NZ758849A - Drenching platform or system, consumables thereof and related aspects - Google Patents

Abstract

The disclosure relates to anthelmintic compositions in the form of a stable granule comprising: (a) levamisole HCL; (b) an anthelmintic active selected from (i) one or more imidazothiazoles, (ii) one or more benzimidazoles selected from oxfendazole, albendazole or fenbendazole, (iii) one or more macrocyclic lactones selected from avermectin, ivermectin and abamectin, and (iv) praziquantel; (c) a wetting agent; and (d) a suspending agent if the anthelmintic actives comprise a benzimidazole or praziquantel; and the stable granule being readily dispersible in water to provide a homogenous mixture of the anthelmintic actives for administration to a non-human mammal.

Description

GRANULATED ANTHELMINTIC PREPARATIONS AND DELIVERY SYSTEMS TECHNICAL FIELD The present invention relates to beneficial granules suitable as a platform technology for providing anthelmintic agents to animals.

More particularly the t invention relates to anthelmintic granules, kits involving packs of granules, methods of treating an animal using such granules, and methods of stering at least one anthelmintic active.

BACKGROUND In the US Patent 6013636 Ashmont Holdings Limited report in respect of ML mintic actives including, but not limited to, the avermectins, ivermectin, doramectin, abamectin, milbemycin and moxidectin that they are difficult to formulate. There they report for injectable solutions, pour-on compositions and oral compositions formulations requiring not only a vegetable oil (such as soya bean oil, sesame oil and corn oil) but also a co-solvent which is an alcohol of 4 or more carbon atoms (eg benzyl alcohol).

In WO 98/06407 (PCT/NZ97/00096) Ashmont Holdings Limited rely on an organic solvent able to dissolve both praziquanel and at least one ML anthelmintic as a pathway to a mixed phase packaged composition for direct oral administration to warm-blooded non-human s. Most examples at manufacture include an aqueous phase and a solvent phase. An example of a drench form without water has N-MethylPyrrolidone present as a solvent.

WO 98/06407 reports a eous injectable solution of abamectin and praziquantel used as manufactured (ie without r dilution). formulation capable of stably including avermectins or ycins together with levamisole.

In stating a claim to stability they refer to formulations having to be “stable” to be of commercial use. They report a commercially able anthelmintic formulation as one which is “stable” at room ature for a period of at least 6 months. t reports the great ulty in formulating such a combination product in order to achieve the required stability.

They also address the issue of the content of New d patent specification 336139 of Nufarm pointing to the attempt to formulate a combination avermectin/milbemycin and levamisole product reliant upon emulsion technology.

Ashmont in order to achieve their aim in maintaining stability of the avermectins and/or milbemycins in the presence of levamisole indicate they have found it ary to 88485556_2.doc 88485556.2 dissolve the actives in a pyrrolidone t, most preferably N-methyl pyrrolidone or 2- pyrrolidone.

Bomac in WO2008/072985 () report a storage stable pour on veterinary formulation of an ML nd (optionally also with another active) in at least one glyceryl acetate solvent (optionally with co-solvents).

We believe on farm dilution allows stable liquid formulations of ML actives to be made available and for customisation at dilution prior to stration. At the time of such dilution other components can be added and with the relatively brief time between dilution and administration stability becomes less of an issue. nly extended shelf life of an ML/BZ, ML/LEV and/or ML/BZ/LEV formulation can be rendered irrelevant while at the same time ing maximisation of customisation.

It may be a r or alternative object to provide for fine ML particles or a ML present in a micro-emulsion in a final (and preferably customised) formulation including targeted on farm diluents(s) (whether water, aqueous, non-aqueous or other) having substantial homogeneity of particle spread and/or active spread.

It may still be a further or ative object of the invention to provide a low volume liquid concentrate of at least one ML mintic active stable in that form for a satisfactory manufacture/supplier chain/user storage shelf life without ntial loss of ML and/or significant reduction in its dilutability.

It may be a further or alternative object to provide a liquid concentrate of an ML able to be added to levamisole and/or a benzimidazole in water or an aqueous composition or a nonaqueous composition on farm just prior to administration.

It may be a further or ative object to provide at least substantially (and preferably) pyrrolidone free and/or glyceryl acetate free formulations of at least one ML active.

SUMMARY According to a first aspect, the present disclosure may broadly provide an anthelmintic composition in the form of stable granules comprising two or more different anthelmintic s selected from one or more imidazothiazoles, one or more benzimidazoles, one or more macrocyclic lactones, praziquantel, wherein the composition comprises at least levamisole HCI and a macrocyclic lactone as the anthelmintic actives, n the granules further comprise a suspending agent or rheology modifier and wherein the ding agent or rheology modifier is a gum, and n the granules further comprise a wetting agent and a dispersant and wherein the granules are readily dispersible in water to provide a homogenous mixture of the anthelmintic actives for administration to a non-human mammal.

A composition comprising sole HCL, a benzimidazole and a macrocyclic lactone. 88485556_2.doc 88485556.2 The macrocyclic lactone is selected from avermectin, ivermectin and abamectin.

The benzimidazole is selected from oxfendazole, albendazole or fenbendazole.

A composition comprising a particulate source of one or more minerals.

The wetting agent is polysorbate 80.

The dispersant is colloidal silicon dioxide.

The es comprise 30, 35, 40, 45, 50, 55, 60, 65 or 70% w/w of the anthelmintic actives.

The granules comprise .less than 3, 2, or 1% w/w water.

The granules are free of pyrrolidones.

A composition comprising about 1 to about 40% w/ w benzimidazole, a suspending agent, and about 1 to about 70% w/ w levamisole HCL and comprising 1,5, , 15, 20, 25, 30, 35 or 40% w/w yclic lactone.

The granules comprise 0.1 to 10% macrocyclic lactone.

The gum is a xanthan gum.

According to another aspect, the present disclosure may broadly provide a method of forming an anthelmintic composition comprising the steps of: ing two or more anthelmintic actives selected from one or more othiazoles, one or more idazoles, one or more macrocyclic lactones, and praziquantel, wherein the two or more provided anthelmintic actives comprise at least levamisole HCL and a macrocyclic lactone, ing a wetting agent, mixing the macrocylic lactone with a suspending agent, combining the anthelmintic actives, and granulating the anthelmintic actives, wherein a stabilising agent is combined with the anthelmintic actives prior to granulation and wherein the stabilising agent is a gum and n the granules comprise a suspending agent or rheology modifier, n the suspending agent or rheology modifier is a gum and wherein the es comprise an anionic surfactant or g agent and wherein the granules comprise a dispersant.

The granules r comprise a particulate source of one or more minerals.

The wetting agent is polysorbate 80.

The dispersant is colloidal silicon e.

The granules comprise 30, 35, 40, 45, 50, 55, 60, 65 or 70% w/w of the anthelmintic actives.

The gum is a xanthan gum. 88485556_2.doc 88485556.2 In one embodiment the method further ses a step before the providing step of determining the ent needs of one or more animals. Determination of the treatment needs of one or more animals can be carried out by a skilled worker with regard to that skill and the teaching of this specification.

In one embodiment the method further comprises administering the liquid to one or more animals. In another embodiment the method further comprises immediately administering the liquid to one or more s.

Another aspect of the invention relates to a method of forming an anthelmintic composition sing the steps of: providing an imidazothiazole, providing one or more anthelmintic actives selected from benzimidazoles and macrocyclic lactones, ing a suspending agent if the one or more anthelmintic active comprises a macrocyclic lactone providing a wetting agent if the one or more anthelmintic active comprises a benzimidazole mixing the macrocylic lactone with the suspending agent if a macrocylic lactone is present, mixing the idazole with the wetting agent if a benzimidazole is present, ing the anthelmintic actives, and granulating the mixture of mintic actives.

The following embodiments may relate to any of the above aspects.

In some embodiments the imidazothiazole is levamisole HCL.

In some embodiments the composition comprises levamisole and a macrocyclic lactone.

In some embodiments the composition comprises levamisole and a benzimidazole.

In some embodiments the comprises levamisole, a benzimidazole and a macrocyclic lactone.

In some ments the composition comprises a particulate source of one or more ls. Unless where specifically stated, reference to minerals in this specification should be taken to be nce to any minerals required by the non-human animal to be treated, including but not limited to selenium, cobalt, magnesium, zinc, iodine and any ation of any two or more thereof.

In some embodiments the granules comprises a suspending agent. 88485556_2.doc 88485556.2 In some ments the es comprises a gum. Gums that may be useful in any embodiment described herein include but are not limited to agar, alginic acid, alginate, sodium alginate, carrageenan, arabic, ghatti, tragacanth, karaya, guar, locust bean, beta-glucan, chicle, dammar, glucomannan, mastic, psyllium seed husk, spruce, tara, gellan, and xanthan gums and any combination of any two or more thereof.

In some embodiments the granules comprises an anionic surfactant.

In some embodiments the granules comprise about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% w/w of anthelmintic active.

In various ments, a composition useful herein may comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % w/w of one or more anthelmintic actives useful herein and useful ranges may be selected between any of these values (for e, about 1 to about 10, about 1 to about 20, about 1 to about 30, about 1 to about 40, about 1 to about 50, about 1 to about 60, about 1 to about 70, about 1 to about 80, about 1 to about 90, about 10 to about 20, about 10 to about 30, about 10 to about 40, about 10 to about 50, about 10 to about 60, about 10 to about 70, about 10 to about 80, about 10 to about 90, about 20 to about 30, about 20 to about 40, about 20 to about 50, about 20 to about 60, about 20 to about 70, about 20 to about 80, about 20 to about 90, about 30 to about 40, about 30 to about 50, about 30 to about 60, about 30 to about 70, about 30 to about 80, about 30 to about 90, about 40 to about 50, about 40 to about 60, about 40 to about 70, about 40 to about 80, about 40 to about 90, about 50 to about 60, about 50 to about 70, about 50 to about 80, about 50 to about 90, about 50 to about 60, about 50 to about 70, about 50 to about 80, about 50 to about 90, about 60 to about 70, about 60 to about 80, about 60 to about 90, about 70 to about 80, or about 70 to about 90). It should be understood that these values and ranges may relate to one anthelmintic active or a combination of anthelmintic actives. For example, a composition useful herein may comprise one, two, three or more anthelmintic actives and these values and ranges may relate to each active individually or to the combination of actives. Formulation of a particular combination of two or more actives can be carried out by a skilled worker with regard to that skill and the teaching of this specification.

In some embodiments the granule comprises less than 3, 2, 1% w/w water.

In some embodiments the granules are free or at least substantially free of pyrrolidones.

In some ments the composition comprises  from about 1 to about 40% w/w idazole, and  from about 1 to about 70% w/w levamisole HCL.

In some embodiments the composition comprises 1, 5, 10, 15, 20, 25, 30, 35 or 40% w/w macrocyclic lactone. 56_2.doc 88485556.2 In some embodiments the granules se a particulate thixotrope, particulate rheology modifier and/or gum.

In some embodiments the granules n a suspending agent.

In some embodiments the suspending agent is added to the liquid.

In some embodiments the suspending agent is a gum.

In some embodiments the suspending agent of (a)(i) is a non-colloidal agent.

In some embodiments the non-colloidal agent is silicon e.

In some embodiments the liquid is water.

In some embodiments the liquid is an anthelmintic concentrate.

In some embodiments the liquid contains avermectin and/or milbemycin in a liquid concentrate form.

In some embodiments the liquid delivery formulation is suitable for administration to animals for up to one month after mixing.

In some embodiments the granules comprise  from about 1 to about 40% w/w benzimidazole, and  from about 1 to about 60% w/w levamisole HCL.

Preferably the diluents is water or an aqueous composition. ably xanthan gum is the or a thixotrope and/or suspending agent for a particulate BZ in the delivery liquid composition.

Preferably granules of at least one BZ and also containing LEV provide for a ulate BZ presence in the delivery liquid composition.

In an aspect the invention is a diagnosis of the anthelmintic needs of a herd of warmblooded non-human animals and the provision of a corresponding kit of (ii) and/or (iii) type packs for use in a method as aforesaid.

In another aspect the invention is a use of one or more pack of granules and/or a liquid trate to provide for one or more of LEV, BZ and/or ML s in a delivery liquid composition.

The present invention includes the use of dilutable powders, ble granules, and dilutable liquid concentrate(s) and/or semisolid concentrates to provide a multiactive anthelmintic formulation capable of oral, spray and/or l delivery.

Preferably the es at least in respect of one anthelmintic active result from a fluidised bed granulation of anthelmintic particles. 88485556_2.doc 88485556.2 Various aspects of the present invention will now be described but not exclusively of other aspects as will be apparent from process flow ms, use diagrams and other aspects disclosed herein.

Optionally another anthelmintic (e.g. uantel) can be present in a granule, powder or liquid of the system.

Various anthelmintic actives have been considered for use in granules of the present invention. These e at least, by way of example,  benzimidazoles such as oxfendazole, albendazole, fenbendazole, mebendazole, dazole, oxibendazole, bendazole, netobimin, thiabendazole, and febantel,  salicylanilide such as closantal, nide, clioxanide, niclosamide, oxyclozanide, rafoxanide, bithionol, disophenol, hexachlorophene, nitroxynil, diamfenetid, and niclofolan menichlophola,  imidazothiazoles such as levamisole HCL, levamisole base, pyrantel pamoate, butamisole, and tetramisol, and  macrocyclic lactones such as abamectin, avermectin, moxidectin, doramectin, ctin, emamectin, eprinomectin, selamectin, milbemycin, and cydectin.

A preferment is both granules and powder(s) rather than just es alone.

Preferably at least one benzimidazole is present in each granule.

Preferably a levamisole is present in each granule or some granule(s).

The other inclusion preferably include a gum as a athixotrope.

Preferably a gum is present as a suspending agent for at least the benzimidazole content y, when diluted, there will be substantial homogeneity of the resultant suspension.

Preferably the anthelmintic agent(s) of each granule accounts for at least about 30% w/w (more ably at least about 40% w/w) (still more preferably at least about 50% w/w) (and most preferably from about 40% w/w to about 70% w/w) of the granule weight.

Preferably the granules have less than about 3% w/ w (more preferably less than about 2% w) of water. ably the granules are free or at least substantially free of water.

Preferably the granules are free or at least substantially free of pyrrolidones.

Preferably a non-aqueous liquid is present in the anthelmintic granules in the range up to about 20% w/w of the granule (preferably at least about 10% w/w).

Most preferably some water is present and some non-aqueous liquid is present in the anthelmintic es. 88485556_2.doc 88485556.2 Preferably any alcohol (e.g. benzyl alcohol) is present in an amount less than that needed to dissolve all of any anthelmintic active present.

Whilst they can be prepared by any granulation technique (e.g. single pot granulation, fluid bed top spray granulation, high sheer ation/fluid bed drying combination, continuous fluid bed granulation, spray drying, etc), preferably the granules, at least in respect of one anthelmintic active, result from a fluidised bed granulation reliant on spraying of a solids stream that includes the anthelmintic les. At time we may choose to use dry compaction (dry granulation) and wet extrusion followed by drying and sizing.

By way of example only a preferred double anthelmintic active granule can have: QUANTITY ONALITY A PREFERENCE to 40% w/w a benzimidazole azole or albendazole about 15 to about 25% w/w to 60% w/w levamisole HCI about 30 to about 40% w/w A suitable levamisole is levamisole HCl.

Suitable benzimidazole(s) include those sparingly soluble in water.

Examples include oxfendazole, azole, fenbendazole, mebendazole, flubendazole, oxibendazole, triclabendazole, netobimin, thiabendazole, febantel, etc.

Most preferably the BZ is oxfendazole, albendazole or fenbendazole.

Praziquantel might also be included in granule(s) powder(s).

Preferably a benzimidazole active ingredient is dable.

Preferably the suspendable anthelmintic particles are no larger than those of that anthelmintic actives starting material particles. ably a levamisole active ingredient is present. ally granulation involves one or more sprays of a solids stream on a fluidised bed.

A spray may e a liquid antifoaming agent and/or minerals and/or vitamins.

A spray may involved a liquid in which the benzimidazole is more soluble than it is in water but in insufficient quantity to fully dissolve the benzimidazole starting material(s).

A spray may involve a ML mycin).

In another aspect the ion is a dosage system for orally dosing animals with at least one beneficial agent (preferably at least one anthelmintic active), said system requiring 88485556_2.doc 88485556.2 (a) one or more packs of granules of the beneficial agent(s) of the present invention, (i) a drenching device and a mixing container, or (ii) a drenching device having a mixing reservoir, when one or other, or both, (A) and/or (B) is in physical association with instructions whereby use of (a) the one or more packs (b) a said mixing container or said mixing reservoir with water or a aqueous carrier as instructed in, and (c) the ing device for its fixed dosage s or a calibratable variable dosage will deliver, in use, an effective amount of the beneficial agent(s) to each drenched target In another aspect the invention is a dosage system for orally dosing animals with plural anthelmintic actives, said system comprising or including (a) one or more packs of granules of at least one anthelmintic active of the present invention, and (b) at least one container with an avermectin and/or milbemycin active in a liquid concentrate form (i) a drenching device and a mixing container, or (ii) a drenching device having a mixing reservoir, when one or more of (A), (B) and/or (C) is in physical association with instructions whereby use of (a) all of one or more pack content(s), (b) all of one or more container content(s), (c) the mixing container or mixing reservoir with water or an aqueous carrier as instructed, and (d) the drenching device for its fixed dosage s or its calibratable variable amount, will deliver, in use, an effective amount of the plural mintic agents to each drenched target animal. 56_2.doc 88485556.2 In another aspect the invention is the use of a pack or quantity of anthelmintic granules to deliver a recommended dose orally per animal when d with water or other aqueous carrier as instructed, the granules being y associable with the water or aqueous carrier.

In another aspect the invention is a method of treating an animal which comprises or includes, in any order (A (i) to A (iv)): (a) (i) providing or taking at least one volume of mintic granules rably of substantial homogeneity] able to be associated (eg, by dispersion) with water or an aqueous composition to provide a (preferably thixotropic or pseudoplastic) liquid composition containing one or more anthelmintic actives, (optionally (ii) ing or taking a liquid concentrate of at least one avermectin and/or at least one milbemycin), (iii) providing or taking a volume of water and/or an aqueous composition, and (iv) providing or taking apparatus able to administer a (preferably thixotropic) liquid composition to such an animal; and (b) associating in any order (i) and (iii) or (i), (ii) and (iii), whether in the apparatus of A(iv) or not; and (c) using the apparatus of A(iv) to administer the (preferably thixotropic or plastic) aqueous ition resulting from (B) to such an animal.

In another aspect the invention is a method of administering a mix of anthelmintic actives to an animal which comprises (1) preparing an aqueous delivery composition (a) from a dry granular composition of at least one anthelmintic active of the present invention, or (b) from both a dry composition of at least one anthelmintic active of the present invention and a liquid concentrate of at least one other anthelmintic active, and (2) administering an effective amount of the aqueous delivery composition to the animal.

In an aspect the invention is an on-farm preparation for administration to an animal, the preparation being an aqueous suspension of ML anthelmintic particles derived from a non- aqueous trate upon its aqueous dilution, the concentrate not necessarily (and preferably not) having the ML antibiotic present in a ulate form.

Preferably a gum suspends the les, the gum being derived from the concentrate.

Preferably the administration is to be by any of the routes herein described.

In another aspect the invention is an on-farm preparation as aforesaid that includes other components added in a substantially dry form. 56_2.doc 88485556.2 In yet another aspect the invention is an on-farm anthelmintic preparation prepared by dilution of a concentrate in a liquid or gel form of at least one ML anthelmintic active.

Preferably the concentrate is as herein described.

Optionally the dilution is with water, an aqueous ition or a non-aqueous liquid.

In another aspect the invention is at least one pack of granules of at least one anthelmintic active for use in an, on farm, customisation of a liquid delivery formulation of beneficial agents to animals.

In another aspect the invention is a webcast, website, blog, flyer, brochure, datasheet or other (substrated) material(s) providing or extolling the ability or virtue of granules (eg as defined herein) and/or liquid concentrate(s) (eg as defined in our patent application(s) filed simultaneously th) and/or dispensing apparatus in respect of the stration of one or more beneficial agent (eg to a target species animal type).

Another choice of course are liquid or semisolid (eg gel) preparations (and particularly concentrates) for a targeted diluent type. In particular, although not solely, the ion relates to stable liquid concentrates of at least one ML active (ie, Macrocyclic Lactone anthelmintic (s)).

We envisage a product, the whole content of which, is to be on farm diluted (eg water or oil on) for animal administration. This we believe can maximise shelf-life and availability of the active(s) as well as allowing isation at the dilution stage of the active(s) and cial agents to be stered.

We believe on farm dilution allows stable liquid or semisolid formulations of ML actives to be made available with a shelf life or at least about 6 months and for customisation at dilution prior to administration. At the time of such dilution other components can be added and with the vely brief time between dilution and administration stability becomes less of an issue.

Certainly extended shelf life of an ML/BZ, ML/LEV and/or ML/BZ/LEV formulation can be rendered irrelevant while at the same time providing maximisation of customisation.

We envisage providing a contained stable anthelmintic liquid or semi solid concentrate ed for dilution prior to animal stration, the concentrate being a solution, emulsion, microemulsion, micronized sion, nanonised suspension, or some combination thereof; wherein at least one ML anthelmintic is present in (i) a water miscible organic solvent and/or (ii) an oil or organic liquid miscible type solvent; and wherein at least one non ML anthelmintic agent and/or other beneficial component(s) may be present; and wherein a gum or alginate, or both, is present; 88485556_2.doc 88485556.2 and wherein chelating agent(s), stabilizer(s), etc may be t; and wherein the whole concentrate content of the container of the concentrate is for dilution prior to animal administration.

Preferably the concentrate is liquid.

Preferably the concentrate is free of pyrrolidone solvent and/or is free of glyceryl acetate solvent.

We envisage both high gum and low gum formulations, low gum being below 5%w/w and high gum 5% w/w (eg 5-20% w/w) Gums can be Xanthan. Alginates of different viscosity grades may be used.

Preferably the gum provides a thixotropic mix when diluted.

Another prospect is a storage stable and contained liquid or gel ation (eg a liquid concentrator a gelled concentrate) of at least one ML anthelmintic active for dilution in a diluent, to provide a deliverable composition, prior to administration (orally, as a pour on and/or as a spray or dip) to a target species of animal: wherein the ML active(s) is at least substantially stable in its concentrate liquid or gel environment.

The ML active(s) can be more stable in the concentrate than were it to be y diluted with the intended diluents(s), yet is readily mixable with such a diluent prior to administration.

Preferably the formulation is for a target diluent des a range of ts) and the formulation is or includes: (i) at least one ML active, (ii) an organic solvent or organic solvents in which the ML active(s) is(are) , and (iii) at least one suspending agent, whereby, when in the or a targeted diluents(s), the at least one ML active, as a precipitate or as a microemulsion, will be suspended.

The ation is ideally at least almost totally non-aqueous.

Preferably where the diluent is, or is to be, water or an aqueous composition.

Preferably said solvent is water le.

In other embodiments the diluent is, or is to be, an organic vehicle such as one or more vegetable oil (eg soya bean, sesame oil, corn oil, etc) Preferably said solvent is vegetable oil le.

Preferably the ML active is selected from the group consisting of avermectins and milbemycins eg more preferably is one or more of abamectin, moxidectin, doramectin, ivermectin, tin. 56_2.doc 88485556.2 Preferably the concentrate is free of pyrrolidone solvent and/or is free of glyceryl acetate solvent.

We also envisage a stable liquid concentrate in a container or pack and intended for s dilution to an anthelmintic delivery or dosage form, the concentrate comprising or ing at least one ML anthelmintic active, an organic solvent of the ML active(s), and a suspending agent able to suspend the ML active(s) in the aqueous diluents(s) (even if water rather than an aqueous composition); and optionally a preservative; and optionally an am agent to reduce foaming on aqueous dilutions, and optionally a bulking agent.

Benzyl alcohol is a preferred preservative. rbate80™ is a preferred surfactant/antifoam agent . Sodium lauryl sulphate is another option. A molten wax may also be present.

Fumed silicon dioxide is a preferred building agent.

Preferably the concentrate is free of pyrrolidone solvent and/or is free of glyceryl acetate solvent. r option is a stable liquid concentrate in a container or pack and intended for non- aqueous dilution to an anthelmintic delivery or dosage form, the concentrate sing or including at least one ML anthelmintic active, an organic solvent of the ML active(s), and a suspending agent able to suspend the ML active(s) in the non-aqueous diluents.

Preferably the solvent is one or more glycol ether, and/or one or more cyclic-ether.

A preferred solvent is glycerol formal, propylene glycol or glycerol formal and propylene glycol. r water miscible solvent option (alone or with any other) is ine.

A particularly red solvent is glycerol formal.

A preferred suspending agent for a non-aqueous diluent (eg a vegetable oil) is as mentioned above.

Preferably the concentrate is free of idone solvent and/or is free of glyceryl acetate 88485556_2.doc 88485556.2 Yet another option is a liquid trate in the form of a solution, the solution having (a) at least one ML active (b) at least one organic solvent in which the ML active(s) is(are) stable, and (c) at least one gum as suspending agent, whereby in water or an aqueous composition with which it is le for dilution, the at least one ML active, as a precipitate, will be suspended or be dispersed (eg as in a fire emulsion) and the aqueous suspension, dispersion or emulsion is suitable for administration to an animal orally, as a pour-on or as a spray or dip formulation.

Microemulsions are preferred as a pour-on.

Optionally the liquid concentrate includes a glycol ether or cyclic ether as the solubilizer and/or stabilizer, or at least one said organic solvent.

A preferred solvent is ol formal, propylene glycol or glycerol formal and propylene glycol.

Preferably said ML active is one or more of an tin, moxidectin, doramectin, ivermectin, emamectin etc.

Preferably said solvent is one or more glycol ether and/or cyclic ether. The solvent is preferably glycerol formal.

Preferably the liquid concentrate includes an antifoam agent.

Preferably a preservative and a bulking agent is also present.

A preferred preservative is benzyl alcohol also able to act as a co-solvent.

A preferred bulking agent is fumed silicon dioxide.

A preferred suspending agent for a non-aqueous diluents (eg a vegetable oil) is as ned above. ably the concentrate is free of pyrrolidone solvent and/or is free of glyceryl acetate solvent.

We envisage, in a container, a liquid trate being a formulation as previously d, and ated with ctions as to dilution prior to administration to an animal.

We envisage an on-farm preparation for administration to an animal, the preparation being an aqueous suspension of ML anthelmintic particles derived from a non-aqueous concentrate upon its aqueous on, the concentrate not necessarily (and preferably not) having the ML anthelmintic present in a ulate form.

Preferably a gum suspends the particles, the gum being derived from the concentrate.

Preferably the administration is to be by any of the routes herein described. 88485556_2.doc 88485556.2 We also envisage an on-farm preparation as aforesaid that includes other ents added in a substantially dry form.

We also envisage an m anthelmintic preparation prepared by dilution of a concentrate in a liquid or gel form of at least one ML anthelmintic active.

In another aspect the invention is a webcast, website, blog, flyer, brochure, datasheet or other (substrated) materials ing or extolling the ability or virtue of granules and/or granules and powders and/or liquid and/or semisold concentrate(s) and/or dispensing apparatus in respect of the administration of one or more beneficial agent (e.g. to a target species animal type).

As used herein “diluent”, “target diluents”, etc preferably (but not arily) refers to a diluent with which a liquid content of the concentrate granule(s) is miscible.

As used herein “LEV” means a sole and “BZ” means a benzimidazole.

As used herein “semisolid” envisages gelled or other such forms, as a mass whether le or not, able to be diluted with the target diluent type.

As used herein “on-farm” or the equivalent can mean in close time proximity for use with the animals eg. A veterinarian may dilute a customized selection of concentrate(s), granules and/or powder(s) for a farmer.

Reference to “animal(s)” preferably includes any suitable animal, warmblooded or not, farmed, domestic, companion or other (ruminant or otherwise and can include fish).

Reference to “beneficial agent(s)” includes but is not restricted to trace elements and vitamins. It can include anti-bloat agents, digestion ads, growth promotants, etc.

As used herein the term “and/or” means “and” or “or”, or both.

As used herein “(s)” following a noun means the plural and/or singular forms of the noun.

Reference to “animal(s)” preferably es any suitable warm-blooded animal ruminant or otherwise.

Reference to icial s)” includes but is not restricted to trace ts and vitamins. It can include anti-bloat , digestion ads, growth promotants, etc.

The term “comprising” as used in this ication means “consisting at least in part of”.

When interpreting statements in this specification which include that term, the features, prefaced by that term in each statement, all need to be present but other features can also be present.

Related terms such as “comprise” and “comprised” are to be interpreted in the same manner. 88485556_2.doc 88485556.2 It is intended that nce to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational s within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7).

The nce in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as, an acknowledgement or ion or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general dge in the field of endeavour to which this specification relates.

The term “comprising” as used in the specification and claims means “consisting at least in part of.” When interpreting each ent in this specification that es the term “comprising,” features other than that or those prefaced by the term may also be present. Related terms “comprise” and “comprises” are to be interpreted in the same manner.

BRIEF DESCRIPTION OF THE GS The invention will now be described by way of e only and with reference to the drawings in which: Figure 1 is one of several flow diagrams able to produce granules as described, such a formulation being exemplified hereafter (NB Granulation Solution 1 may or may not include a drug, anthelmintic and/or cial agent(s)), Figure 2 shows stability of the Example 6 formulation over time in months (M) and the temperatures shown in (c).

Figure 3 shows the stability of a concentrate as in Example 7 in a typical package being by way of example aluminium foil (but it could be a plastic sachet), bottle eg. HOPE or other), Figure 4 shows the stability of a concentrate as in Example 9, Figure 5 shows the stability of a concentrate as in Example 10, and Figure 6 shows the stability of a concentrate of Example 11.

Figure 7 is one of several flow diagrams able to e a liquid concentrate as described, such a formulation being exemplified, by way of example, by Example 12 hereafter, Figure 8 shows the stability of a concentrate as in Example 12 in a typical bottle (by way of example, a glass or plastic bottle (HDPE or other)), Figure 9 shows the stability of a concentrate as in Example 13 in a typical container. 88485556_2.doc 88485556.2 DETAILED DESCRIPTION The present ion recognises that for many purposes animal health products are supplied in formulations that are greater than 80% water or other diluent.

The present ion recognises the age to be derived for many situations where anthelmintic and/or cial agents are to be administered or self administered (“administered”) to an animal (warmblooded or not farm animals, companion animals, fish, etc) to e a platform that obviates the need of the provision h from manufacture to end user of unnecessary water and/or other liquid carrier(s).

The present invention in addition or instead recognises that for some beneficial agents, there are advantages insofar as transport, storage and inventory costs are concerned of having beneficial agents provided in a form able to be readily associated with water or other diluent (without a requirement of specialist mixing ent) prior to administration to an animal.

In many instances there are single or combinations of beneficial agents that advantageously can be ined in association in at least ntially fixed proportions without the instability sometimes encountered in liquid formulations.

By way of e, the present invention recognises how single or a combination or combinations of anthelmintic actives can be combined into a granular product (whether in each individual granule or in blends of different granules) advantageously (or both granules and powder forms) with respect to the advantages discussed as well as not being significantly detrimental to end usage and/or stability during storage. Indeed for some such formulations, preferably in a simple or complex granular form, there are stability advantages over having one or more of the actives in a simple liquid formulations.

Such single or combined mintic actives (granulated, granulated and powder, and/or liquid concentrate) can be directly or indirectly associated with mineral supplements and vitamins either in the granule itself and/or in ancillary concentrated forms to be ated with the anthelmintic active or actives when ream (eg with the farmer) in a ry or dosage liquid formulation.

Various anthelmintic actives have been considered for use in the platform technology of the present invention, these include by way, of example, in granulated form benzimidazole(s) typified by oxfendazole, albendazole, etc and levamisole(s) typified by its variations including levamisole, base levamisole HCl or any of its salts.

Praziquantel and MLs are r possibility.

Typical of anthelmintic actives that lend themselves to a liquid concentrate are avermectins and milbemycins (eg tin, ivermectin, etc). 88485556_2.doc 88485556.2 Beneficial agents considered in respect of the platform technology and related aspects of the t ion include mineral supplements, vitamins, etc.

Target species include farmed or unfarmed s, ic or companion animals (eg cattle, sheep, horses, deer, swine, dogs, cats, fish etc). The invention is ably for use with target ruminants being farmed where significant quantities can be diluted for serial animal administration. This enables on farm customisation of beneficial agents in a liquid mix (preferably aqueous) prepared ately or soon prior to administration.

Such cial agents preferably include trace element additions (eg selenium, magnesium, cobalt, zinc, iodine, etc) and/or vitamins or vitamin precursors.

Suitable ding agents include one or more of - gums (such as n, guar, gellan, etc) - fumed or colloidal silicon dioxides (eg AEROSIL R972®, AEROSIL 200 Mesh, - THIXCIN R (a nonhydroscopic castorwax derivative of castor oil).

A most preferred suspending agent is particulate xanthan gum either in the dry mix to be granulated by any process or in the dry mix and/or granulating fluid of a fluidised bed granulation process.

Such beneficial agents can include or be added using anthelmintic liquid concentrate additions. ation of dual anthelmintic active granules and with a cobalt and um source as r beneficial agents can be prepared as in Figure 1 which shows a fluidised bed top spray granulation process using two sprays in series.

A solids stream of particulate benzimidazole(s) (“BZ”), a levamisole (“LEV”), a cobalt source (“Cobalt”) and xanthan gum (“XG”) is fed to the fluidised bed.

First a granulating solution of Tween 80 and benzyl alcohol (“BA”) is sprayed. This may or may not have any active in a fully or partially dissolved. Second a granulating solution of a buffer and a selenium source (NaSe).

This leads then the granules being formed and dried prior to sizing and packing eg in plastic, aluminium or like bags, containers, etc.

Suitable applicators for administering the r composition are those available from N J Phillips Pty Limited, Instrument Supplies Ltd, Simcrotech Ltd and PrimaTech Ltd. Particularly preferred are backpack reservoired applicators of N J Phillips Pty Limited (eg with 2.5 litre backpack) and a variable dose capability. 88485556_2.doc 88485556.2 Liquid impregnated granules optionally can be one of the following:  It can be mixture of a Liquid Surfactant and a liquid preservative (e.g. Polysornate 80 and Benzyl Alcohol)  It can be a e of a Liquid surfactant/s + Solvent (usually water miscible type but not d to e.g. glycerol formal, Propylene glycol) + Liquid or a solid Preservative.

Usually below 10%w/w low liquid content granules and above 10%w/w is regarded as high liquid content granules. Liquid/s are described above. Usually these liquid impregnated granules contain a potent organic soluble drug/s e.g. Abamectin not limited to ML can be any organic drug, beneficial chemical agent.

The drugs may be in a solubilised state or a partially solubilised state (which reduces the particle size of the drug).

The aim of impregnating granules is to make the granules function as a liquid and as a solid. The liquid part after coming in contact with the reconstitution medium either precipitates the drug as a fine suspension or may form a micro-emulsion or even a coarse emulsion (i.e. thermodynamically unstable). on of water miscible components can lower the freezing point of the reconstituted formulation if water is to be used as a reconstituting medium. 1. Multi-active granules In some embodiments the invention consists in anthelmintic granules (preferably of substantial homogeneity notwithstanding historical particles may still be st in part in the granules) able to be associated (eg, by dispersion) with water or an aqueous composition to provide a [preferably thixotropic or pseudoplastic] liquid composition able to be administered (eg ically administered, or able to be self administered), to an animal or to s, the granules being of, or d from, at least (a) from about 1 to about 70% w/w of at least one particulate mintic active (b) from about 0 to about 20% w/w of at least one particulate beneficial agent (c) from about 1 to about 10% w/w of a particulate thixotrope, particulate rheology modifier and/or gum.

In another embodiment the composition is, or is formulated as, an anthelmintic granules, ably of substantial homogeneity notwithstanding historical particles may still be st in part in the granules, that is able to be associated (e.g. by sion) with water or an aqueous composition to provide a liquid composition able to be administered (e.g. mechanically 88485556_2.doc 88485556.2 administered, or able to be self administered), to an animal or to animals, the granules being of, or derived from, at least (a) from about 1 to about 20% w/w of at least one particulate anthelmintic active (b) from about 0 to about 20% w/w of at least one ulate beneficial agent (c) from about 1 to about 10% w/ w of a particulate thixotrope, particulate rheology modifier and/or gum. Preferably the composition is thixotropic or pseudoplastic.

In r embodiment the ition is a ated t capable of dilution to a delivery composition form to which other active(s) and/or beneficial s) might also have been, be or are to be added, the product being (a) produced substantially as herein described or analogously thereto, OR (b) substantially as herein defined or exemplified, or analogous thereto, OR (c) having a ed deliverable content of anthelmintic active(s) post agglomeration or granulation from particles of at least 30% w/ w (and preferably higher).

In another embodiment the composition is an oral dosage aqueous composition having present one or both: (a) at least one or two anthelmintic actives derived from a pack of granules of such actives, and (b) at least one anthelmintic active derived from a container of a liquid or semisolid trate of that anthelmintic active.

Preferred anthelmintic granules include able to be ated with water or an aqueous composition to provide a liquid composition able to be administered (mechanical administered, or able to be self administered), to an animal or to animals, the granules being of at least (a) from about 1 to about 30% w/w of at least one mintic active, and (b) from about 0 to about 20% w/w of at least one beneficial agent, and (c) Up to about 80% w/w of other ion(s).

In another embodiment the composition consists in granules, or a blend of granules, having one or more benzimidazole, a levamisole, or both, in individual granules wherein the granules can release into diluent water or an aqueous diluent composition (a) particles of said at least one benzimidazole, and (b) sufficient suspending agent(s) to hold the benzimidazole particles at substantial homogeneity.

In another embodiment the composition consists in anthelmintic granules able to be associated with water or an aqueous composition to provide a liquid ition able to be administered (mechanical administered or able to be self administered), to an animal or to animals, the granules being of at least 88485556_2.doc 88485556.2 (a) from 1 to 30% w/w of at least one anthelmintic active, (b) from 0 to 20% w/w of at least one beneficial agent, and (c) up to 80% w/w of other ion(s).

In another ment the anthelmintic granules has at least both some liquid content and anthelmintic content and having an ability of being converted for liquid carried animal administration with a diluent.

In some embodiments the invention is, as a dilutable source of at least one anthelmintic active, are granules of at least one anthelmintic agent (preferably two but optionally three or more) optionally having other beneficial agent inclusions, or being in admixture with one or more powdered and/or granulated source of other agent (e.g. anthelmintic, beneficial or ; wherein one or more of the following applies  a benzimidazole is t,  a levamisole is present  an ML anthelmintic is present  a gum or other particle suspension agent effective upon aqueous on is present  an at least substantially homogeneous suspension of at least one anthelmintic agent can be created with aqueous on  an at least substantially homogeneous diluted composition can be created by non- aqueous dilution (e.g. with a suitable oil, alcohol and/or glycol).  a particulate source of one or more mineral is present  selenium particles are present  water is absent or below 3%w/w of the granules is present in the granules  a liquid other than water of from about 5 to about 20% w/w (preferably about 10 to about 20% w/w)  an inclusion of the es has been microencapsulated  an anionic surfactant is present in the granules  the granules, or granules and other ed and/or granulated material, is packed to a volume of from about 100 to about 600 ml (more preferably about 200 to about 400 ml).

In some embodiments the invention is an anthelmintic granules or a blend of anthelmintic granules to e a benzimidazole active or both a benzimidazole active and a levamisole active, the granules having a suspending agent for at least most of the benzimidazole content if and when ed into water or an aqueous diluent, and optionally with other inclusions; wherein all or some of the granules have an anthelmintic active content of from about to about 80% w/w. 88485556_2.doc 88485556.2 In some embodiments the invention is anthelmintic granules having an anthelmintic content er of one or more anthelmintic actives) of at least about 30% w/ w and having been formed by a granulation process in which one or more anthelmintic active(s) has(have) been presented as particulate starting material(s); wherein the granulation process has involved at least a suspending agent; and n, upon ry dilution prior to administration to a warm-blooded animal, the suspending agent will suspend particles of at least one granule included anthelmintic active ingredient.

Without wishing to be tied to a theory, anthelmintic actives in a e or a mix of anthelmintic actives in a granule, where the matrix of the granule(s) includes carrier als (which can be other beneficial agent(s)) not ive to chemical and/or physical ility of the anthelmintic active(s) s the within granule and/or granule to granule interface of the different anthelmintic actives. Similarly where a pack (e.g. a sachet) might contain at least one granule type whether with or without any other particulate content (e.g. ed anthelmintic active, vitamins, minerals, etc).

For benzimidazole(s) and levamisole a suspending agent such as a gum can be used in the matrix. Likewise other inclusions that can be conducive to mance post dilution with a target or non-targeted diluent, and/or prior dilution with a targeted or rgeted diluent, and/or to deliver other beneficial agents to the recipient(s). For example a suspending agent suitable in a diluent that is nonaqueous such as castor oil or soya oil or other thick oil. For example a suspending agent suitable for aqueous dilution.

In some embodiments the granules remain stable for at least one month.

In some embodiments the granules remain stable for at least 2, 3, 4, 5, or 6 months.

In some embodiments the granule comprises about 25 to about 50% imidazothiazoles.

In some embodiments the granule comprises about 15 to about 50% benzimidazole.

In some ments the granule comprises about 10 to about 25% praziquantal.

In some embodiments the granule comprises about 0.10 to about 10% macrocyclic lactone.

In some embodiments the benzimidazoles is selected form one or more of oxfendazole, albendazole, fenbendazole, mebendazole, dazole, oxibendazole, triclabendazole, netobimin, thiabendazole, and febantel.

In some embodiments the salicylanilide is selected form one or more of closantal, brotianide, clioxanide, niclosamide, oxyclozanide, rafoxanide, bithionol, disophenol, hexachlorophene, nitroxynil, netid, and niclofolan menichlophola. 56_2.doc 88485556.2 In some embodiments the imidazothiazoles is selected form one or more of levamisole HCL, sole base, pyrantel pamoate, butamisole, and tetramisol.

In some embodiments the macrocyclic es is selected form one or more of abamectin, avermectin, moxidectin, doramectin, ctin, emamectin, eprinomectin, selamectin, milbemycin, and cydectin. 2. Stable liquid delivery In some ments the invention is an agglomeration of benzimidazole and levamisole particles without any substantial or full dissolution of either species of particle and in the presence of a suspending agent effective (a) upon dilution with water or an aqueous composition of ding evolved benzimidazole les, or (b) upon dilution with a solvent for the benzimidazole, to suspend the evolved levamisole particles, or (c) upon dilution with an organic liquid to suspend any evolved particles in that organic liquid.

Preferably, if (a), the suspending agent is a gum such as n gum.

If (b) or (c), preferably an alcohol is present at dilution, or, more preferably a vegetable oil is present at dilution.

In some embodiments the packs of granules or es and powder(s) are emptied for dilution into a delivery system reservoir dilution to a delivery system reservoir volume. Likewise any liquid or semisolid concentrate.

In some embodiments the invention is an mintic delivery liquid composition having BZ particles derived from es of at least one BZ active or both at least one BZ active and a LEV active suspended in an aqueous carrier or water, the suspension agent being at least in part derived from the granules.

In some embodiments the composition also includes an ML active made available to the remainder of the ry liquid composition from a liquid concentrate of the ML active.

In some embodiments the liquid concentrate has the ML active carried (at least in part) in an organic liquid or in organic liquids. 3. Method of manufacturing a granule In some embodiments the granules for aqueous and/or nonaqueous dilution for oral dosing es(s), have been prepared by a process wherein: 88485556_2.doc 88485556.2 1. a particulate mintic agent or particulate anthelmintic agents (and optionally one or more other particulate beneficial agent(s)) and at least one particulate suspending agent and/or rheology modifier and/or gum is provided on a fluidised bed, and 2. one or more liquid composition(s) adding to the solids on the fluidised bed to provide the resultant granules.

Powder type: Mix the drug/s (bulky drugs) either in a suitable mixer with other ingredients. In some cases the mixing might be done in a high shear mixer or a ball mill. The powders may be compacted i.e. dry granulated if flow problems arise.

Granule type: a dry mix of powders will be granulated using one or more granulating fluids. In some cases ball milled powders may be used for granulation in a wet/dry granulator.

Hybrid type: Part of the formulation may be granulated (wet or dry) and part of it may be mixed in a suitable mixer. Essentially it is a mix of the other two types indicated above. This helps in avoiding full batch granulation saving on processing costs.

Other special cases: Microcapsules or pellets may be loaded to the granule platform if need arise. Relevant processes apply under those circumstances.

Note: The choice of process will depend on the type of formulation. ation presentation notes The final granule or powder formulation may be sold as sachet pack/s or may be sold as es. Kit will n items like spray guns/ e delivery s e.g. capsule gun.

Incompatible drugs may be packed separately as s.

Sachet pack (Liquid Product): Granules/powders etc discussed till now may be sed in one or more sachets. The following are some of the options but not tive.

Capsule type: The granules/powders may be filled in hard capsules which may or may not contain drug contain. They may include flavour enhancing chemicals.

Indeed flavor ing chemical(s) can be added to granules and/or powders of the invention.

A typical red liquid concentrate anthelmintic particularly suitable for water or aqueous dilution for use a deliverable drench composition or for lesser dilution for delivery as a pour on composition can have or include: A preference Functionality Quantity (w/w) Abamectin anthelmintic active 1–20% preferably from 2–8% 88485556_2.doc 88485556.2 ol formal organic solvent 4–85% ably from 20–85% more preferably from 50–85% n gum suspending agent, rheology 0.1–20% modifier and/or gum preferably below 5% preferably from 5–20% anti-microbial agent/co-solvent 0–10% benzyl alcohol preferably from 0.1–6% Polysorbate 80 surfactant/ antifoam agent 0–8% preferably 0.1–5% Low gum formulations preferably are 5% w/w or below and high gum formulations about 5 to about 20% w/w.

The gum can be xanthan. tes of different viscosity grades may be used as well or instead.

Levamisole base may be added by the manufacturer or by the farmer prior to addition.

Prior to use (ie at dilution) any suitable form of levamisole (eg levamisole base, levamisole HCI, etc) and any suitable BZ(s) can be added.

The formulation may n a gum that can gel in water for formulations to be made up using water or it might contain thickeners that thicken in oil phase like Aerosil 200 or Thixcin R or a combination of both for formulations intended to be reconstituted hangeably using water or oil.

Liquid content of the concentrate can be or include water miscible solvents (eg glycerol formal, propylene glycol, glycerine, etc). Non aqueous diluents(s) can be one or more of those or an oil.

Drench formulations are preferably given at 1 ml per 4 kg body weight or 1 ml per 5 kg body weight for sheep.

For cattle it is 1 ml per 10 kg body weight if a drench or 1 ml per 20 kg body weight if a pour on. Thus a need for higher active in the pour on deliverable composition.

All these are after dilution with water or a non-aqueous diluent.

Pour-on dose volume is preferably a maximum 1 ml/20 kg in current products.

For example about 50 to 70 ml of the concentrate might be needed to make up a litre of Abamectin drench. A greater 150 to 200 ml of the concentrate might be ed to make 1 litre of pour on.

The ratios will vary depending upon the drug used.

An example as produced by the process of Figure 7 is that of Example 0. 88485556_2.doc 88485556.2 In Figure 7 there is a high shear mixer used to provide a solution of glycerol formal (“GF”), benzyl alcohol (“BA”), Tween80™ and abamectin (“ABA”). To this is added a mix of the xanthan gum (“XG”), colloidal or fumed n dioxide (“silica”), and the antifoam agent (“A/foam”).

This mixture of a solution/suspension leads to a storage stable liquid concentrate in the form of a suspension but with the ML active in solution. 4. Use of a granule In one ment the invention is a method of co-administration of anthelmintic actives to warm-blooded man animals which ses (A) preparing a delivery liquid composition containing (i) a diluent, (ii) a liquid or semisolid concentrate of an ML active, and (iii) (a) powdered and/or granulated material(s) having an LEV active, (b) powdered and/or granulated al(s) having a BZ active, and/or (c) granulated material(s) having both an LEV active and a BZ active, said delivery liquid including, as a consequence of (ii) and/or a (iii) presence, sufficient suspending agent for at least one particulate active from (ii) and/or (iii) in the deliver liquid composition to ensure a disperse consistency, and (B) administering such delivery liquid composition in a dosage amount to each said animal.

In one embodiment the invention is a method of treating an animal which comprises or includes, in any order (A (i) to A (iv)): (A) (i) providing or taking at least one volume of anthelmintic granules [preferably of substantial homogeneity] able to be associated (eg, by sion) with water or an aqueous composition or with a nonaqueous liquid or liquid system to provide a (preferably thixotropic or pseudoplastic) liquid composition ning one or more anthelmintic actives, (optionally (ii) providing or taking a liquid concentrate of at least one avermectin and/or at least one milbemycin), (iii) providing or taking a volume of water and/or an aqueous composition and/or nonaqueous liquid and/or liquid , and (iv) ing or taking apparatus able to administer a rably thixotropic) liquid composition to such an animal; and (B) associating in any order (i) and (iii) or (i), (ii) and (iii), whether in the tus of A(iv) or not; and (C) using the tus of A(iv) to administer the (preferably thixotropic or pseudoplastic) aqueous and/or nonaqueous composition resulting from (B) to such an animal. 88485556_2.doc 88485556.2 In one embodiment the invention is a method of orally treating an animal which comprises or includes, in any order (A (i) to A (iii)): (A) (i) providing or taking at least one volume of granules containing at least one beneficial agent able to be dispersed into water or an aqueous composition to e a liquid dispersion of at least substantial homogeneity, (ii) providing or taking a volume of water and/or an aqueous composition, and (iii) providing or taking apparatus able to administer a thixotropic liquid composition to such an animal; and (B) associating in any order (i) and (ii), whether in the apparatus of A(iv) or not; and (C) using the apparatus of A(iii) to administer orally s composition ing from (B) to such an animal.

In one embodiment the invention is a method of administering a mix of anthelmintic s to an animal which comprises (A) preparing an aqueous delivery composition (i) from a dry granular composition of at least one anthelmintic active, or (ii) from both a dry composition of at least one anthelmintic active and a liquid concentrate of at least one other anthelmintic active, and (B) administering an effective amount of the aqueous delivery composition to the animal.

In one embodiment the invention is a dosage system for orally dosing animals with at least one beneficial agent (preferably at least one anthelmintic active), said system requiring (a) one or more packs of granules of the beneficial agent(s), and (ii) a drenching device and a mixing container, or (iii) a drenching device having a mixing reservoir, when one or other, or both, (A) and/or (B) is in physical association with instructions y use of the one or more packs (A) a said mixing container or said mixing reservoir with water or a aqueous carrier and/or a nonaqueous liquid or liquid system as instructed in, and (B) the drenching device for its fixed dosage amounts or a calibratable variable dosage amount, (C) will deliver, in use, an ive amount of the beneficial agent(s) to each drenched target .

In one embodiment the invention is a dosage system for orally dosing animals with plural anthelmintic s, said system comprising or ing 88485556_2.doc 88485556.2 (A) one or more packs of granules and/or granules and powder(s) of at least one anthelmintic active, and (B) at least one container with an avermectin and/or milbemycin active in a liquid and/or semisolid concentrate form (C) (i) a drenching device and a mixing container, or (ii) a drenching device having a mixing oir, when one or more of (A), (B) and/or (C) is in physical association with instructions whereby use of (a) all of one or more pack content(s), (b) all of one or more container content(s), (c) the mixing container or mixing reservoir with water or a aqueous carrier and/or a (d) eous liquid or liquid system as instructed, and the drenching device for its fixed dosage amounts or its calibratable variable amount, will deliver, in use, an effective amount of the plural anthelmintic agents to each ed target animal.

The granules offer an ability to hold in storage for farm/veterinary customization mixing/assessment of needs.

One or more packs and optionally one or more volumes of an ML liquid trate and/or other beneficial contents can be diluted into a drench gun for animal administration.

The present invention includes the use of dilutable powders, dilutable granules, and able liquid concentrate(s) and/or semisolid concentrates to provide a multiactive anthelmintic formulation capable of oral, spray and/or purion delivery.

Preferably packs of es or es and powder(s) are emptied for on to a delivery system reservoir dilution to a delivery system reservoir volume. Likewise the liquid or semisolid concentrate(s).

As a kit packs and/or containers as modular amounts for ation or not would be provided of granules (single , dual active, etc and optionally with trace elements and/or vitamins) and of a liquid concentrate of at least one ML nally with additives).

Preferably packs of granules or granules and powder(s) are emptied for dilution to a delivery system reservoir dilution to a delivery system oir volume. Likewise the liquid or semisolid concentrate(s).

In another aspect the invention is a drench gun (or like apparatus) dosing a delivery liquid composition as previously defined. 88485556_2.doc 88485556.2 Analysis or experience can allow on farm customization of each mix at dilution for animal administration.

EXAMPLES 1. Single active powder formulations 1.1 Praziquantel Ingredient name % (w/w) Praziquantel 38.7 l 200 40.82 SLS (solid) or Polysorbate 80 (liq) or other .4 (SLS) surfactant (solid or liq) The fill weight is about 50 g/L of formulation. The adjuvant quantities may be optimized later. The delivery dose is 0.2 ml/kg (sheep).

In some embodiments minerals are additionally added.

Other adjuvants such as a buffer, suspending agents like xanthan gum, guar gum, or alginates may be added.

Wet granulation may be used using electrolyte solutions, buffers, and minerals, whereby the ingredients are sprayed on to the bulking agent.

Dual active formulations (e.g. including abamectin), may also include a wetting solution.

The g agent can be a low or high liquid ning impregnated granule. 1.2 Triclabendazole Ingredient name % (w/w) Triclabendazole 62.5 Aerosil 200 25 SLS (solid) or rbate 80 (liq) or other tant 12.5 (SLS) The fill weight is about 160 g/L of formulation.

A ball milling step may be used prior to the fluidized bed system for aggregate forming drugs.

In some embodiments if a liquid surfactant is used, such as polysorbate 80, the surfactant remains in the granules.

Granulation can be used to add potent drugs or beneficial agents (present below 5 %) or in general to orate very dense (i.e. denser than 1 bulk density) materials (formulation ingredients) like metal salts where there is a perceived risk of segregation either in the es or 88485556_2.doc 88485556.2 in the tituted product. Granulation will also be used if a flow problem is perceived in general or if the formulation tends to lump on storage (making it non user ly or may cause ulty during reconstitution). 2. Dual active powder formulations (low surfactant) 2.1 Levamisole and albendazole Ingredient name % (w/w) Levamisole HCl 35.4 Albendazole 22.12 Cobalt EDTA 15.93 Aerosil 200 17.7 SLS (Solid) or Polysorbate 80 (Liq) or other surfactant (may be liq or solid) 8.8 (SLS) The composition is reconstituted at 117 g/L and administered at 0.2 ml/kg.

In some embodiments a l can be added along with other adjuvants like buffers or suspending agents like xanthan gum, guar gum, and alginates. 2.2 Levamisole and praziquantal Ingredient name % (w/w) Levamisole HCl 37.4 Praziquantel 17.75 Cobalt EDTA 16.8 l 200 18.7 SLS ) or Polysorbate 80 (Liq) or other surfactant (Liq or Solid) 9.35 (SLS) The composition is reconstituted at 107 g/L and administered at 0.2 ml/kg. 2.3 Levamisole and triclabendazole Ingredient name % (w/w) Levamisole HCl 29 Triclabendazole 36.23 Cobalt EDTA 13.04 Aerosil 200 14.4 SLS (Solid) or Polysorbate 80 (Liq) or other surfactant 7.2 (SLS) The composition is reconstituted at 138 g/L. 3. Dual active granule formulations (low surfactant) 3.1 Levamisole and albendazole Ingredient name % (w/w) Levamisole HCl 43.20 88485556_2.doc 88485556.2 azole 27.42 Cobalt EDTA 19.2 Xanthan Gum 3.3 Polysorbate 80 (Other surfactant) 1.6 Sodium selenate 1.32 Citric Acid 3.3 NaOH 0.625 Abamectin ------- Benzyl Alcohol ----- Colloidal Silicon dioxide ------- The composition is reconstituted at 91 g/L and administered at 0.2 ml/Kg.

This formulation is a dual active formulation comprising a low surfactant polysorbate 80 (below 10 % is less), a mineral (sodium selenate), and a bulk mineral (cobalt EDTA). In some ments a preservative can also be added. The stability of this formulation is shown in Figure 2.

In some embodiments ball milling is used prior to charging in to the fluidized bed system, such as aggregate forming drugs (e.g. azole). 3.2 Levamisole and oxfendazole Ingredient name % (w/w) Levamisole HCl 46.65 Oxfendazole 26.42 Cobalt EDTA 20.4 Xanthan Gum 1.2 Polysorbate 80 (Other surfactant) 3 Sodium selenate 1.4 Citric Acid 0.9 NaOH 0.2 Abamectin ------- Benzyl l ----- Colloidal Silicon dioxide ------- The composition is reconstituted at 171.5 g/L. The same comments made for 3.2 apply.

The stability data for this composition is shown in Figure 3. 4. Dual active e formulation (high surfactant) 4.1 Levamisole and oxfendazole Function Excipient Class (% Dry Wt) ient Actives Drugs Total (57.5 %) Levamisole HCl (36.7%) & oxfendazole (20.8) Suspending Agent Gum (1.4 %) Xanthan Gum 56_2.doc 88485556.2 Rheology er Anti-microbial preservative Preservative (2.8 %) Benzyl Alcohol Wetting Agent Surfactant (13.8 %) rbate 80 pH Stabilizer Buffer (1.6 %) Citric Acid & NaOH Adsorbent, Flow modifier, Bulking Agent (5.7 %) Colloidal SiO2 Bulking Agt; Gum & Drug Dispersant; Disintegrating Agt l Supplements Minerals (17.2 %) Cobalt EDTA & Na Selenate The composition is reconstituted at 220 g/L to L) and administered at 0.1 ml/Kg. This formulation exhibits good stability (e.g. as for the triple high surfactant example).

This formulation is a dual active formulation utilising the high surfactant polysorbate 80 (above 10 % is high), a potent mineral (sodium selenate) and a bulky l (Cobalt EDTA).

This can be used as a dual standalone.

In some embodiments ball milling is used prior to charging in to the fluidized bed system, such as aggregate g drugs (e.g. albendazole).

In-Use suspendability The concentration of the reconstituted granule in water was 1.1kg/5L. Oxfendazole was chosen as a marker compound for drug suspension stability.

(Levamisole fully soluble) Initial : 100 mg/g 2 h : At the top was 96 mg/g and at the bottom was 105.2 mg/g 4 h : At the top was 98 mg/g and at the bottom was 99 mg/g 4 days : At the top was 95.7 mg/g and at the bottom was 98 mg/g These s demonstrated that the reconstituted suspension is physically stable up to 4 days.

In-Use Stability – Physico-Chemical The stability of reconstituted drug product was investigated after storage at 30 and 40° C for 1 month. It was found that there was no chemical degradation of the benzimidazole and less than 2% degradation of Levamisole. It was onally found that there was no significant change in the pH or ity of the reconsitituted granule formulation. 88485556_2.doc 88485556.2 In-Use Flow Testing Using a standard drench gun it was found that the in-use flow testing was excellent.

The dual and triple active granule formulations are thixotropic (shear ng) with a ity of 500–900 cP at 20° C.

Little change was observed when the formulation was combined with a liquid concentrate of an ML active.

. Triple active granule formulations (low surfactant) In the low surfactant methods abamectin is first micronised, precipitated and then reconstituted and sprayed. 5.1 Levamisole, oxfendazole Ingredient name % (w/w) sole HCl 45.82 Oxfendazole 25.95 Cobalt EDTA 20 Xanthan Gum 1.43 Polysorbate 80 (Other tant) 2.9 Antifoam AF Emulsion 0.3 Sodium selenate 1.4 Citric Acid 0.9 NaOH 0.16 tin ** ------- Benzyl Alcohol ----- Colloidal Silicon dioxide ------- The composition is reconstituted at a concentration of 175 g/L. The stability is shown in Figure 4. .2 Levamisole, albendazole Ingredient name % (w/w) Levamisole HCl 42.4 Albendazole 26.51 Cobalt EDTA 18.6 Xanthan Gum 3.2 Polysorbate 80 (Other surfactant) 2.65 Antifoam AF Emulsion 0.53 Sodium selenate 1.27 Citric Acid 3.2 NaOH 0.6 Abamectin ** ------- Benzyl Alcohol ----- Colloidal Silicon e ------- 88485556_2.doc 88485556.2 The composition is reconstituted at 94 g/L and stered at 0.2 ml/Kg. The stability is shown in Figure 5. 6. Triple active granule formulations (high surfactant) In the high surfactant methods abamectin is incorporated as a fine dispersion after dispersal in benzyl alcohol. 6.1 Levamisole, oxfendazole and tin Ingredient name % (w/w) Levamisole HCl 35.42 Oxfendazole 20 Cobalt EDTA 15.5 Xanthan Gum 1.77 Polysorbate 80 (Other surfactant) 15.5 am AF Emulsion ---- Sodium selenate 1.06 Citric Acid 1.32 NaOH 0.25 Abamectin (microfine) 0.93 Benzyl Alcohol 2.66 Colloidal Silicon dioxide 5.53 The abamectin was first dissolved in glyceryl formal and polysorbate 80 e ryl formal 88 % and polysorbate 80 3.6 %). The percentage indicates the composition ratio used, and is not related to the formulation. The abamectin is then precipitated out in water under agitation (Silverson).

The fine precipitated abamectin is obtained from the dispersion by centrifuging (4200 rpm for 5 min) the sion after decanting the atant layer (i.e. glyceryl formal and polysorbate 80 is removed during centrifuging followed by decanting). The microfine abamectin was then reconstituted quantitatively using wetting solution made up of water and polysorbate 80.

It is envisaged that the stability of labile drugs will be further improved if separate granulation of actives occurs. For example, the contents in a sachet may be a mixture of two es to prevent intimate contact of the labile drugs. In some embodiments the granules may be packed in two te sachet packs.

The composition is reconstituted at 175 g/L and administered at 0.1 ml/Kg. The stability is shown in Figure 6. 88485556_2.doc 88485556.2 Chemical and Physical Stability – Abamectin When reconstituted with water, the sstability of abamectin in the reconstituted triple active formulation was investigated after storage at 30 and 40° C for 1 month. It was ed that abamectin had less than 2% degradation and there was no physical change in pH or viscosity.

In-Use Flow Testing – Reconstituted Drug ts Using a standard drench gun it was found that the in-use flow g was excellent.

The dual and triple active granule formulations are thixotropic (shear thinning) with a viscosity of 500–900 cP at 20° C. 7. Triple active granule manufacture A triple active e was prepared in ance with the table below.

Name of ingredient Qty per L (g) Qty % (w/w) Levamisole HCL 80 36.4 Oxfendazole 45.3 20.6 Cobalt EDTA 35 15.9 Sodium Selenate 2.4 1.09 Abamectin 2.1 0.96 Xanthan Gum 3 1.36 Colloidal Silicon Dioxide 12.5 5.69 Polysorbate 80 30 13.64 Benzyl Alcohol 6 2.73 Citric Acid 3 1.36 Sodium Hydroxide 0.57 0.26 76.2–114.3 Water (1) - (for ABA) –42 ml Water (2) - (for mineral) 2–3 ml Water (3) - (to flush lines) TOTAL 219.87 100 % The manufacturing process for the triple granule comprises the steps of: 1. dry mixing levamisole HCL, cobalt EDTA and xanthan gum, 2. mixing oxfendazole and the aerosil in a polybag and passing it through a 0.8–1 mm sieve, 3. dissolving the abamectin in benzyl alcohol and adding polysorbate 80 to it while under agitation, 88485556_2.doc 88485556.2 4. adding water to the abamectin while under agitation untill a hazy white coloured dispersion is produced which is free from particulates culates which are observed ly), . loading the powders from steps 1 and 2 into the FBP bowl and mixing for five s, 6. spraying the step 3 dispersion, 7. prepare a solution of citric acid, sodium hydroxide and sodium selenate in water, 8. spraying the step 7 solution and g the fluidised bed warm (40–55 C), and 9. drying the granules till the re content of 2–3% is achieved (KF method).

The granule produced by this method had good stability and dispersed well in water. 8. Triple Active granule efficacy study A triple active granule was prepared in accordance with the table below.

Raw Material Percentage Batch Levamisole Hydrochloride 35.071% w/w 526.06 g Oxfendazole 19.859% w/w 297.88 g Abamectin 95 % 0.969% w/w 14.54 g Cobalt EDTA 15.343% w/w 230.15 g Sodium Selenate 1.052% w/w 15.78 g n Gum 1.973% w/w 29.59 g Colloidal Silicone Dioxide 200 (CSD) 8.386% w/w 125.79 g Benzyl l 2.630% w/w 39.45 g rbate 80 13.152% w/w 197.27 g Distilled Water (0 – 35% w/w) (0 – 700 g) Citric Acid Anhydrous 1.315% w/w 19.73 g Sodium Hydroxide 0.250% w/w 3.75 g Distilled Water (14.667% w/w) (220 g) Total 100% w/w 1,499.99 g The granules were produced using the following process: 1. sodium selenate was dissolved in purified water, citric acid anhydrous and sodium hydroxide were added to the solution and mixed well to produce the Se solution, 2. abamectin was dissolved in benzyl alcohol, polysorbate 80 was added to the solution and mixed well, and then a le quantity of water (0–700 g) was added to the solution and mixed well to produce the ABA solution, 3. levamisole HCL, cobalt EDTA and xanthan gun were passed through a 40-mesh screen and mixed, 4. oxfendazole and colloidal silicon dioxide 200 were passed through a 40-mesh screen and mixed, . the powder mixtures of (3) and 94) were placed in glatt granulator/dryer insert, 88485556_2.doc 88485556.2 6. the powder mixtures of (5) were fluidized and warmed up, 7. the ABA solution was sprayed onto the powder mixtures at a variable spray rate (20–40 g/minute) with a variable inlet air temperature (30–60° C) with suitable fluidising, 8. the Se solution was sprayed onto the powder mixtures with a spray rate of 15 g/minute and an inlet air temperature of 50° C with suitable sing, 9. the granule formed was dried with an inlet air temperature of 50° C until the product temperature reached 50° C, . the granule was cooled to 25° C, 11. the dried granule was passed h a 18-mesh (850 µm) sieve, grinding up any lumps too big to pass through, 12. the granule was tested for Loss on Drying (LoD), Mean le er (MPD) and density ( bulk and tapped). 8.1 Stability study The study was conducted to review the quantity of spray solution, spray rate and inlet air temperature. Statistical analysis of the se data including flow-ability, dispersing-ability in water and sedimentation speed will be used to identify the optimal level of ty of spray solution, spray rate and inlet air temperature.

The quantity of spray solution (0, 350, 700 g), spray rate (20–40 g/min) and inlet air temperature (30–60 C) was varied in an attempt to understand the effect of changing these variables, individually and in combination, to identify an optimal ation of quantity of spray solution and process parameters to produce suitable granule. 8.2 Efficacy study A cross-over study was performed to determine the blood plasma concentrations of abamectin, oxfendazole and sole following oral ent with reconstituted granule product containing these three anthelmintics. The efficacy of the reconstituted triple granule was compared to Matrix Hi Mineral Oral Drench for Sheep.

Eight female romney sheep of similar age and body weight were used. The criteria for selection was to include animals that had not been dosed with a persistent anthelmintic formulation within 6 months of selection for the trial. Persistent anthelmintics include slow release es (e.g. Bionic), injectable or oral forms of ctin and closantel. Sheep were acclimated to the study site for 14 days before treatment.

Each sheep was randomly assigned to the treatment group and received one treatment and then the alternate treatment 21 days later.

The study procedures were as follows: 88485556_2.doc 88485556.2  sheep were d using calibrated scales on Day -1 for weight ranking and allocation to ent groups. They were weighed again on Day 20, with the treatment doses calculated from the Day -1 or Day 20 weights respectively.

 Triple-Active Granules were reconstituted in the laboratory on Day -1 and Day 20, the day immediately before the treatment days. Granules were d and added with the calculated volume of water to a 2 litre schott bottle and ed a number of times until the granules were wetted and fully dispersed. On the morning of treatment the schott bottle was again gently inverted 3 or 4 times to ensure a homogeneous mix and approximately 100 mL was decanted from which the syringe was filled for dosing.

 Treatments were administered on Day 0 and Day 21 at a dose volume of l ml/5kg. Dosing was done using a l2 mL ted syringe. Dose volume and time of administration was recorded and checked for each sheep.

 Blood samples were collected before treatment, and after treatment at 0.5, 1, 2, 6, 8,1 2, 15, 24 and 36 hrs. Samples were assayed for abamectin, oxfendazole and levamisole, or their metabolites.

 Samples of both the reconstituted triple-active granule liquid and the Matrix Hi Mineral positive control product as used for the treatments, were assayed for abamectin, oxfendazole and/or levamisole.

First Treatment day Treatment 1  Reconstituted ation granule  Assay: abamectin, 1.06 g/L, oxfendazole 22.63 g/L, levamisole HCL 40.87 g/L Treatment 2  Positive control “Matrix Hi Mineral Oral Drench for Sheep”  Assay: abamectin, 1.08 g/L, oxfendazole 23.7 g/L, levamisole HCL 2.187 g/L.

Second Treatment day Treatment 1  Reconstituted ation granule  Assay: abamectin, 1.04 g/L, oxfendazole 22.40 g/L, levamisole HCL 40.60 g/L Treatment 2 88485556_2.doc 88485556.2  Positive control ‘Matrix Hi l Oral Drench for Sheep”  Assay: abamectin, 1.08 g/L, oxfendazole 23.69 g/L, levamisole HCL 42.45 g/L.

The table below shows the results from the blood samples with the pooled mean data for the 8 sheep for each treatment (combined for both phases of the cross-over study). Oxfendazole plasma levels are ted as two separate plasma metabolites: oxfendazole and fenbendazole, and the total of these two expressed as “total – oxfendazole”. All plasma metabolite units are presented as rng/kg ison Treatment Cmax Tmax abamectin 0.017 24 hrs abamectin comparison Matrix Hi Mineral 0.017 24 hrs levamisole 1.445 1 hr levamisole comparison Matrix Hi Mineral 1.405 2 hr azole 0.792 15 hrs oxfendazole comparison Matrix Hi Mineral 0.845 8 hrs fenbendazole 0.209 12 hrs fenbendazole comparison Matrix Hi Mineral 0.189 24 hrs oxfendazole 0.984 12 hrs total oxfendazole comparison Matrix Hi Mineral 0.987 8 hrs This table shows that… 9. Single active liquid concentrate Shown below is a liquid concentrate ation suitable for aqueous dilution.

Function ent Ingredient (% w/w) Single Active Drug (4.5 %) Abamectin Solubilizer & Stabilizer Solvent (82.3 %) Glyceryl Formal Suspending Agent Gum (5.8 %) Xanthan Gum Rheology Modifier Anti-Microbial Agent; co-Solvent Preservative (3.9 %) Benzyl l Wetting Agent Surfactant (1.9 %) Polysorbate 80 Dispersing agent (prevents aggregation on reconstitution) 88485556_2.doc 88485556.2 g Agent Bulking Agent (0.6 %) Colloidal SiO2 Gum & Drug Dispersant Anti-caking Agent ts foam on reconstitution Antifoam Agent (1%) am AF Colloidal SiOz can be present in even greater amounts as a viscosity builder.

In some embodiments the forumulation includes antifreeze, chelating agents, izers, or a penetrant enhances. If a penetrant enhancer is used, then preferably it is for pour on use post dilution. Preferably any such addition use is less than 5% w/w.

Other surfactants (e.g. cationic, anionic or non ionics), gums, buffering systems may be added. The choice of surfactant will depend on drug properties and the medium used to reconstitute the concentrate. Solvents like propylene glycol may be added as cosolvents or solvents replacing glycerol formal. Propylene glycol may also behave as antifreeze or help in preparation of microemulsions (that are clear looking abamectin or other chemically similar drugs in water).

If colloidal silicon dioxide higher than say 2–3 % is used, it not only acts as a king agent but also as a bulking agent/adsorbing agent (for uniform distribution of potent ingredients or as a viscolytic agent for organic based formulations).

It is envisaged that it is diluted with water, an aqueous composition or a non-aqueous liquid or composition, for example, a pour on type concentrate (which will form water based pour ons upon reconstitution). The final product is administered at 1 ml/kg. For example, about 150 or 200 ml is required to make up a litre of pour on with high amectin concentrate. This volume will vary depending upon the drug used in on to the ML anthelmintic.

For example, for levamisole mase (used in a pour on concentrate owing to its ation properties) about 600 to about 700 ml/L for 200 g of base). Levamisole base (200 g) needs glyceryl formal (200 g); Polysorbate 80 (about 400 g) to microemulsify the base.

Stability Trial Post Mix The stability of the reconstituted tin was igated after storage at 20–25° C for 4 days. It was observed that there was no degradation of the abamectin and some degradation of the benzyl alcohol to aldehyde. The reconstituted formulation remained suspended with no settling . Single active oil-based liquid concentrate An oil based liquid concentrate ation example suitable for water or oil dilution: 88485556_2.doc 88485556.2 Ingredient Function w/w Abamectin active 10.3 %, Xanthan Gum suspending agent n R protective colloid Aerosil 200 or R 972 gy modifier Benzyl l Anti-Microbial Agent 67 % Solvent le size er If in water based reconstitution Propylene Glycol (optional) Solvent – especially if water is used for reconstitution) Polysorbate 80 Wetting agent – dispersing agent as 22.45 %, prevents aggregation of drug Colloidal silicon dioxide Anticaking agent – needed if xanthan 0.6 %, is used as a thickener. I f aerosil is used as a thickener may not use it again as an king agent. am Agent (optional) May be an emulsion or free flowing powder The formulation should be diluted to 12–15 ml/L. The concentration of the abamectin may be d to below 5% w/w if needed by increasing the quantity of benzyl alcohol and polysorbate in the above ratio.

Other surfactants (cationic, anionic or non ionics), gums, buffering systems may be added.

The stability is shown in Figure 9.

Whilst the liquid concentrate is preferably in a container such as a bottle (glass or plastic) in some aspects the concentrate can be in capsules (eg hard or soft gelatine – with or without drug or flavour enhancing agents). This is particularly so if any added beneficial agent is malodorous. If for e in that form they can be still d prior to administration or be administered as is.

Suitable applicators for administering and of the delivery composition are those available from N J Phillips Pty Limited, Instrument Supplies Ltd, Simcrotech Ltd and PrimaTech Ltd.

Particularly preferred are backpack reservoired applicators of N J Phillips Pty d (e.g. with 2.5 litre backpack) and a variable dose capability.

Although embodiments have been described with reference to a number of illustrative embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. 88485556_2.doc 88485556.2 Many modifications will be apparent to those skilled in the art without departing from the scope of the present invention as herein described with reference to the anying drawings. 88485556_2.doc 88485556.2 WE

Claims (25)

CLAIM

1. A stable granule comprising at least two or more different anthelmintic actives selected from one or more othiazoles, one or more benzimidazoles, one or more macrocyclic lactones, and praziquantel, wherein the composition comprises a macrocyclic lactone as an anthelmintic active, wherein the granules r comprise a suspending agent or gy modifier and wherein the suspending agent or rheology modifier is a gum, and n the granules are readily dispersible in water to provide a homogenous mixture of the mintic actives for administration to a non-human mammal.

2. A composition of claim 1 wherein the gum is, or includes, xanthan gum.

3. A ition of claim 1 or 2 wherein the granules further comprise a wetting agent.

4. A composition of any one or more of claims 1 to 3 comprising levamisole hydrochloride (HCl).

5. A composition of any one of claims 1 to 4 comprising levamisole HCl, a benzimidazole and a macrocyclic lactone.

6. A ition of any one of claims 1 to 5 wherein the macrocyclic lactone is selected from avermectin, ivermectin and abamectin.

7. A composition of any one of claims 1 to 6 wherein the benzimidazole is selected from oxfendazole, albendazole or fenbendazole.

8. A composition of any one or more of claims 1 to 7 comprising a particulate source of one or more ls.

9. A composition of any one of claims 3 to 8 wherein the wetting agent is polysorbate 80.

10. A composition of any one of claims 1 to 8 sing a dispersant.

11. A composition of claim 10, wherein the dispersant is colloidal silicon dioxide.

12. A composition of any one or more of claims 1 to 11 wherein the granules comprise 30 to 70% w/w of the anthelmintic actives.

13. A composition of any one or more of claim 1 to 12 wherein the es comprise less than 3, 2, or 1% w/w water.

14. A composition of any one of claims 1 to 13 wherein the granules are free of pyrrolidones.

15. A composition of any one of claims 1 to 14 n the granules comprise 0.1 to 10% w/w macrocyclic lactone.

16. A composition of any one of the preceding claims comprising  1 to 40% w/w benzimidazole,  a suspending agent,  1 to 70% w/w levamisole HCL, and  0.1 to 10% w/w macrocyclic lactone.

17. A method of forming an anthelmintic composition comprising the steps of: providing two or more anthelmintic actives selected from one or more imidazothiazoles, one or more benzimidazoles, one or more macrocyclic lactones, and praziquantel, n the granule comprises at least a macrocyclic lactone, mixing the macrocylic lactone with a suspending agent, in the form of a gum, on a sed bed, adding a further anthelmintic active to the fluidised bed.

18. A method of claim 17 wherein the macrocylic lactone is dry mixed with the suspending agent.

19. A method of claim 18 wherein the further anthelmintic active is dry mixed with the macrocyclic lactone.

20. A method of claim 17 or 18 wherein the further anthelmintic active is sprayed onto the fluidised bed as a first granulating solution comprising a wetting agent.

21. A method of claim 20 wherein the wetting agent is polysorbate 80.

22. A method of any one of claims 17 to 21 wherein the granules comprise an anionic surfactant and a non-aqueous vent.

23. A method of any one of claims 17 to 22 wherein the granules further comprise a particulate source of one or more minerals.

24. A method of any one of claims 17 to 23 comprising a buffering agent.

25. A method of claim 24 n the buffering agent is dry mixed with the macrocyclic lactone, or added to the fluidised bed as a second granulating solution. 56_2.doc 88485556.2