figures) that is configured to receive and hold the core (110).
The housing (120) tapers along its length. For instance, the distance between the external surfaces of distal sides of the housing (120) increases along the length of the bolus (400). For instance, as is indicated in Figure 4A, the width (X) is less than the width (Y).
Alternatively, the bolus (400) may have side walls of substantially constant thickness, but which are structured and orientated to define a taper for the bolus (400).
James & Wells Ref: 316642NZ This configuration may allow for better controlled degradation of the core (110) and thereby provide additional l for e of the inhibiting agent.
Fourth ate Housing Embodiment ing now to Figure 5A which shows an ative embodiment of a bolus (500) according to an embodiment of the invention.
Aspects of the bolus (500) are similar to those described above, and therefore like references refer to like components.
The bolus (500) includes a reservoir (580) adapted to hold a relatively concentrated form of the inhibiting agent e.g. bromoform in a substantially pure, liquid form.
The bolus (500) includes a sing mechanism which is configured to dispense predetermined dose(s) of the inhibiting agent from the reservoir (580).
In the illustrated embodiment, the dispensing ism is a pump (590) in communication with a valve. At predetermined times, the pump (590) dispenses a dose of the inhibiting agent via the valve (590), to release the inhibiting agent to the rumen to which the bolus (500) has been administered.
The dispensing mechanism may be configured to release a consistent e.g. the same, amount of the ting agent at defined intervals.
Alternatively, the dispensing mechanism may be configured to vary the amount of inhibiting agent released at different times. This may be useful to enable the bolus (500) to provide an effective amount of inhibiting agent which accounts for growth of the animal. In addition, or alternatively, it may compensate for other factors changes e.g. seasonal variations in methane production which would necessitate a higher dose of inhibiting agent.
In a further embodiment, the bolus (500) may include sensors (not shown). For example, temperature sensors may be included within the bolus (500). Additionally, or James & Wells Ref: 316642NZ atively, other sensors may also be included in the bolus, such as locomotion and pH. The addition of such sensors can provide valuable information on the feed intake of the animal and assess whether the amount of inhibiting agent is sufficient for the animal.
Fifth Alternate Housing Embodiment Referring now to Figures 6A and 6B which show an ative embodiment of a bolus (600) according to an embodiment of the invention.
The bolus (600) can be adapted to include additional features within the cavity of the housing, such as grooves or ribs (680) formed on an inner wall of the housing (120) that defines the cavity.
Aspects of the bolus (600) are similar to those of the bolus (100), and ore like references refer to like components.
A series of ribs (680) are provided along an internal surface of the g (120).
The ribs (680) may provide additional structural strength to the bolus (600), and/or provide additional means to retain the contents of the core formulation within the cavity of the housing. onally, or alternatively, the (680) ribs may also assist with the retention of the core within the housing. Further, the ribs may also provide controlled dissolution of the core formation from the bolus (600) to the ruminant animal.
In one embodiment, the external surface of the housing will remain smooth or uniform.
Sixth Alternate Housing Embodiment Referring now to Figures 15A to 15D which show a further embodiment of a bolus (700) according to an aspect of the present invention. Dimensions of the bolus in the Figure are provided in mm. ably, the bolus has a length of 13 cm, a diameter of 3.4 cm and preferably a weight of about 250 gm.
James & Wells Ref: 316642NZ The bolus (700) can be adapted to include additional es with the internal reinforcing structure on the housing.
Aspects of the bolus (700) are similar to those of the bolus (100), and ore like references refer to like components.
The bolus (700) includes at least one reinforcing rib (710) located inside a cavity (unnumbered) defined by the housing structure. A cap (720) may also be provided e.g. releasably attached to the bolus (700) to close the open end of the bolus (700). Attachment may be provided by a on fit arrangement, or a screw thread arrangement in which corresponding screw threads on the housing and cap engage each other. Alternatively, the cap may be attached to the g by an adhesive or other mechanical er.
The reinforcing rib(s) (720) may improve the structural integrity of the bolus (700) and assist it to hold its shape.
Method of Manufacture Referring now to Figure 7, which is a flow chart showing representative steps in a method of manufacturing (800) a bolus e.g. (100), (200), (300), (400), according to the present invention.
In general terms, the method includes the step (810) of g the housing (120) and the step (820) forming a core (110).
Housing Forming the housing (120) may occur using any technique as should be known to one skilled in the art. For instance, a suitable material may be extruded into a desired shape defining a cavity. Alternatively, an additive layering manufacturing process could also be used to build the housing shape ng a cavity. It is also ged that a moulding process could be used e.g. a sacrificial moulding or injection moulding process, 3D printing or hot melt extrusion processes may be used.
James & Wells Ref: 316642NZ In step 820, the core (110) is manufactured.
Step 820 may include one or more of the following steps: Step 822 which involves melting a carrier material to provide a melted carrier material; Step 824 which involves adding the inhibiting agent(s) to the melted carrier material; Step 826- which involves mixing the inhibiting agent and the melted carrier material to create a substantially homogenous mixture.
Step 828 which es forming the substantially neous mixture into a desired shape.
It should be understood that the substantially homogenous mixture contains the inhibiting agent(s) at a concentration ient to achieve the desired release profile for the inhibiting agent on administration of the device to a nt animal. The concentration can be varied according to the type of ruminant animal to be treated, the shape and dimensions of the device, or the desired release profile to be achieved.
It should be tood that the step of forming the ntially homogeneous mixture into a desired shape may involve providing the e to a mould. In a particularly preferred form, the ntially homogenous mixture is added (poured) into a cavity in a housing (120) manufactured at step 810.
Alternatively, the mould may be a separate component which receives the substantially homogenous mixture. In these embodiments, once the desired shape has been formed, the core can subsequently be provided to a cavity in a housing (120).
James & Wells Ref: 316642NZ The method also includes the step of allowing the substantially homogenous mixture to cool. As it cools, the carrier material hardens and assumes a shape according to the shape of the mould or housing into which it has been provided. e formulations The following cores were formulated for use in the bolus of the present invention.
Amount (w/w %) e 1 2 3 4 5 6 7 8 9 10 11 12 Bromoform 20 20 20 25 12.5 8.3 25 12.5 8.3 25 12.5 8.3 Paraffin 80 30 30 50 50 50 - - - - - - Beeswax 50 - - - - 50 50 50 - - - PEG 4000 - - - - - 50 50 50 PEG 400 - - - - - - - - - - - AC - - Kaolin - - - 37.5 - - 37.5 - - 37.5 - Zeolite - - - - 41.7 - - 41.7 - - 41.7 Amount (w/w %) Example 13 14 15 Bromoform 20 33 33 Paraffin Beeswax - - 66 PEG 4000 50 - - PEG 400 30 - - AC - - - Kaolin - - - Zeolite - - - The following additional high bromoform content cores were also formulated for use in the bolus of the t invention.
James & Wells Ref: 316642NZ Amount (w/w %) Example 16 17 18 19 20 21 22 23 24 25 26 27 Bromoform 33 50 67 75 33 50 67 75 33 50 67 75 Beeswax 67 50 33 25 - - - - - - - - Paraffin - - - - 67 50 33 25 - - - - Carnauba - - - - - - - - 67 50 33 25 Castor Wax - - - - - - - - - - - - Activated - - - - - - - - - - - - Carbon Bentonite - - - - - - - - - - - - Zinc Oxide - - - - - - - - - - - - Amount (w/w %) Example 28 29 30 31 32 33 34 35 36 Bromoform 33 50 67 75 50 50 50 50 50 Beeswax - - - - - - - 25 25 Paraffin wax - - - - - - - - - Carnauba wax - - - - - - - - 25 Castor Wax 67 50 33 25 - - Activated Carbon - - - - - - ite - - - - - - Zinc Oxide - - - - - - Validation Example 1: Release/Diffusion study Trials with 2mm thick 3D printed large capped boluses (LCB2) filled with 66.7% (by weight) bromoform and 33.3% (by weight) beeswax in the RME (Rumen Emulator) (RME trial 2) were conducted to determine the ion rate of bromoform from the bolus.
James & Wells Ref: 316642NZ Bolus Design A reinforced bolus as shown in Figure 15 was used for this study. It includes an al reinforcing structure as well as ribs spread apart to support the wall, an upper part was adapted for the attaching a cap. The bolus with reinforcing was found to be more robust and held its shape better than without reinforcing when the molten bromoform/beeswax mixture was poured in and cooled, as well as a more physically robust bolus for the trial.
Method Materials Bromoform (reagent grade, Sigma Aldrich, 96% bromoform, 4% ethanol), beeswax (food grade, NZ Beeswax, MP 65 ⁰C) and zinc oxide from Native Ingredients NZ.
Bolus Manufacture The boluses were drawn in Solidworks, converted to .stl files, opened in FlashPrint to create the print jobs. The s were printed in three parts (case, internal structure and cap) on FlashForge Creator Pro 3D rs using E-Sun PLA+ at 100% fill, standard resolution, first layer height 0.27 mm, layer height 0.18 mm, 2 perimeter shells, 3 top solid layers, 3 bottom solid layers, fill n hexagon, print speed 60 mm/s, extruder temperature 200°C and plate temperature 50°C.
Eight LRB boluses were prepared at 67% (by weight) bromoform, eight LRB boluses were prepared at 75% (by weight) bromoform, and six LCB2 boluses with no bromoform (controls). Ingredients are listed below (Table 1). All ingredients were weighed in beakers on a calibrated 4dp electronic balance. Bromoform solutions were covered with parafilm to prevent evaporation. ients were prepared by melting pre-weighed beeswax and zinc oxide in beakers at 100°C (Thermoprism Oven), letting the mixture cool to 80°C, adding the bromoform and the e kept well mixed to prevent the zinc oxide from settling out, before pouring into the s. Caps were press fitted and soldered to seal the bolus.
Table 1. Preferred compositions for the shortened reinforced boluses Per bolus Total James & Wells Ref: 316642NZ Zinc Zinc Oxide Beeswax Bromoform Oxide Bromoform Type Quantity (g) (g) (g) (g) Beeswax (g) (g) LCB2 6 28.0 80.4 0.0 168.0 482.7 0.0 LRB1 8 28.0 47.3 96.1 224.0 378.8 769.0 LRB1 8 28.0 39.7 119.0 224.0 317.3 952.0 Total 616.0 1178.7 1721.0 The boluses were placed in 500 ml polypropylene bottles with approximately 380 ml 0.02M phosphate buffer (Merck) in distilled water, prepared in 2L or greater s, adjusted to pH 6.5 using 1M HCl (Merck) and a pre-calibrated pH meter (using pH 4, 7, and 10 pH buffers). The bottles were sealed and placed in the incubator at 40oC. 10 ml samples were collected and the entire solution d every 24 hours. ml samples was collected using a 10 ml autopipette in 15 ml Falcon tubes. 1 g of sodium chloride was added to each Falcon tube. For GC-MS analysis, 1 ml of ethyl acetate (analytical grade, Merck) was added to each Falcon tube. When GC-FID was used 2 ml of ethyl e was added to each Falcon tube. The Falcon tubes were capped, well mixed using a Vortex, and centrifuged at 4000 rpm for 15 minutes. For GC-MS analysis, all the ethyl acetate was recovered using a graduated glass syringe and the volumes noted.
For GC-FID analysis, 0.5 ml of ethyl acetate was recovered. For GC-FID is, 200 ul of sample was ed using an autosampler, and analysed using a ZB5HT 30 m capillary column using a temperature ramp of 30-300°C over 20 minutes, at 5 ml/min nitrogen gas flow, in splitless mode. Bromoform had a retention time of 7.5 minutes. Peak areas were compared to ation standards made up in ethylene acetate to determine the mass of bromoform (mg). This was divided by the volume injected to obtain the concentration of bromoform in the ethyl e (mg/L). The concentration in ethyl acetate was multiplied by the total volume of ethyl acetate added to the sample and divided by the recovery to obtain mass of bromoform in the sample. This was then divided by the volume of sample ted to obtain a concentration in the solution, which was then multiplied by the volume of on in the Shott bottle to obtain mass transferred from the bolus to the solution. Bromoform recovery from James & Wells Ref: 316642NZ solution was checked using rd solutions made up to different concentrations of bromoform and was typically 43%. GC-FID performance was checked for each run of ten samples using a calibration sample as a nce.
Results A lower diffusion rate ed by a rapid increase in diffusion rate was observed for both boluses (Figure 8). The 67% bolus had a lag time of 4-5 days before reaching its maximum diffusion rate, whereas the 75% reached maximum diffusion rate with 3 days.
The rate of diffusion was higher for the 75% bolus at 1010 mg/day when compared to 66.7% which was 730 mg/day. This was a surprising, but also good result (as it means that a single bolus could be used to dose 700 kg bulls and achieve methane reduction), as the predicted diffusion rates for an LCB1 bolus for 67% bromoform was 300 mg/day and 462 mg/day for an LCB1 bolus with 75% bromoform. The expectation for the LRB boluses was a lower diffusion rate because it had a reduced e area at 1 mm thick (about 71% that of a LCB1 bolus) (Table 2). In theory the LRB bolus should only be delivering 220 mg/day for 67% bromoform and 344 mg/day for 75%.
James & Wells Ref: 316642NZ Table 2. Expected ion rate for an LRB bolus from the different parts of the bolus. t o t T To (% ) 8 d n . 9 . 3 1 . . n io 0.75 3 0 84.9 0 0 1 r a t u G ib r t n C o 0.67 7 4 . 4 . 5 0 84.3 1 . 0 . 1 0 . 3 3 . 3 . 4 4 9 Total ) y 3 . 1 . 7 4 6 . 0 a 0.75 1 1 0 3 4 0 3 d 292.4 3 1 / g m ( 0.67 7 . 2 9 . 7 1 . 1 186.4 3 0 . . 1 3 2 3 1 . 2 2 7 3 3 Exposed wax 2 2 a y ) . 2 . 2 . . d 6 6 6

Claims (59)

Claims What we claim is:
1. A delayed release dosage form or a bolus configured for administration to an animal, wherein said dosage form and said bolus is configured to release a hydrophobic substance to the animal over a period of time.
2. A delayed release dosage form or a bolus for administration to a ruminant animal, wherein said delayed release dosage form and said bolus is configured to release an effective amount of the substance.
3. A delayed release dosage form or a bolus for administration to a ruminant animal, wherein said delayed release dosage form and said bolus comprises: a core, wherein the core includes at least one substance to be administrated to the ruminant animal mixed with a carrier; and a housing which covers at least a portion of the core; wherein, the bolus is configured to release the substance through the housing over a predetermined period of time.
4. The bolus as claimed in any one of claims 1-3, wherein the carrier and the substance have a relatively higher affinity for each other compared to the affinity of the housing and the substance for each other.
5. The bolus as claimed in claim 4, wherein the substance is a hydrophobic substance.
6. The bolus as claimed in any one of claims 1 - 5, wherein the substance is at least one inhibiting agent.
7. The bolus as claimed in claim 6, wherein the inhibiting agent is a haloform, wherein the haloform is preferably selected from the list of bromoform, chloroform, iodoform, and combinations thereof.
8. The bolus as claimed claim 7, wherein the at least one inhibiting agent is bromoform. James & Wells Ref: 316642NZ 64
9. The bolus as claimed in any one of claims 7 and 8, wherein the haloform, preferably bromoform, is comprised in the core in an amount of between 30 wt% to 80 wt% and preferably in an amount of between 30 wt% and 70 wt%.
10. The bolus as claimed in any one of claims 7 to 9, wherein the haloform, preferably bromoform, is comprised in the core in an amount of at most 55 wt%.
11. The bolus as claimed in any one of claims 7 to 10, wherein the haloform, preferably the bromoform, is comprised in the core and the carrier comprises or consists of wax.
12. The bolus as claimed in any one of claims 3-11, wherein the carrier is a polar substance.
13. The bolus as claimed in claim 12, wherein the carrier includes polar functional groups such as ester, alcohol or carbonyl groups.
14. The bolus as claimed in any one of claims 3-13, wherein the carrier is selected from the group consisting of myristic acid, stearic acid, steryl alcohol, cetyl alcohol, cetosteryl alcohol, castor wax, bee’s wax, paraffin wax, PEG4000, Carnauba, Candellila, Jojoba, Lanolin, and a combination thereof.
15. The bolus as claimed in claim 14, wherein the wax(es) is (are) mixed with said haloform (preferably bromoform), wherein preferably the carrier comprises bees wax, paraffin wax and/or castor wax, and more preferably wherein the carrier comprises castor wax and paraffin wax in a weight ratio of castor to paraffin wax of between 40:60 to 60:40.
16. The bolus as claimed in either one of claims 11 or 12, wherein the carrier comprises paraffin wax and castor wax.
17. The bolus of any one of claims 13 to 16, wherein the at least one piece of metal.
18. The bolus as claimed in any one of claims 3-17, wherein the housing includes a cavity in which at least a portion of the core is located. James & Wells Ref: 316642NZ 65
19. The bolus as claimed in any one of claims 3-18, wherein the housing includes an open end.
20. The bolus as claimed in any preceding claim, wherein the bolus includes a cap configured to close the open end.
21. The bolus as claimed in any preceding claim, wherein the housing and the cap substantially or completely cover and surround the core to define a core.
22. The bolus as claimed in any one of claims 3-21, wherein the housing completely covers and surrounds the core.
23. The bolus as claimed in any one of claims 3-22, wherein the housing is formed from a substance having a Shore D hardness of at least 40.
24. The bolus as claimed in any one of claims 3-23, wherein the housing is formed from a substance having a Shore D hardness of less than 70.
25. The bolus as claimed in any one of claims 3-24, wherein the housing is formed from a material through which the inhibiting agent can migrate.
26. The bolus as claimed in any one of claims 3-25, wherein the housing is made from a plastic material.
27. The bolus as claimed in claim 26, wherein the plastic is one or more of poly lactic acid (PLA), poly glycolic acid (PGA), poly lactic glycolic acid (PLGA), polypropylene, SLA polymer, PBS, PBAT or a combination thereof.
28. The bolus as claimed in any of claims 3-27, wherein the housing is made from a material comprising poly lactic acid (PLA) and Polybutylenadipat-terephthalat (PBAT) and the carrier comprises or consists of wax. James & Wells Ref: 316642NZ 66
29. The bolus as claimed in claim 28, wherein the material comprises poly lactic acid (PLA) and Polybutylenadipat-terephthalat (PBAT)in a weight ratio ranging from 100:0 to a 40:60 poly lactic acid (PLA): Polybutylenadipat-terephthalat (PBAT)ratio and where the carrier comprises wax.
30. The bolus as claimed in any one of claims 3-29, wherein the housing is made from a material that includes one or more excipients.
31. The bolus as claimed in claim 30, wherein the one or more excipients includes plasticisers, hardeners and/or colourants.
32. In bolus as claimed in any of claims 3-31, wherein the housing has a material thickness of below 2 mm and preferably a material thickness in the range of 0.3 – 1.5 mm.
33. The bolus as claimed in any one of claims 3-32, wherein the housing is configured to degrade over a predetermined period of time.
34. The bolus as claimed in any one of claims 3-33, wherein the core has a melting point greater than 37°C.
35. The bolus as claimed in any one of claims 3-34, further comprising a barrier layer between at least a portion of the housing and the core to isolate the portion of the housing and the core from contact with each other.
36. The bolus as claimed in any one of claims 7-35, wherein the bolus is adapted to reach a maximum release rate of approximately 0.05g to 2g of bromoform per day into the rumen.
37. The bolus as claimed in claim 36, wherein the bolus is adapted to reach a maximum release rate of approximately 0.1 to 0.5g of bromoform per day into the rumen, preferably of about 0.2 to 0.3g of bromoform per day into the rumen. James & Wells Ref: 316642NZ 67
38. The bolus as claimed in any one of claims 1-37, wherein the bolus is adapted to release the substance over a period of at least two months.
39. The delayed release dosage form of any of claims 1-3, wherein the substance is a substance as defined in any of claims 4-38 (and most preferably bromoform), wherein the core is a core as defined in any of claims 4-38 and the housing is a housing as defined in any of claims 4-38.
40. A method for administering a substance to an animal, the method comprising the step of administering to said animal the bolus as claimed in any one of claims 1-38 or the delayed release dosage form of any of claims 1-3 or 39.
41. A method for reducing methane production in a ruminant animal, the method comprising the step of administering to said ruminant animal the bolus as claimed in any one of claims 1-39 or the delayed release dosage form of any of claims 1-3 or 39.
42. Use of a methane inhibitor and a carrier in a bolus for reducing methane production in a ruminant animal.
43. Use of a methane inhibitor and a carrier in a bolus for reducing methane emission from a ruminant animal.
44. Use of a haloform in the manufacture of a bolus for reducing the emission of one or more greenhouse gases (“GHGs”) from a ruminant animal.
45. A method of manufacture of a bolus of any one of claims 1 to 38, comprising: a. forming a housing which has a cavity; b. forming a core which includes the substance; c. transferring the core to the cavity.
46. The method of claim 45, wherein the step of forming the core involves mixing a carrier material with the substance. James & Wells Ref: 316642NZ 68
47. The method of claim 45 or 46, wherein the step of forming the core involves heating the carrier material to melt the carrier material prior to mixing the carrier material with the substance to create a mixture.
48. The method of any one of claims 45 to 47, wherein the step of transferring the core to the cavity involves pouring the mixture into the cavity.
49. A delayed release dosage form adapted to be administered to a ruminant animal, wherein the system comprises a mixture of a wax and a haloform.
50. The delayed release dosage form according to claim 49 for administration to a ruminant animal, wherein said delayed release dosage form comprises: a core, wherein the core comprises said wax and said haloform (preferably bromoform); and a coating, which covers at least a portion of the core and preferably covers the entire core; wherein the delayed release dosage form releases the haloform.
51. The delayed release dosage form according to claim 50, wherein the coating is the housing as defined in any of claims 4-38 and wherein the core is a core as defined in any of claims 4-38.
52. The delayed release dosage form according to any one of claims 49 to 51, wherein the haloform is bromoform.
53. The delayed release dosage form according to any one of claims 49 to 52 or the bolus according to any of claims 3-38, wherein the carrier comprises or consists of wax and the coating/housing comprises PLA, PBAT or a mixture of both; preferably the coating/housing comprises PLA.
54. The delayed release dosage form according to any one of claims 1, 2, 39 or 49-53 or the bolus according to any of claims 1-38, wherein the core of the delayed release dosage form or the bolus comprises one or more metal particles (preferably steel particles), wherein the particles are preferably rounded and wherein the total of all particles per bolus or per delayed release dosage form has a mass of at least 100 grams. James & Wells Ref: 316642NZ 69
55. The delayed release dosage form or the bolus according claim 54, wherein the particles are granules and/or spheres.
56. The delayed release dosage form according to any one of claims 49-55, wherein the wax is paraffin and/or carnauba and/or castor wax.
57. The delayed release dosage form according to any one of claims 49-56, wherein the core comprises between 30 wt% and 75 wt% haloform, preferably bromoform.
58. The delayed release dosage form according to any one of claims 49-57, wherein the thickness of the coating/housing is less than 2 mm.
59. The delayed release dosage form of any one of claims 49-58, wherein the delayed release dosage form has the shape of a bolus.
NZ785890A 2021-08-25 2020-12-08 Improvements to devices and methods for delivery of substances to animals NZ785890A (en)

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