WO2021242481A1

WO2021242481A1 - Bi-modal release intra-ruminal capsule device and methods of use thereof

Info

Publication number: WO2021242481A1
Application number: PCT/US2021/030550
Authority: WO
Inventors: Jian Han; Alan Johnson; Edson De Souza Moura; Mark Doherty
Original assignee: Boehringer Ingelheim Animal Health USA Inc.
Priority date: 2020-05-28
Filing date: 2021-05-04
Publication date: 2021-12-02
Also published as: AU2021278871A1

Abstract

This invention relates to an intra-ruminal capsule device that provides bi-modal release of active ingredients, particularly sustained release followed by fast release of one or more actives, into the rumen of a ruminant animal, such as a sheep, cow, goat, deer, etc. The invention also provides for improved methods for delivering actives such as anti-parasiticides, vitamins, minerals, and therapeutics to an animal.

Description

BI-MODAL RELEASE INTRA-RUMINAL CAPSULE DEVICE AND METHODS OF USE THEREOF

FIELD OF THE INVENTION

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Application No. 63/031,064, filed May 28, 2020, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

There are a number of intra-ruminal devices and sustained release capsules and formulations presently available. In general, the devices currently available are in the form of a capsule, which comprises: a substantially hollow tubular body, which is sealed at one end by a cap, and partially sealed at the second end by an annular flange, which defines an opening. There is provision within the body for the inclusion of a solid therapeutic composition.

Many of the currently available intra-ruminal devices contain a spring and plunger mechanism for urging the solid therapeutic composition towards the opening. In some devices, the solid therapeutic composition is a stack of tablets. The diameter of the opening in the capsule can be adjusted to control the rate of extrusion of the therapeutic composition. The cap end may also have attached to it a plurality of resilient arms designed to prevent regurgitation of the device by the animal.

Intra-ruminal devices are inserted through the oesophagus into the animal’s rumen. Once in the rumen, rumen fluid enters the capsule via the opening and penetrates the therapeutic composition, and liquefies the therapeutic composition, whereupon the therapeutic composition is released through the opening over a prolonged period of time. A number of such formulations are available which are all capable of releasing a single therapeutic drug, such as an anthelmintic, and in some cases a range of supplementary trace elements.

Sustained release capsules have been available for over twenty years. These devices release active ingredients or trace elements into the rumen of an animal for a period of 90-180 days.

There are two main types of sustained released intra-ruminal capsule devices: Simple Erodible Systems

These were the first type of sustained release device introduced to the market. They are generally of a waxy or metallic construction and are in the shape of a simple cylinder. Erosion either occurs from over the entire surface of the device, or, in some cases, the device may have been dipped in a coating material so that only the ends of the device are exposed. In this case, payout of the active can be controlled more effectively. The interaction with the rumen contents (amount of grass and liquid content) determines the rate of erosion of the device.

Examples of such devices include:

Alltrace Mineral Bolus (Agrimin, UK) - This is an erodible bolus containing: Copper (16,379 mg), Cobalt (236 mg), Selenium (251 mg), Manganese (8,326 mg), Zinc (13,382 mg), Iodine (497 mg), Vitamin A (549,408 i.u.), Vitamin D (3109,881 i.u.) and Vitamin E (1,099 i.u.). Two boluses are administered to each animal weighing 150 kgs or more, with the payout period being 240 days. To retain the bolus in the rumen, the device has a solid metal densifier element which erodes after the lighter mineral elements have dissolved. The advantage of the device is the high loading of active ingredients and the fact that the device will fully erode leaving no part retained in the animal. A disadvantage of this style of erodible bolus is that it is not possible to achieve a linear release rate.

Optimag Magnesium Bolus (Norbrook, UK) - A solid metallic bolus containing lOOg of magnesium released over approximately 4 weeks. These are used in adult cattle as an aid to maintenance of magnesium intake. In both of the above cases, the aim of bolus administration is to maintain mineral levels in the treated animal for a prolonged period of time. Neither device allows for complex payout profiles as might be required if the farmer wished to deliver an immediate short-acting dose of a particular active ingredient to be followed by the sustained payout of the minerals or an active, or vice versa.

Sustained-release devices

Another intra-ruminal device technology is the category of sustained-release devices. In general, these are in the form of a plastic capsule comprising: a substantially hollow tubular body, which is completely sealed at one end, for example, by a cap, and is partially sealed at the second end by an annular flange, which defines an opening. There is provision within the body for the inclusion of a solid therapeutic composition, such as a stack of tablets.

Many of the currently available sustained release devices contain a spring and plunger mechanism for urging the solid therapeutic composition (either in the form of solid wax or stack of tablets) towards the opening. Other devices rely on osmotic pressure to expand a driver portion in the base of the capsule. This driver portion causes the active contents to be expelled from the open end of the capsule. The diameter of the opening can be selected to increase or restrict the speed of payout of the device.

The capsule may be retained in the rumen of the animal either by a plurality of resilient arms protruding from the cap or sealed end of the device, or by a weighted metal densifier element within the body of the device. Typically, this style of device is used to deliver active ingredients requiring a greater precision of payout such as anthelmintics. In these cases, the daily dose of anthelmintic is low compared to the amount recommended in a standard oral dose.

Examples of sustained release devices include:

IVOMEC SR Bolus (MSD Agvet) - Containing 1.72g ivermectin releasing over 140 days. This device uses osmotic pressure to expand a driver portion in the base of the capsule. The expansion of this driver portion urges the solid wax formulation containing ivermectin towards the opening.

EXTENDER SeCo (Merial) - Containing 4.62g albendazole releasing over 100 days, and IVOMEC Maximizer Capsule (Merial) - Containing 160mg ivermectin releasing over 100 days. Both of these devices utilise a spring portion to urge a stack of tablets containing the active ingredients towards the opening. At the opening, the face of the exposed tablet forms a gel which is released into the rumen.

BIONIC Hi -Mineral Combination Sheep Capsules (Merial) - Containing 160 mg abamectin, 4.62 g albendazole, 24 mg selenium, and 120 mg cobalt releasing over 100 days. There are times, however, when sustained release of one or more substances over a prolonged period is insufficient to satisfy animal health needs. In certain cases the farmer may wish to deliver an additional substance in an immediate or quick release fashion prior to or following the period of sustained release. The dose delivered prior to the sustained release dose is referred to herein as a dump dose or a priming dose. A dose delivered after the sustained release is referred to herein as an exit dose.

Examples of sustained plus immediate release cases could include: When a secondary trace element or mineral treatment is required to be given to an animal at the same time as a sustained release treatment of an anthelmintic. Traditionally this would mean that the farmer would administer a separate treatment in the form of a liquid drench or oral capsule. An example of this is that farmers will often give a copper oxide needle treatment in the form of a gelatin capsule for preventing copper deficiency. It can be recognised that this separate treatment is time consuming and inconvenient.

A further example is that the manufacturers of EXTENDER SeCo recommend that a large “primer” or initial dose of an effective oral anthelmintic is given at the same time as the capsule is inserted into the animal. The purpose of this primer dose is to control the adult stage parasites that are resident in the animal. Once this is done, the capsule will be able to effectively control any new incoming larvae for the effective payout period of the device.

Another example is that there is a concern that some single active sustained release anthelmintic devices may not effectively control all parasites for the full duration of the payout period. In some cases it may be desirable to administer to the animal what is known as an “exit” dose. This is a large dose of anthelmintic administered at a single time point sufficient to control adult parasites that may have survived the smaller sustained dose of anthelmintic.

There have been attempts to incorporate priming and/or exit doses into sustained release capsules so that there is no need for the farmer to administer a separate treatment. These are typically made by incorporating one or more fast releasing tablets into a stack of sustained release tablets contained within the device. These fast release tablets contain disintegrants and effervescent materials. Unfortunately the fast release of the tablet can allow moisture to seep through the annular flange defining the opening and down the inside of the capsule body. This can then impede release of subsequent sustained release tablets.

WO2011/014078 (Merial Limited) relates to intra-ruminal sustained release capsules which are capable of delivering a sustained release dose of a first medicament to an animal as well as either, or both, of a dump dose of a second medicament or mineral and an exit dose of a third medicament or mineral. The exit dose may be contained in a hollow piston with an apertured face that is aligned with the capsule aperture that enables release of the medicaments to the rumen. A coil spring encircles the piston and functions to bias a medicament or table stack contained with the body of the device.

There is a need for improved intra-ruminal devices and/or an improved sustained release capsules, which would at least provide the public with a useful and dependable choice for eradicating, controlling, and preventing parasite infections in an animal, and for delivering therapeutics. More specifically, there is a need for reliable intra-ruminal devices which provide continuous release and immediate release of actives within the same device.

INCORPORATION BY REFERENCE

Any foregoing applications, and all documents cited therein or during their prosecution (“application cited documents”) and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.

Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides an intra-ruminal capsule device designed for, and when loaded, providing, bi-modal release of one or more actives. In one embodiment, the intra-ruminal capsule device is configured to provide sustained release of one or more actives followed by subsequent, fast release of an exit dose of one or more actives.

According to one embodiment, the intra-ruminal capsule device comprises a) a hollow tubular body sealed at a first end, b) an apertured cover at the second end of the hollow tubular body, c) an apertured spring cap slidably positioned within the hollow tubular body, and d) a spring located between one face of the apertured spring cap and the sealed first end of the hollow tubular body, wherein a first chamber is defined within the tubular body between the apertured cover and the proximal face of the apertured spring cap, said first chamber being sized to contain a first delivery means for at least one sustained release active or mineral, and a second chamber is defined within the interior of the spring, said interior of the spring being sized to contain a second delivery means for at least one exit dose active or mineral.

In one embodiment, the intra-ruminal capsule device preferably releases one or more actives over an extended period of time, i.e., the device provides continuous release of one or more actives. According to one embodiment, the capsule device has a first delivery means for sustained release of one or more actives that comprises a stack of tablets that dissolve upon contact with rumen fluid. In one embodiment, the release period of the sustained released active(s) (i.e. the payout period) is over a period of any number of days such as about 100 days.

In one embodiment, the intra-ruminal capsule device comprises a sustained release dose of one or more actives. In one embodiment, the capsule device comprises an exit dose of one or more actives.

According to one embodiment, the exit dose active(s) and/or minerals releases quickly upon contacting rumen fluid, after the sustained release active(s) and/or mineral(s) is substantially released, i.e., the exit dose of one or more actives and/or or minerals is released substantially after the pay-out period of the sustained release active(s) and/or mineral(s). In one embodiment, the exit dose active(s) and/or exit dose of minerals is contained with a capsule, such as a gelatin capsule, which comprises the delivery means for the exit dose active(s) and/or exit dose of minerals. In one embodiment, the delivery means for the exit dose active(s) and/or exit dose of minerals comprises a coated tablet.

In one embodiment, the intra-ruminal device comprises a plurality of actives.

In one embodiment, the intra-ruminal device comprises a tablet stack comprising albendazole and abamectin as a sustained release dose, and a gelatin capsule comprising levamisole as an exit dose. In another embodiment, the intra-ruminal device comprises a tablet stack comprising an isoxazoline compound as a sustained release dose, and a gelatin capsule comprising levamisole as an exit dose.

In a second aspect, the invention provides a method of treating an animal, including the steps of

1) placing an intra-ruminal capsule device according to the first aspect in an animal’s rumen, and

2) sequentially releasing at least one sustained release active and/or mineral and at least one exit dose active and/or mineral into the animal’s rumen such that the at least one exit dose active and/or mineral is released after the at least one sustained release active and/or mineral is substantially released.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an intra-ruminal capsule device 1 according to one embodiment of the invention, wherein the capsule body 2 has an orifice 3 for admitting rumen fluid, a stack of 11 tablets 4 containing one or more active(s) and/or mineral(s) for sustained release (e.g. a Bionic^® abamectin, albendazole, Se, Co tablet), a spring cap 5 with a hole 6, and a capsule 7 contained within a spring 8, wherein the capsule contains at least one exit dose active (e.g. a gelatin capsule containing 500 mg levamisole HC1).

FIG. 2 depicts an intra-ruminal capsule device (IRC) 1 according to one embodiment of the invention, wherein the IRC has one sustained release tablet 4 (e.g. a Bionic^® abamectin, albendazole, Se, Co tablet) in the body 2 that has an orifice 3, a spring cap 5 with a hole 6, and an exit dose active contained in a capsule 7 within the interior space of a spring 8 (e.g. a gelatin capsule containing 500 mg levamisole HC1).

FIG. 3 is a payout graph showing the doses of albendazole and levamisole remaining in an intra-ruminal device having one tablet as depicted in FIG. 2. The y axis scale is mg of active; the x axis scale is days. FIG. 4 depicts an intra-ruminal capsule device (IRC) 1 according to one embodiment of the invention, wherein the capsule 1 has 3 sustained release tablets 4 in the body 2 (e.g. a Bionic^® abamectin, albendazole, Se, Co tablet) that has an orifice 3, a spring cap 5 with a hole 6, and an exit dose active contained in a capsule 7 within the interior space of a spring 8 (e.g. a gelatin capsule containing 500 mg levamisole HC1).

FIG. 5 is a pay-out graph showing the doses (by weight) of albendazole and levamisole remaining in an intra-ruminal device having three albendazole tablets as depicted in FIG. 4. The y axis scale is mg of active; the x axis scale is days The levamisole exit dose is in a capsule.

FIG. 6 is a pay-out graph showing the doses (by weight) of albendazole and levamisole remaining in an intra-ruminal device having three albendazole tablets as depicted in FIG. 4. The y axis scale is mg of active; the x axis scale is days. The levamisole exit dose is in a tablet.

DETAILED DESCRIPTION

This invention relates to, in a first aspect, an intra-ruminal capsule device (“IRC”) that provides bi-modal release of actives. Bi-modal release means that the active(s) in the IRC is released at two rates: in the first rate of release, an active in a first medicament is released over a period of time, i.e. it is released over a sustained period of time, for instance, over a number of days; in the second rate of release, an active in an exit dose of a second medicament is released quickly upon contact with rumen fluids. Thus, in particular, the IRC according to the invention provides sustained release of one or more actives (the sustained release dose) followed by fast release of one or more actives (the exit dose), into the rumen of a ruminant animal. Example ruminant animals suitable for the instant invention include but are not limited to sheep, cows, goats, and deer.

The IRC according to the invention as described herein provides surprising well- controlled dispensation of the sustained release dose and exit dose to the animal. The rate of dispensation of the actives is well-controlled such that an animal does not receive doses that are too high, which may be harmful to the animal, nor doses that are too low, and thus be ineffectual or insufficient for treating the animals. In addition, the instant device provides well controlled dispensation in that the sustained release active is substantially released before the exit dose active is released. Substantially released means that the sustained release active is 70, 80, 90, 95, 96, 97, 98, 99, or 100% released, or that any amount between 70 and 100% of the dose in the IRC is released before the exit dose of active begins to be dispensed.

The dispensation of the first and second actives contained in the IRC occur when the medicament compositions containing the actives come into contact with rumen fluid. Rumen fluid has a pH between about 5.7 and 7.3, wherein pH ranges greater than 7 and less than 6 may occur due to poor quality diets and acidosis, respectively.

In certain embodiments, the instant invention may be usefully employed for treating mineral deficiency in a ruminant animal and/or for eradicating a microbial pathogen, such as bacteria, or a parasite, such as a parasitic worm (a helminth).

Actives useful in the present invention include active agents suitable for administration to the rumen of a ruminant animal.

In certain embodiments, the actives in the IRC according to the invention include anti-parasiticides, vitamins, and/or minerals. In one embodiment, the actives preferably comprise anthelminthics, minerals, or both.

In one embodiment, the IRC comprises at least one macrocyclic lactone active agent, including, but not limited to, avermectins or milbemycins. In some embodiments, the avermectin or milbemycin active agent is eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin. In certain embodiments, one or more macrocyclic lactone actives such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, moxidectin, or selamectin is included in the IRC.

In one embodiment, the IRC preferably includes abamectin. In one embodiment, the IRC preferably includes eprinomectin. In one embodiment, the IRC preferably includes ivermectin. In yet another embodiment, the IRC preferably includes doramectin. In one embodiment, the IRC preferably includes selamectin.

In one embodiment, the IRC sustained release active comprises or consists of a macrocyclic lactone. In one embodiment, the IRC sustained release active comprises or consists of abamectin. In one embodiment, the IRC sustained release active comprises or consists of eprinomectin.

In certain embodiments, the IRC comprises a benzimidazole, including, but not limited to, albendazole, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, oxibendazole, oxfendazole, parbendazole, thiabendazole, thiophanate and its o,o-dimethyl analogue may be included in the IRC. In one embodiment, the IRC preferably comprises albendazole.

In one embodiment, the IRC sustained release active comprises or consists of a benzimidazole. In one embodiment, the IRC sustained release dose comprises or consists of albendazole.

In other embodiments, at least one macrocyclic lactone and at least one benzimidazole are contained in an IRC according to the invention. In one embodiment according to the invention, the IRC contains abamectin and albendazole. In one embodiment according to the invention, the IRC contains eprinomectin and albendazole.

In one embodiment, the IRC sustained release active comprises or consists of a macrocyclic lactone and a benzimidazole and optionally, one or minerals including but not limited to selenium and cobalt. In one embodiment, the IRC sustained release active comprises or consists of abamectin and albendazole, and optionally, one or minerals including but not limited to selenium and cobalt. In one embodiment, the IRC sustained release active comprises or consists of eprinomectin and albendazole, and optionally, one or more minerals including but not limited to selenium and cobalt.

In other embodiments, the IRC of the invention comprises imidazothiazole compounds including, but not limited to, tetramisole, levamisole and butamisole, or salts thereof. In some embodiments, the IRC of the invention preferably comprises a levamisole salt. In one embodiment, the IRC of the invention preferably comprises levamisole or its HC1 salt. In one embodiment, the IRC exit dose of active comprises or consists of an imidazothiazole compound. In one embodiment, the IRC exit dose of active comprises or consists of levamisole hydrochloride. In one embodiment, the IRC exit dose of active comprises or consists of levamisole base.

In some embodiments, the IRC exit dose active is desirably contained within a dissolvable capsule, a gel cap, tablet or a coated tablet. By “dissolvable”, it is meant that the capsule, gel cap, tablet, or coated tablet dissolves in the rumen upon contact with rumen fluid. The period of time that it takes for dissolution will determine, to some extent, the release period of the exit dose. The dissolution time is also impacted by the design of the IRC, including the location and arrangement of the capsule within the IRC. In some embodiments, the capsule (or tablet, coated tablet, or gel cap) is constructed from a “somewhat” water resistant material, such as a slow dissoving gelatin or vegetable derived material . By “somewhat” water resistant is meant that the material has a comparatively slower disintegration rate than, for instance, commonly used commercial capsules. In some embodiments, the tablet as well as the exit dose composition is customized for dissolution in the rumen of an animal over a particular window of time.

In one embodiment, the IRC comprises a macrocylic lactone, a benzimidazole, an imidazothiazole compound, and optionally, one or minerals including but not limited to selenium and cobalt. In one embodiment, the IRC according to the invention comprises a macrocylic lactone, a benzimidazole, and optionally one or more minerals are sustained release actives, and an imidazothiazole compound is an exit dose active.

In one embodiment, the IRC according to the invention comprises a macrocyclic lactone selected from one or more of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, moxidectin, and selamectin, a benzimidazole, an imidazothiazole compound, and optionally, one or minerals including but not limited to selenium and cobalt.

In one embodiment, the IRC according to the invention comprises a macrocyclic lactone, a benzimidazole selected from one or more of albendazole, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, oxibendazole, oxfendazole, parbendazole, thiabendazole, thiophanate and the O,O-dimethyl analogue of thiophanate, an imidazothiazole compound, and optionally, one or minerals including but not limited to selenium and cobalt.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising abamectin, albendazole, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole HC1 which is encapsulated within a gelatin or vegetable capsule, a gel cap or a table or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising abamectin, albendazole, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole base which is encapsulated within a gelatin or vegetable capsule, a gel cap or a tablet or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising eprinomectin, albendazole, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole HC1 which is encapsulated within a gelatin or vegetable capsule, a gel cap or a tablet or a coated tablet. In one embodiment, the IRC according to the invention comprises a sustained release active comprising eprinomectin, albendazole, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole base which is encapsulated within a gelatin or vegetable capsule, a gel cap, table, or a coated tablet.

In some embodiments, the IRC according to the invention comprises an isoxazoline active. In certain embodiments, the IRC according to the invention comprises a sustained release active which is at least one isoxazoline compound.

Certain isoxazole and isoxazoline-containing compounds have been demonstrated to be effective against parasites that harm animals. For example, US 7,964,204 (to DuPont, incorporated by reference herein in its entirety) discloses isoxazoline compounds according to formula (I) below, which are active against ectoparasites and/or endoparasites.

In addition, published patent application nos. US 2010/0254960 Al, WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 Al, US7951828 & US7662972, US 2010/0137372 Al, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al and WO 2007/075459 A2 and U.S. Patent Nos. 7,951,828 and 7,662,972 describe various other parasiticidal isoxazoline compounds. Other published patent applications that describe various other parasiticidal isoxazoline compounds and compositions comprising the same include WO 2007/079162 Al, WO 2008/154528 Al, WO 2009/002809 A2, WO 2011/149749 Al, WO 2014/439475 Al, US 8,466,115, WO 2012/120399, WO 2014/039484, WO 2014/189837, (Zoetis) and WO2012 120135A1 (Novartis).WO 2012/089623 describes topical localized isoxazoline compositions comprising glycofurol. WO 2013/039948 Al provides for topical veterinary compositions comprising at least one isoxazoline active agent and WO 2013/119442 A1 provides for oral veterinary compositions such as a soft chew which comprising at least one isoxazoline active agent. WO2017/147352 A1 provides new isoxazoline active agents with long-lasting efficacy against ectoparasites.

In one embodiment, the present disclosure provides for an IRC comprising antiparasitic effective amounts of at least one isoxazoline of formula (I) shown below, or a pharmaceutically or veterinarily acceptable salt thereof, where variables A¹, A², A³, A⁴, A⁵, A⁶, B¹, B², B³, R¹, R², R⁴, R⁵, W and n are defined herein.

In another embodiment, the present invention provides for an IRC comprising a parasitic effective amount of an isoxazoline active agent of formula (la):

(la), or a pharmaceutically acceptable salt thereof, in combination and a pharmaceutically or veterinary acceptable polymer matrix. The compound of formula (la) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-l- naphthalanecarboxamide (INN afoxolaner). In another embodiment, the present disclosure provides for an IRC comprising an isoxazoline compound of formula (Ic):

or a pharmaceutically acceptable salt thereof; wherein X¹, X² and X³ are each independently H, halogen, Ci-C3alkyl or Ci-C3haloalkyl. In another embodiment, the invention provides an antiparasitic external device comprising a compound of formula (Ic) wherein X¹ is chloro, X² is fluoro and X³ is CF3 have been shown to have surprising excellent efficacy against external parasites.

In another embodiment, the present invention provides for an IRC comprising a parasitic effective amount of an isoxazoline active agent of formula (Id):

or a pharmaceutically or veterinarily acceptable salt thereof.

In other embodiments, the invention provides for an IRC comprising a parasitic effective amount of an isoxazoline active agent of formula (lb), (II), (III), (IV), (V), (Va), (VI) or (Via) described herein, or pharmaceutically acceptable salts thereof. The isoxazoline compounds used in the IRC of the invention are highly active against arthropod pests and parasites and useful for protecting animals, including livestock and companion animals such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle, from parasites that infest or infect such animals.

Thus, in one aspect, the present disclosure provides for novel and inventive IRCs for the treatment or prevention of parasitic infections or infestations in an animal comprising an antiparasitic effective amount of at least one isoxazoline compound, as defined herein

In an embodiment, the present disclosure provides for novel and inventive IRCs for the treatment or prevention of parasitic infections and/or infestations in an animal comprising an antiparasitic effective amount of at least one isoxazoline compound in combination with an antiparasitic effective amount of one or more additional active agents.

The present disclosure also provides novel and inventive methods and uses for the treatment and/or prophylaxis of parasitic infections and/or infestations in or on animals, comprising administering to an animal in need thereof an IRC comprising an antiparasitic effective amount of at least one isoxazoline compound.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prophylaxis of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of at least one isoxazoline active agent, which is: i) an isoxazoline compound of formula (I):

wherein:

A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from the group consisting of CR³ and N, provided that at most 3 of A¹, A², A³, A⁴, A⁵ and A⁶ are N;

B¹, B² and B³ are independently selected from the group consisting of CR² and N; W is O or S;

R¹ is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R⁶; each R² is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkoxy carbonyl, — CN or — NO2; each R³ is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, — CN or — NO2;

R⁴ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxy carbonyl;

R⁵ is H, OR¹⁰, NRⁿR¹² or Q¹; or Ci-Ce alkyl, C₂-Ce alkenyl, C₂-Ce alkynyl, C₃-Ce cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R⁷; or R⁴ and R⁵ are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, — CN, — NO2 and C1-C2 alkoxy; each R⁶ is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, Ci- Ce alkylsulfinyl, C1-C6 alkylsulfonyl, — CN or — NO2; each R⁷ is independently halogen; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, Ci- Ce alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxy carbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, — NH2, — CN or — NO2; or Q²; each R⁸ is independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, Ci-C6haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2- C4 alkoxycarbonyl, — CN or — NO2; each R⁹ is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, — CN, — NO2, phenyl or pyridinyl;

R¹⁰ is H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one of more halogen;

R¹¹ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl;

R¹² is H; Q³; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R⁷; or

R¹¹ and R¹² are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, — CN, — NO2 and C1-C2 alkoxy;

Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or 10- membered fused bicyclic ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents independently selected from R⁸; each Q² is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R⁹; Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R⁹; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof; and/or ii) an isoxazoline compound of formula (II):

(P) wherein:

Ri is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R?S(0)-, R7S(0)2-, R?C(0)-, R7RSNC(0)-, R70C(0)-, R7C(0)0-, R7C(0)NRS-, -CN or -NO2;

X is aryl or heteroaryl, which may be unsubstituted or substituted by one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(0)-, R7S(0)₂-, R7C(0)-, R7RsNC(0)-, R₇0C(0)-, R₇C(0)0-, R7C(0)NR₈-, -CN or -NO2;

Ai is oxygen; and A2 is oxygen, NR2 or CR7R8;

G is G-l or G-2;

G-l G-2

Bi, B2, B3, B4 and B5 are independently N or C-R9; Y is hydrogen, halogen, -CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R?S(0)-, R7S(0)2-, R?C(0)-, R7RsNC(0)-, R70C(0)-, R7C(0)0-, R7C(0)NRS-, -CN or -NO2; or Y is Y-l, Y-2, Y-3, Y-4, Y-5, Y-6, Y-

7, Y-8, Y-9, Y-10, Y-ll, Y-12 or Y-13;

R2, R3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, RioS(O)-, RIOS(0)₂-, RioC(O)-, RIOC(S)-, RioRnNC(O)-, RioRnNC(S)- RioOC(O)-;

R4, R5 and R6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

R7 and Rx are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;

R9 is hydrogen, halogen, -CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(0)-, R7S(0)₂-, R?C(0)-, R7RSNC(0)-, R₇0C(0)-, R₇C(0)0-, R7C(0)NR₈-, -CN or -

NO2;

Rio, R11, R12 and R13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or

Rio together with R11 form =0, =S or =NR₂; or R12 together with R13 form =0, =S or =NR₂;

W is O, S orNR₂; n is 1-4; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or iii) an isoxazoline compound of formula (III)

(III) (INN Aural aner) or a pharmaceutically acceptable salt thereof; and/or iv) an isoxazoline compound of formula (IV)

or a pharmaceutically acceptable salt thereof; and/or v) an isoxazoline compound of formula (V):

wherein R¹, R² and R³ are independently H, Cl, F or CF3; Y is the diradical group

T is a Ci-C6-alkyl group which is unsubstituted or substituted by halogen, cyano, nitro, amino, hydroxyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, Ci-C6-alkylthio, C1-C6- alkylthio, carboxy, carbamoyl or C2-C6-alkanoyl group which may be unsubstituted or substituted in the alkyl portion by halogen or a pharmaceutical acceptable salt thereof; and/or vi) an isoxazoline compound of formula (VI):

wherein Y is hydrogen, fluoro, chloro or bromo;

R¹ is phenyl substituted with 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy;

R² is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;

R^3a and R^3b are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R^3a and R^3b together combine with the carbon to which they are attached to form a cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (la)

(la) (INN afoxolaner) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC comprising an antiparasitic effective amount of an isoxazoline compound of formula (lb)

or a pharmaceutically acceptable salt thereof, wherein

R² independently is halogen, C1-C6 alkyl or C1-C6 haloalkyl R⁴ is H or Ci-Ce alkyl; R⁵ is C1-C4 alkyl optionally substituted with one or more R⁷; and R⁷ is C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxy carbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl (e.g., CH₂C(0)NHCH₂CF3); and n is 0, 1 or 2.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (Ic)

(Ic) or a pharmaceutically acceptable salt thereof, wherein

X¹, X² and X³ are each independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

In one embodiment, the IRC of the present disclosure comprises a compound of formula (Ic) wherein X¹ and X³ are independently halogen and X² is hydrogen.

In another embodiment, the long-acting antiparasitic external devices of the present disclosure comprise a compound of formula (Ic), wherein X¹, X² and X³ are each independently halogen. In another embodiment of the present disclosure, the IRC comprises a compound of formula (Ic), wherein X¹ and X³ are each independently halogen and X² is Ci- C3haloalkyl.

In still another embodiment, the present disclosure provides an IRC comprising a compound of formula (Ic), wherein X¹ and X² are independently halogen and X³ is Ci-C3haloalkyl. In another embodiment, the present disclosure provides an IRC comprising a compound of formula (Ic), wherein X¹ and X² are independently halogen and X³ is CF₃. In another embodiment, the present disclosure provides an IRC comprising a compound of formula (Ic), wherein X¹ and X³ are chloro and X² is hydrogen.

In yet another embodiment, the present disclosure provides an IRC comprising a compound of formula (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF3.

In another embodiment, the present disclosure provides an IRC comprising a compound of formula (Ic), wherein X¹ and X³ are chloro and X² is fluoro.

(Ic) or a pharmaceutically acceptable salt thereof, wherein

X¹ and X³ are each independently halogen or C1-C3 haloalkyl; and X² is halogen or hydrogen. In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof, wherein

X¹ and X² are each independently chloro or fluoro; and X³ is chloro or CF3.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof wherein

X¹ and X³ are each chloro; and X² is fluoro or hydrogen.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof, wherein

X¹ is chloro;

X² is fluoro; and X³ is CF₃.

X¹ and X³ are chloro; and X² is fluoro.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof, wherein X¹, X² and X³ are each chloro.

X¹, X² and X³ are each independently chloro or fluoro. In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of at least one isoxazoline compound of formula (Id)

(Id) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC comprising an antiparasitic effective amount of at least one isoxazoline compound of formula (II) as described above, or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides for an IRC comprising an antiparasitic effective amount of at least one isoxazoline compound of formulae II-1.001 to H-1.025 or II-2.001 -II-2.018:

Compounds II- 1.001 to II- 1.025

Compounds II-2.001 to II-2.018

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of at least one isoxazoline compound of formulae II-1.001 to II-1.025 or II-2.001-II- 2.018 as described above, or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides for an IRC comprising an antiparasitic effective amount of an isoxazoline compound of formula (III)

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (IV)

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of at least one isoxazoline compound of formula (V)

or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of an isoxazoline compound of formula (Va)

or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of at least one compound of formula (VI)

(VI) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides for an IRC for the treatment and/or prevention (prophylaxis) of parasitic infections and/or infestations in or on animals comprising an antiparasitic effective amount of at least one compound of formula (Via)

or a pharmaceutically acceptable salt thereof. Stereoisomers

The compounds of formula (I) through formula (Via) shown above can exist as stereoisomers, and each individual stereoisomer present is encompassed by the structural formulas depicted herein. Where compounds within the IRC of the present disclosure include n chiral centers, the compounds may comprise up to 2ⁿ optical isomers. The present disclosure encompasses IRCs comprising the specific enantiomers or diastereomers of each compound as well as mixtures of different enantiomers and/or diastereomers of the compounds of the present disclosure that possess the useful properties described herein. In addition, the present disclosure encompasses IRCs comprising one or more conformational isomers (e.g. rotamers) as well as mixtures of conformational isomers. Conformational isomers of the isoxazoline compounds may be produced, for example, by a restriction of rotation about the amide bond bonded to the aryl or heteroaryl ring (e.g. the amide bonded to the naphthyl group in formula (I)). For avoidance of doubt, when an isoxazoline compound (e.g. any of the isoxazoline active agents as described herein) includes two or more stereoisomers (e.g. an ( S )- and (//(-enantiomers) the formulae depicted herein that does not explicitly include stereochemical configurations encompasses each of the possible stereoisomers. One of skill in the art will understand that one stereoisomer of an active isoxazoline compound may be more active and/or may exhibit beneficial properties relative to the other enantiomer. In addition, the skilled person in the art knows how to separate, enrich, and/or selectively prepare a stereoisomer of the isoxazoline compounds described herein. The isoxazoline compounds described herein contain a chiral quaternary carbon atom in the five-membered isoxazoline ring (shown by the asterisk (*) in the structures below); therefore, the compounds will contain at least two possible stereoisomers. As an example for the compound of formula (la), the two possible stereoisomers resulting from the quaternary carbon are shown as formulae (ri)-Ia and (i?)-Ia:

(i?)-Ia

The compound of formula (<S)-Ia above has the (S) configuration at the chiral carbon atom and the compound of formula (i?)-Ia has the (R) configuration. Molecular depictions drawn herein follow standard conventions for depicting stereochemistry. To indicate stereo configuration, bonds rising from the plane of the drawing and towards the viewer are denoted by solid wedges wherein the broad end of the wedge is attached to the atom rising from the plane of the drawing towards the viewer. Bonds going below the plane of the drawing and away from the viewer are denoted by dashed wedges wherein the narrow end of the wedge is attached to the atom further away from the viewer. Constant width lines indicate bonds with a direction opposite or neutral relative to bonds shown with solid or dashed wedges; constant width lines also depict bonds in molecules or parts of molecules in which no particular stereo configuration is intended to be specified.

The optically active forms of the isoxazoline compounds can be prepared by methods known in the art, for example, by resolution of the racemic forms by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution.

It will be appreciated that in addition to the compounds of formula (la), the other isoxazoline compounds of formula (I), formula (lb), formula (Ic), (Id), formula (II), formula (II- 1.1001) to formula (II- 1.025), formula (II-2.001) to formula (II- 2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) and formula (Via) will also have at least two possible enantiomers as a result of the quaternary carbon atom on the isoxazoline ring. In addition, certain compounds may include other chiral centers in one or more substituents resulting in diastereomers.

In one embodiment of the present disclosure, the more biologically active enantiomer is believed to be formula fV)-Ia. Similarly, the more biologically active enantiomers of isoxazoline compounds of formula (lb), (Ic), (Id) and (II) to (Via) are believed to have the (S) configuration at the chiral carbon of the isoxazoline ring. In certain embodiments, an isoxazoline compound of the present disclosure, or compositions comprising the compound, are enriched in an enantiomer that displays significant in vitro and in vivo activity (the eutomer) with a favorable toxicity profile relative to a compound or a composition enriched with the other corresponding enantiomer that displays significantly less in vitro and in vivo activity (the distomer).

When enantiomerically enriched, one enantiomer is present in greater amounts than the other, and the extent of enrichment may be defined by an expression of enantiomeric excess ("ee"), which is defined as (2x-l) 100 %, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20 % corresponds to a 60:40 ratio of enantiomers). In some embodiments, the compositions of the present disclosure comprise compounds that have at least a 50 % enantiomeric excess. In other embodiments, the compositions of the present disclosure comprise compounds that have at least a 75 % enantiomeric excess, at least a 90 % enantiomeric excess, or at least a 94 % enantiomeric excess of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer (the eutomer).

This present disclosure comprises racemic mixtures, for example, equal amounts of the enantiomers of the isoxazoline compounds of formulae (I) to (Via). The present disclosure also includes compounds of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II- 1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that are enriched in one enantiomer compared to the racemic mixture. Also included are the essentially pure enantiomers of the compounds of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II- 1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via).

Hence, in one embodiment, the IRC of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), which is substantially enriched in one enantiomer, or a pharmaceutically acceptable salt thereof. The term “substantially enriched” means that the compound is enriched in a weight: weight ratio of at least about 1.5 or higher in favor of the desired enantiomer. In another embodiment, the long-acting compositions of the present disclosure comprise at least one isoxazoline compound of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via) that are enriched in one enantiomer in a weight: weight ratio of at least 2:1, at least 5:1 or at least 10:1. In another embodiment, the compositions comprise at least one compound of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II- 2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), which is enriched in one enantiomer in a weightweight ratio of at least 15:1 or at least 20:1, or a pharmaceutically acceptable salt thereof. In an embodiment, the isoxazoline compounds of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II- 1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via) present in the compositions of the present disclosure are essentially pure enantiomers.

In another embodiment of the present disclosure, the IRC comprises a compound of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II- 2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is enriched in the fV)-enantiomer in a weightweight ratio is at least approximately 1.5:1 or 2:1. In yet another embodiment, the IRC of the present disclosure comprises a compound of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II- 1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is enriched in the (S)-enantiomer in a weightweight ratio of at least about 5:1 or greater. In still another embodiment, the compositions of the present disclosure comprise a compound of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is enriched in the (S)-enantiomer in a weightweight ratio of at least approximately 10:1, 20:1, or greater. In still another embodiment, the IRC of the present disclosure comprises a compound of formula (I), formula (la), formula (lb), formula (Ic), formula (Id), formula (II), formula (II- 1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is essentially the pure (S)-enantiomer. In one embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is substantially enriched in an enantiomer. In another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is substantially enriched in the (S)- enantiomer. In another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is substantially enriched in the (//(-enantiomer.

In another embodiment of the present disclosure, the IRC comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is enriched in the (<S)-enantiomer in a weightweight ratio is at least approximately 1.5:1 or 2:1 or greater. In yet another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is enriched in the (<S)-enantiomer in a weight: weight ratio of at least about 5:1 or greater. In still another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is enriched in the fY)-enantiomer in a weight: weight ratio of at least approximately 10:1, 20:1, or greater. In still another embodiment, the compositions of the present disclosure comprise a compound of formula (I), (la), (lb), (Ic) or (Id) that is essentially the pure fS')-enantiomer.

In another embodiment of the present disclosure, the IRC comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is enriched in the (//(-enantiomer in a weightweight ratio is at least approximately 2:1 or greater. In yet another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is enriched in the (iZ)-enantiomer in a weight: weight ratio of at least about 5:1 or greater. In still another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is enriched in the (iZ)-enantiomer in a weightweight ratio of at least about 10:1, 20:1, or greater. In still another embodiment, the IRC of the present disclosure comprises a compound of formula (I), (la), (lb), (Ic) or (Id) that is essentially the pure (iZ)-enantiomer.

In another embodiment of the present disclosure, the IRC comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is enriched in the (//(-enantiomer in a weightweight ratio is at least approximately 2:1 or greater. In yet another embodiment, the IRC of the present disclosure comprises a compound of formula (II), formula (II- 1.1001) to formula (II- 1.025), formula (II-2.001) to formula (II- 2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is enriched in the (//(-enantiomer in a weightweight ratio of at least about 5:1 or greater. In still another embodiment, the IRC of the present disclosure comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is enriched in the (//(-enantiomer in a weight: weight ratio of at least approximately 10:1, 20:1, or greater. In still another embodiment, the IRC of the present disclosure comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II- 2.001) to formula (II-2.018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (Via), that is essentially the pure (//(-enantiomer.

In another embodiment, the IRC of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline disclosed in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617 WO 2008/122375, WO 2014/439475 A1 and WO2012 120135A1, all of which are incorporated herein by reference in their entirety.

In yet another embodiment, the IRC of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline compound described in WO 2009/02451A2 and WO 2011/075591 Al, both incorporated herein by reference in their entirety.

In other embodiments, the IRC of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline compound and one or more additional active agents. In one embodiment, the IRC of the present disclosure comprises at least one isoxazoline compound and at least one macrocyclic lactone active agent, including, but not limited to, avermectins or milbemycins.

In one embodiment, the IRC comprises at least one isoxazoline compound, an imidazothiazole compound, and optionally, one or minerals including but not limited to selenium and cobalt.

In one embodiment, at least one isoxazoline compound, and optionally one or more minerals, are sustained release actives, and an imidazothiazole compound is an exit dose active.

In one embodiment, the IRC comprises a macrocylic lactone, at least one isoxazoline compound, an imidazothiazole compound, and optionally, one or minerals including but not limited to selenium and cobalt.

In one embodiment, a macrocylic lactone, at least one isoxazoline compound, and optionally one or more minerals are sustained release actives, and an imidazothiazole compound is an exit dose active.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising a macrocyclic lactone, an isoxazoline compound of formula (Id), or a pharmaceutically acceptable salt thereof, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole HC1 which is encapsulated within a gelatin or vegetable capsule, a gel cap or a table or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising a macrocyclic lactone, an isoxazoline compound of formula (Id), or a pharmaceutically acceptable salt thereof,, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole base which is encapsulated within a gelatin or vegetable capsule, a gel cap or a tablet or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising abamectin, an isoxazoline compound of formula (Id), or a pharmaceutically acceptable salt thereof, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole HC1 which is encapsulated within a gelatin or vegetable capsule, a gel cap or a table or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising abamectin, an isoxazobne compound of formula (Id), or a pharmaceutically acceptable salt thereof,, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole base which is encapsulated within a gelatin or vegetable capsule, a gel cap or a tablet or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising eprinomectin, an isoxazobne compound of formula (Id), or a pharmaceutically acceptable salt thereof,, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole HC1 which is encapsulated within a gelatin or vegetable capsule, a gel cap or a tablet or a coated tablet.

In one embodiment, the IRC according to the invention comprises a sustained release active comprising eprinomectin, an isoxazobne compound of formula (Id), or a pharmaceutically acceptable salt thereof, and optionally, one or minerals including but not limited to selenium and cobalt, and an exit dose comprising levamisole base which is encapsulated within a gelatin or vegetable capsule, a gel cap, table, or a coated tablet.

In some embodiments, the IRC according to the invention comprises one or more actives that are natural or synthetic hormones, or hormone-like substances, such as anabolic steroids and progesterone and estrogen analogues, including estrogen, estradiol and melengestrol acetate. In certain embodiments, the IRC according to the invention comprises antibiotics.

According to one embodiment, the intra-ruminal capsule device comprises • a hollow tubular body sealed at a first end,

• an apertured cover at the second end of the hollow tubular body,

• an apertured spring cap slidably positioned within the hollow tubular body, and

• a spring located between one face of the apertured spring cap and the sealed first end of the hollow tubular body wherein a first chamber is defined within the tubular body between the apertured cover and the proximal face of the apertured spring cap, said first chamber being sized to contain a first delivery means for at least one sustained release active or mineral, and a second chamber is defined within the interior of the spring, said interior of the spring being sized to contain a second delivery means for at least one exit dose active.

In one embodiment, the intra-ruminal capsule device according to the invention preferably releases one or more actives over an extended period of time, i.e., the device provides a sustained release dose of one or more actives. According to one embodiment, the IRC has a first delivery means for sustained release of one or more actives that comprises a stack of tablets that erode by dissolving upon contact with rumen fluid. In one embodiment, the release period of the sustained released active(s) (i.e. the payout period of the sustained release dose) is over a period of any number of days, such as about 100 days. In certain other embodiments, the payout period of the sustained release dose is less than or more than about 100 days, such as about 30 days, about 60 days, about 90 days, or about 120 days. In certain embodiments, the payout period of the sustained released dose is between about 30 and 60 days, between about 60 and 90 days, or between about 90 and 120 days.

In one embodiment, the IRC according to the invention comprises an exit dose of one or more actives. According to one embodiment, the exit dose active(s) releases quickly upon contacting rumen fluid after the sustained release active(s) is substantially released, i.e., the exit dose of one or more actives is released substantially after the payout period of the sustained release active(s).

In one embodiment, the exit dose releases over a period of about 1 day, over a period of about 2 days, or over a period of about 3, 4, 5, 6, 7, 8, 9, or 10 days. In one embodiment, the exit dose active(s) is contained with a capsule, such as a gelatin capsule, which comprises the delivery means for the exit dose active(s). In certain embodiments, the capsule is a vegetable capsule such as a plant polysaccharide, carrageenan, starch and/or a cellulose capsule. Vegetable capsules include hydroxypropyl methylcellulose (INN name: hypromellose) and pullulan, a polysaccharide polymer made from starch.

The capsule, gel cap or tablet is a size that fits within the inner space of the spring in the IRC according to the invention. The IRC is configured to permit the capsule, gel cap or tablet to fit within the spring interior and still for an effective dose of the sustained release active. In such case, it may be necessary to increase the concentration of active within the sustained release medicament to ensure a sufficient amount of the active can be delivered to the animal. In some embodiments, more than one capsule, gel cap or tablet are contained in the spring interior in order to provide the desired dose of exit does active over a pay-out period.

An effective or sufficient amount of an active is meant herein to be an amount that provides the therapeutic outcome, such as eradication of a parasite, or raise levels of trace minerals or vitamins to levels considered to conducive to good health for the animal.

By active is meant any therapeutic compound, including a parasiticide, anthelminthic, mineral, vitamin, etc.

The capsules, tablets, coated tables, and gelcaps in the IRC according to the invention are dissolvable, whereby it is meant that the capsule, tablet, coated tablet or gelcap as the case may be dissolves when contacting rumen fluid.

Empty gelatin and vegetable capsules are commercially available in a variety of sizes, and as such, they are one option for encapsulating an active for use in an IRC according to the invention. According to standard capsule sizing, a #5 capsule is smaller than a #1 capsule, and a “000” (triple zero) capsule is the largest size available. A capsule size ‘00’ is composed of a body half and a cap half, and the two pieces together are about 23 mm in length, is about 8.5 mm in diameter, and has about a 0.9 mL capacity.

In one embodiment, the IRC according to the invention comprises an active encapsulated in a capsule size ‘00’. In yet other embodiments, the IRC according to the invention comprises an active encapsulated in a capsule size ‘0’ or a capsule size ‘000’. In one embodiment, the IRC according to the invention comprises an active encapsulated in a plurality of capsules, such as two, three, four, or more than four capsules. Similarly, when the active is contained in a tablet, coated tablet, or gel cap, a plurality of tablets, coated tablets or gel caps are included in certain embodiments of the invention.

In one embodiment, the IRC according to the invention comprises an exit dose of active encapsulated in a size ‘00’ gelatin or vegetable capsule.

In one embodiment, the IRC according to the invention comprises an exit dose of active encapsulated in more than one size ‘00’ gelatin or vegetable capsule, or more than one size ‘000’ gelatin or vegetable capsule.

In one embodiment, the IRC according to the invention comprises an exit dose of levamisole encapsulated in a size ‘00’ gelatin or vegetable capsule.

In one embodiment, the IRC according to the invention comprises an exit dose of levamisole encapsulated in at least one size ‘000’ gelatin or vegetable capsule.

In one embodiment, the IRC according to the invention comprises an exit dose of levamisole HC1 encapsulated in a size ‘00’ gelatin or vegetable capsule.

In one embodiment, the IRC according to the invention comprises an exit dose of levamisole HC1 encapsulated in a size ‘0’ or a size ‘Ό00’ gelatin or vegetable capsule.

In one embodiment, the IRC according to the invention comprises an exit dose of levamisole HC1 encapsulated in a size ‘00’ gelatin capsule. In one embodiment, the delivery means for the exit dose active(s) comprises a tablet or a gel cap. The tablet or gel cap contains at least one active and additionally includes excipients typical for tablets and gel caps as the case may be. Gel caps are typically made of a mixture of sugar and gelatin. Common tablet excipients include diluents such as sugar compounds (e.g. lactose, dextrin, glucose, sucrose, and sorbitol) and inorganic compounds (e.g. silicates, calcium and magnesium salts, sodium or potassium chloride); binders, compression aids, and granulating agents (e.g. natural or synthetic polymers such as starches, sugars, sugar alcohols and cellulose derivatives); disintegrant (e.g. starch, cellulose derivatives, alginates, and crospovidone); lubricants such as stearic acids and its salts (e.g. magnesium stearate), and coloring agents (synthetic dyes and natural colors).

In certain embodiments, any tablets in the IRC according to the invention may be uncoated or else may be coated. The tablets may be coated, for instance, as a protection against degradation, such as degradation due to moisture, degradation due to contact with rumen fluid, to increase the mechanical strength, and/or to modify release of the active agent.

In some embodiments, the intra-ruminal capsule device has an overcap which is releasably attached to the device at one end thereof to form a void between an end of the device and the overcap capable of containing a dose of an active within the void so that, in use, the dose of active in the overcap void is delivered to the rumen when the overcap is breached or detaches from the device. Preferably the overcap is releasably attached to the capsule by a dissolvable attachment. Preferably the overcap is made of a material which will dissolve or breakup in the rumen.

In some embodiments, the overcap is preferably made of a material selected from the group comprising cellulosic fibre, cardboard, paper, a water soluble plastics material, and starch.

In one embodiment, the active in the overcap comprises copper needles. In another embodiment, the active in the overcap comprises one or more anthelmintics. Preferably the overcap is releasably attached to the capsule by a dissolvable attachment.

Preferably the overcap is made of a material which will dissolve or breakup in the rumen. In some embodiments, the hollow tubular body of the intra-ruminal capsule device has at least one external protrusion adapted in use to assist in retaining the capsule in the rumen of an animal. In one embodiment, the at least one protrusion consists of a pair of foldable wings. When fully assembled with the wings folded downwards, the wings can be held in place by a biodegradable attachment such as a tape made from starch or other dissolvable material.

In a second aspect, the invention provides a method of treating an animal, including the steps of ,

1) placing an intra-ruminal capsule device according to the first aspect in an animal’s stomach, and 2) sequentially releasing at least one sustained release active and at least one exit dose active in the animal’s stomach such that the at least one exit dose active is released after the at least one sustained release active is substantially released.

In certain embodiments, the invention provides for improved methods for delivering actives such as anti-parasiticides, vitamins, minerals, and therapeutics to an animal.

In certain embodiments, the invention provides for improved methods for eradicating, controlling, and preventing parasite infection and infestations in an animal.

According to one embodiment, the method of treating an animal comprises

1) placing an intra-ruminal capsule device comprising a stack of tablets comprising at least one sustained release active and a capsule, tablet, coated tablet, or gel cap comprising at least one exit dose active in an animal’s stomach, and 2) sequentially releasing the at least one sustained release active and the at least one exit dose active in the animal’s stomach such that the at least one exit dose active is released after the at least one sustained release active is substantially released.

In certain embodiments, the method of treating an animal preferably comprises placing an intra-ruminal capsule device in an animal’s stomach wherein an exit dose active is contained in a capsule contained within a spring in the intra-ruminal capsule. As herein described, the spring is located between one face of an apertured spring cap and the sealed first end of the hollow tubular body portion of the intra-ruminal capsule device.

In one embodiment, the method of treating comprises placing an intra-ruminal capsule device that is loaded with a stack of tablets comprising at least one macrocyclic lactone, at least one benzimidazole, and optionally one or more minerals. In one embodiment, the method treating comprises placing an intra- ruminal capsule device that is loaded with a capsule, tablet, coated tablet, or gel cap comprising an imidazothiazole.

In one embodiment, the method of treatment comprises placing an intra-ruminal capsule device as described herein, wherein the intra-ruminal capsule device is loaded with a stack of tablets providing sustained release of albendazole, abamectin, and optionally one or more minerals, and an exit dose of a levamisole salt. In one embodiment, the levamisole salt is levamisole HC1. In another embodiment, the levamisole salt is levamisole phosphate. In one embodiment, the intra-ruminal capsule device provides sustained release of one or more minerals. In one embodiment, the intra-ruminal device provides sustained release of one or more minerals, at least one benzimidazole, and at least one macrocyclic lactone, and release of an exit dose thereafter of an anthelminthic.

In one embodiment, the intra-ruminal device provides sustained release of albendazole and abamectin, optionally one or more minerals, and release of an exit dose of an imidazothiazole. In one embodiment, the imidazothiazole is a levamisole salt. In one embodiment, the levamisole salt is levamisole HC1. In one embodiment, the levamisole salt is levamisole phosphate. According to one embodiment, the intra-ruminal device provides sustained release of albendazole, abamectin, Se, and Co, followed by release of an exit dose of a levamisole salt, wherein the levamisole salt is selected from levamisole HC1 and levamisole phosphate. In one embodiment, the levamisole salt is preferably HC1. In one embodiment, the invention provides an intra-ruminal capsule device (IRC) comprising a hollow tubular body sealed at a first end, a spring biasing an apertured spring cap towards a second end of the body, an apertured cover at the second end to define a first chamber between the aperture spring cap and the apertured cover capable of containing a first dose of active within the hollow tubular body for subsequent sustained release through the apertured cover into the rumen of an animal, wherein the aperture spring cap has an end face facing towards the first dose, a front face facing rearwardly from the end face to assist in locating a spring, and a hollow interior of the spring capable of containing an exit dose of active. In one embodiment, the intra-ruminal capsule device further includes an overcap which is releasably attached to the second end to form a void between the apertured cover and the overcap capable of containing a dump dose of active within the void so that in use the dump dose of active is delivered to the rumen when the overcap is breached or detaches from the second end. Preferably the overcap is releasably attached to the second end of the intra- ruminal capsule device by a dissolvable attachment.

Preferably the overcap is made of a material which will dissolve or breakup in the rumen.

Preferably the overcap is made of a material selected from the group comprising cellulosic fibre, cardboard, paper, a water soluble plastics material and starch.

Preferably the body has at least one external protrusion adapted in use to assist in retaining the capsule in the rumen of an animal.

Preferably at least one protrusion consists of a pair of foldable wings.

Preferably the IRC is loaded with a sustained release dose of active. Preferably the IRC is loaded with a dump dose of active in the overcap.

Preferably the IRC is loaded with an exit dose of active.

Preferably the dump dose of active in the overcap comprises copper needles.

Alternatively the dump dose of active in the overcap comprises one or more anthelmintics.

In one embodiment, the intra-ruminal capsule device contains a dump dose of active within the overcap, a sustained release dose of active within the body of the intra-ruminal capsule device, and an exit dose of active within the interior diameter of the spring. In one embodiment, the exit dose active is preferably contained within a gelatin or vegetable capsule, a gel cap or a coated tablet.

In one embodiment, the invention provides an intra-ruminal capsule device (IRC) comprising a hollow tubular body sealed at a first end, a spring biasing an apertured spring cap towards a second end of the body, an apertured cover at the second end to define a first chamber between the aperture spring cap and the apertured cover capable of containing a first dose of active within the hollow tubular body for subsequent sustained release through the apertured cover into the rumen of an animal, wherein the aperture spring cap has an end face facing towards the first dose, a front face facing rearwardly from the end face to assist in locating a spring, and a hollow interior of the spring capable of containing an exit dose of active, and wherein an overcap is releasably attached to said IRC at one end thereof to form a void between an end of said IRC and the overcap capable of containing a second dose of active within the void so that in use the second dose of active is delivered to the rumen when the overcap is breached or detaches from the device.

Preferably the overcap is attached to the second end of the device to form a void between the apertured cover and the overcap capable of containing the dump dose of active within the void so that in use the dump dose of active is delivered to the rumen when the overcap is breached or detaches from the second end. Preferably the overcap is releasably attached to the IRC by a dissolvable attachment.

Preferably the overcap is made of a material which will dissolve or breakup in the rumen. Preferably the overcap is made of a material selected from the group comprising cellulosic fibre, cardboard, paper, a water soluble plastics material, and starch.

Preferably the at least one protrusion consists of a pair of foldable wings. Preferably the IRC is loaded with a sustained release dose of active.

Preferably the IRC is loaded with a dump dose of active in the overcap.

Preferably the IRC spring interior is loaded with an exit dose of active.

Preferably the dump dose of material in the overcap comprises copper needles.

Alternatively, the active in the overcap comprises one or more anthelmintics. In one embodiment, the IRC according the invention contains a dump dose of active within the overcap, a sustained release dose of active within the body of the capsule and an exit dose of active within the spring.

In one embodiment, the exit dose active within the spring is preferably contained within a gelatin or vegetable capsule, a gel cap or a coated tablet.

Design

Certain embodiments of the intra-ruminal capsule according to the invention provide continuous release of one or more active(s), followed by immediate release of an exit dose of an active. In particular, it is desirable for a sustained release intra-ruminal capsule device to include an exit dose of active that can be released at the conclusion of the sustained release payout. If the intra-ruminal capsule device is used to release a an active such as an anthelmintic over a long period, the exit dose would preferably be in the form of a larger immediate release of anthelmintic sufficient to kill any parasites that may have survived the low level of sustained release of anthelmintic. However there are practical problems with achieving this desired embodiment.

Because a fast release exit tablet must be constructed of a more soluble formulation than the sustained release tablets this can result in the release of the anthelmintic drug through the matrix of the sustained release medicament or tablet stack before it is meant to be released. There is also an additional problem of how to fit such an exit dose into the device when it is desired to include as much medicament or as many sustained release tablets into the capsule as possible.

To address these issues, the invention allows for the inclusion of an exit dose of medicament in the spring within the intra-ruminal capsule device. Current sustained release intra-ruminal capsule devices fitted with a spring have a flat faced piston (which serves as the spring cover, or spring cap). The flat face of the piston contacts the face of the last sustained release tablet within the tablet stack inside the intra-ruminal capsule device.

According to embodiments of the instant invention, the exit dose within a gelatin or vegetable capsule, or in a tablet or a gelcap is provided within the diameter of a spring since there is no piston shank occupying the interior of the spring. The spring cap is modified to have a hole, e.g. a 2- 4 mm hole, which permits inflow of rumen fluid into the spring after payout of the sustained release active.

Thus, in one particular embodiment, the intra-ruminal capsule according to the invention provides continuous release of albendazole plus abamectin for 100 days, and after the end of 100 days, immediate release of an exit dose of levamisole HC1 is provided to kill any albendazole and abamectin resistant worms.

In fact, by means of the IRC invention described herein, the inventors have overcome the problem of rumen fluid wetting the first 3-5 continuous release tablets in an IRC which, in fact, causes a fast release tablet at the end of the stack to disintegrate too early before the continuous release tablets finish paying out. The inventors found that this problem was not circumvented by a slow disintegrating exit dose tablet, because the intended exit dose active concentration (Cmax), specifically the Cmax of levamisole, is not achieved.

To overcome the difficulty described above, the IRC according to the invention as depicted in FIG. 1 herein was developed. The rationale for the IRC design as shown in FIG. 1 is that the physical separation provided by the spring cap and a gelatin capsule (or alternatively a gel cap or coated tablet) containing the exit does of active provides a physical barrier, so that the exit dose does not release too early. After the continuous release tablets pay out, rumen fluid can enter the device and flow through the hole in the spring cap (e.g. diameter ~ 2 mm) to rupture the gelatin capsule (or gel cap) or dissolve a tablet, and release the exit dose contained within.

Having thus described in detail various embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention.

EXAMPLES

The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention.

Example 1

FIG. 2 depicts an intra-ruminal capsule device (IRC) according to one embodiment of the invention, wherein the IRC has one tablet in the body. An in vitro payout trial was conducted for an IRC according to FIG. 2 using a single albendazole/abamectin Bionic^® tablet (i.e. the sustained release active tablet), and a size ‘00’ gelatin capsule filled with 500 mg levamisole HC1 (i.e. the exit dose active).

The in vitro trial setup included a shaking water bath at 39°C). The investigators observed that the gelatin capsule looked intact until day 9, then between days 10 and 12, water flowed into the IRC, ruptured the gelatin capsule, and released the levamisole dose contained in the gelatin capsule.

FIG. 3 shows the dose of albendazole and levamisole HC1 (by weight in mg) remaining in the FIG. 2 IRC device, which shows that albendazole was released continuously over 12 days, and the levamisole dose was released within 3 days later.

Analytical procedure for quantification of albendazole and levamisole Albendazole and levamisole were assayed by HPLC according to the following method:

Column: Kinetex Cl 8, 100mm x 4.6mm, 5 micron particle size.

Column oven temp: 25°C Sample temperature: 20°C

Wavelength: 215nm for levamisole assay, 308nm for albendazole assay Mobile phase A: 5g/L ammonium dihydrogen phosphate in water, pH adjusted to 6.5 withNaOH.

Mobile phase B: acetonitirile

Run time 20 minutes; gradient program:

0 min :90% Mobile phase A, 10% Mobile phase B 8 min :30% Mobile phase A, 70% Mobile phase B 13 min :30% Mobile phase A, 70% Mobile phase B

16 min :90% Mobile phase A, 10% Mobile phase B

20 min :90% Mobile phase A, 10% Mobile phase B

Example 2

The in vitro trial as described in Example 1 was performed again, except the continuous release tablet stack (i.e. the stack of sustained release active tablets) was increased to three tablets as depicted in FIG. 4. The three sustained release active tablets were albendazole/abamectin Bionic® tablets, and the exit dose active was 500 mg levamisole HC1 which was contained inside a size ‘00’ gelatin capsule. FIG. 5 shows the dose of albendazole and levamisole HC1 (by weight in mg) remaining in the IRC device over 50 days.

Example 3

An in vitro pay-out trial was conducted for an IRC as described in Example 2 using three albendazole/abamectin Bionic® tablets, but in this example the exit dose active was a levamisole base tablet (rather than a gelatin capsule containing levamisole HC1 as was used in Examples 2 and 3).

Levamisole tablets used in Example 3 were pressed from the formulation as shown below in Table 1, and assembled into an IRC as depicted in FIG. 4. The IRC were placed into in vitro shaking water bath at 39°C and samples were taking at different time points. Albendazole and Levamisole assays (using HPLC methods) were performed on the IRC samples to monitor the payout.

The pay-out data is plotted in the FIG. 6 pay-out graph, which was generated in the same manner as the graphs depicted in FIGs. 3 and 5. In particular, FIG. 6 shows the dose of albendazole and levamisole HC1 (by weight in mg) remaining in the IRC device over 42 days.

Overall, the in vitro study showed a very good payout of the actives since albendazole payed out in a controlled release manner and levamisole payed out in a “tail cutter” matter (i.e. an immediate release dose at the end).

Table 1: Pressed Exit Dose Tablet Composition

Ingredient Weight (mg)

Levamisole Base 400 Magnesium Stearate 8 Dicalcium Phosphate 152 Maize starch 80 Hydrogenated Castor Oil 160 Total 800mg

Claims

WHAT IS CLAIMED IS :

1. An intra-ruminal capsule device comprising a) a hollow tubular body sealed at a first end, b) an apertured cover at the second end of the hollow tubular body, c) an apertured spring cap slidably positioned within the hollow tubular body, and d) a spring located between one face of the apertured spring cap and the sealed first end of the hollow tubular body, wherein a first chamber is defined within the tubular body between the apertured cover and the proximal face of the apertured spring cap, said first chamber being sized to contain a first delivery means for at least one sustained release active or mineral, and a second chamber is defined within the interior of the spring, said interior of the spring being sized to contain a second delivery means for at least one exit dose active or mineral.

2. An intra-ruminal capsule device according to claim 1, wherein the first delivery means is a stack of tablets.

3. An intra-ruminal capsule device according to claim 1, wherein the second delivery means is a capsule, gel cap, tablet or coated tablet.

4. An intra-ruminal capsule device according to claim 3, wherein the capsule is a gelatin or vegetable capsule.

5. An intra-ruminal capsule device according to any preceding claim wherein the second delivery means is one or more capsules size ‘O’, size ‘00’, and/or size 000

6. An intra-ruminal capsule device according to any preceding claim wherein the second delivery means comprises one or more gelatin capsules, and said gelatin capsule is loaded with at least one anthelminthic, at least one mineral, or both.

7. An intra-ruminal capsule device according to any preceding claim wherein the second delivery means comprises one or more gelatin capsules, and said gelatin capsule is loaded with at least one imidazothiazole.

8. An intra-ruminal capsule according to claim 7, wherein the imidazothiazole is selected from the group consisting of tetramisole, levamisole and butamisole.

9. An intra-ruminal capsule according to claim 8, wherein the imidazothiazole is levamisole.

10. An intra-ruminal capsule according to claim 8, wherein the imidazothiazole is levamisole HC1.

11. An intra-ruminal capsule device according to any preceding claim, wherein the first delivery means comprises a stack of tablets comprising at least one anthelminthic, at least one mineral, or both.

12. An intra-ruminal capsule device according to any preceding claim, wherein the first delivery means comprises a stack of tablets comprising at least one macrocyclic lactone.

13. An intra-ruminal capsule device according to claim 12, wherein said macrocyclic lactone is selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, moxidectin, and selamectin.

14. An intra-ruminal capsule device according to claim 13, wherein said macrocyclic lactone is abamectin, doramectin, eprinomectin, or selamectin.

15. An intra-ruminal capsule device according to any preceding claim, wherein the first delivery means comprises a stack of tablets comprising at least one benzimidazole.

16. An intra-ruminal capsule device according to claim 15, wherein said benzimidazole is selected from the group consisting of albendazole, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, oxibendazole, oxfendazole, parbendazole, thiabendazole, thiophanate and the O,O-dimethyl analogue of thiophanate.

17. An intra-ruminal capsule device according to claim 16, wherein the benzimidazole is albendazole.

18. An intra-ruminal capsule device according to any preceding claim, wherein said device is loaded with one or more minerals.

19. An intra-ruminal capsule device according to claim 18, wherein the one or more minerals comprise selenium, cobalt, or a mixture thereof.

20. An intra-ruminal capsule device according to claim 1, wherein said device is loaded with one or more actives for sustained release.

21. An intra-ruminal capsule device according to claim 1, wherein said device is loaded with an exit dose of one or more actives.

22. An intra-ruminal capsule device according to claim 1, wherein said device is loaded with one or more exit dose actives, and one or more sustained release actives.

23. An intra-ruminal capsule device according to claim 22, where said device is loaded with sustained release actives comprising at least one macrocyclic lactone and at least one benzimidazole.

24. An intra-ruminal capsule device according to claim 23, where the sustained release actives further comprise at least one mineral.

25. An intra-ruminal capsule device according to claim 24, wherein sustained release actives comprise selenium, cobalt, or a mixture thereof.

26. An intra-ruminal capsule device according to any one of claims 23-25, wherein the macrocyclic lactone is abamectin.

27. An intra-ruminal capsule according to any one of claims 23-25, wherein the benzimidazole is albendazole.

28. An intra-ruminal capsule device according to claim 1, wherein said capsule comprises a. a first delivery means comprising a stack of tablets, wherein said tablets comprise a benzimidazole, a macrocyclic lactone, and optionally, one or more minerals b. a second delivery means comprising a capsule, tablet, coated tablet or gelcap, wherein the capsule, tablet, coated tablet, or gelcap comprises an anthelminthic.

29. An intra-ruminal capsule device according to claim 28, wherein the anthelminthic is an imidazothiazole.

30. An intra-ruminal capsule capsule device according to claim 29, wherein the imidazothiazole is a levamisole salt.

31. An intra-ruminal capsule device according to any one of claims 28-30, wherein the benzimidazole is selected from the group consisting of albendazole, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, oxibendazole, oxfendazole, parbendazole, thiabendazole, thiophanate and the O,O-dimethyl analogue of thiophanate.

32. An intra-ruminal capsule device according to clam 31, wherein the benzimidazole is albendazole.

33. An intra-ruminal capsule device according to any one of claims 28-32, wherein the macrocyclic lactone is selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, moxidectin, and selamectin.

34. An intra-ruminal capsule device according to claim 33, wherein the macrocyclic lactone is abamectin.

35. An intra-ruminal capsule device according to any one of claims 28-34 comprising one or more minerals selected from selenium, cobalt, or a mixture thereof.

36. An intra-ruminal capsule device according to any one of claims 28-35 comprising minerals consisting of selenium and cobalt.

37. An intra-ruminal capsule device according to claim 28, wherein the first delivery means comprises a stack of tablets comprising albendazole, abamectin, selenium and cobalt, and the second delivery means comprises a capsule comprising a levamisole salt.

38. An intra-ruminal capsule device according to claim 37, wherein the levamisole salt is levamisole HC1.

39. An intra-ruminal capsule device according to any preceding claim, wherein the payout period of one or more sustained release actives loaded therein is between about 90 and 120 days.

40. An intra-ruminal capsule device according to claim 39, wherein the pay-out period of one or more sustained release actives loaded therein is about 100 days.

41. An intra-ruminal capsule according to any preceding claim, wherein the at least one exit dose active loaded therein releases over a period of about 1 to about 10 days.

42. An intra-ruminal capsule device according to any preceding claim, wherein the capsule further includes an overcap which is releasably attached to the second end to form a void between the apertured cover and the overcap capable of containing a dose of an active within the void so that, in use, the dose of active in the overcap void is delivered to the rumen of an animal when the overcap is breached or detaches from the device.

43. An intra-ruminal capsule device according to claim 42, wherein the overcap is releasably attached to the device by a dissolvable attachment.

44. An intra-ruminal capsule device according to claim 43, wherein the overcap is made of a material which will dissolve or breakup in the rumen.

45. An intra-ruminal capsule device according to claim 43, wherein the overcap is made of a material selected from the group comprising cellulosic fibre, cardboard, paper, a water soluble plastics material and starch.

46. An intra-ruminal capsule device according to any one of the preceding claims, wherein the body has at least one external protrusion adapted in use to assist in retaining the capsule in the rumen of an animal.

47. An intra-ruminal capsule device according to claim 46, wherein the at least one protrusion consists of a pair of foldable wings.

48. An intra-ruminal capsule device as claimed in any one of the preceding claims substantially as herein described with reference to the drawings.

49. A method of treating an animal comprising the steps of i) placing an intra-ruminal capsule device according to any one of the preceding claims in an animal’s stomach, and ii) sequentially releasing at least one sustained release active and at least one exit dose active in the animal’s stomach such that the at least one exit dose active is released after the at least one sustained release active is substantially released.

50. A method of treating an animal according to claim 49, wherein the pay-out period of the at least one sustained release active is about 90 to about 120 days.

51. A method of treating an animal according to claim 50, wherein said pay-out period is about 100 days.

52. A method of treating an animal according to any one of claims 49-51, wherein the at least one exit dose active releases over a period of about 1 to about 10 days.