US 2012023.8516A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2012/0238516 A1 Cleverly et al. (43) Pub. Date: Sep. 20, 2012

(54) GRANULATED Publication Classification PREPARATIONS AND DELIVERY SYSTEMS (51) Int. Cl. (76) Inventors: Douglas Robert Cleverly, A61 K 31/.429 (2006.01) Auckland (NZ);- Debashise A6IP 33/10 (2006.01) Mukhopadhyay, Brockville A61 K 31/418.4 (2006.01) Dunedin (NZ) s A61 K. 3 1/7048 (2006.01) A61 K 31/4985 (2006.01) (21) Appl. No.: 13/414,495 (52) U.S. Cl...... 514/30; 514/250; 514/395; 514/368 (22) Filed: Mar. 7, 2012 (57) ABSTRACT Related U.S. Application Data The present invention relates to anthelmintic compositions comprising two or more anthelmintic active agents selected (63) Continuation-in-part of application No. PCT/IB2010/ from one or more of the following groups; imidazothiazoles 054005, filed on Sep. 7, 2010. such as , such as , or , macrocylic lactones such as or (30) Foreign Application Priority Data , , and . The composi tion being in the form of stable granules that are readily Sep. 7, 2009 (NZ) ...... 579544 dispersible in waterso as to provide a homogenous mixture of Sep. 7, 2009 (NZ) ...... 579545 the anthelmintic agents suitable for administration. Methods Sep. 7, 2009 (NZ) ...... 579546 of preparing the composition are also described. Patent Application Publication Sep. 20, 2012 Sheet 1 of 5 US 2012/0238516 A1

Gran Solution 1 Tween 80 + BA

Granu late Granulate

GranSolution 2. Buffer + Nase

Pack and In-process test Release

FIGURE 1

120 110 evamisole HCl 100 : Initial 1M, 3M, 3M, 3M, 6M, 6M, 6M, 50C 30C, 40C, 50C 30C, 40C, 50C RH RH RH RH 65% 75% 65% 75%

FIGURE 2 Chemical Stability – Levamisole HCI & Oxfendazole (granule combination in Al Sachet Patent Application Publication Sep. 20, 2012 Sheet 2 of 5 US 2012/0238516 A1

— LO-021208 (Granule Stability)

120

110 100 Ed Levamisole HCl º, Oxfendazole 90

80 Initial 1M, 3M, 3M, 3M, 6M, 6M, 6M, 50C 300, 40C, 50C 50 C 30C, 40C, RH RH RH RH 65% 75% 65% 75%

FIGURE 3 Chemical Stability — Levamisole HCI & Albendazole (granule combination in Al Sachet)

(Granule Stability)

Levamisole HCI & Oxfendazole DAbamectin

Initial 1M, 3M, 3M, 3M, 6M, 6M, 6M, 50C 30C, 40C, 50C 50C 30C, 40C, RH RH RH RH 65% 75% 65% 75%

FIGURE 4 Patent Application Publication Sep. 20, 2012 Sheet 3 of 5 US 2012/0238516 A1

(Granule Stability)

Eälevamisole HC & Albendazole DAbamectin

% Initial 1M, 3M, 3M, 3M, 6M, 6M, 6M, º 50C 30C, 40C, 50C 50 C 30C, 40C, RH RH RH RH 65% 75% 65% 75%

FIGURE 5

LOA-190309-2 (Granule Stability)

120 115 110 105 Levamisole HCl 100 95 90 85 80

40C, 50C RH 75%

FIGURE 6 Patent Application Publication Sep. 20, 2012 Sheet 4 of 5 US 2012/0238516 A1

High shear

rºlixer #13 UCIL Add. | wessel add 1. X.G

2. BA § 3. A/Foam i 3. Tween 80 Suspension to the 300L 4. ABA

-i vessel and | mix.

Pack off and release

FIGURE 7 Process Flow Diagram - Liquid Suspension

1 2 0

110

100

Initial 4M, 4M, 4M, 6M, 6M, 6M, 50C 40C, 30C, 30C, 40C, 50C RH RH RH RH 75% 65% 65% 75%

FIGURE 8 Chemical Stability — Abamectin (suspension concentrate in bottle) Patent Application Publication Sep. 20, 2012 Sheet 5 of 5 US 2012/0238516 A1

Abamectin

Abamectin

Initia? 4M, 4M, 4M, 6M, 6M, 6M, 50C 40C, 30C, 300, 40C, 50C RH 75% RH 65% RH 65% RH 75%

FIGURE 9 US 2012/02385.16 A1 Sep. 20, 2012

GRANULATED ANTHELMINTIC the attempt to formulate a combination avermectin/milbemy PREPARATIONS AND DELIVERY SYSTEMS cin and levamisole product reliant upon emulsion technology. [0010] The document mentions that to maintain stability of INCORPORATION BY REFERENCE the and/or in the presence of levamisole, it may be necessary to dissolve the actives in a [0001] This application is a continuation-in-part applica pyrrolidone solvent, most preferably N-methyl pyrrolidone tion of international patent application Serial No. PCT/ or 2-pyrrolidone. M2010/054005 filed Sep. 7, 2010, which published as PCT [0011] Bomac in WO2008/072985 (PCT/NZ2007/ Publication No. WO2011/027333 on Mar. 10, 2011, which 000360) refers to a storage stable pour on veterinary formu claims benefit of New Zealand patent applications Serial Nos. lation of an ML compound (optionally also with another 579544, 579545 and 57954, all filed on Sep. 7, 2009. active) in at least one glyceryl acetate solvent (optionally with [0002] The foregoing applications, and all documents cited co-solvents). therein or during their prosecution (“appin cited documents”) [0012] Embodiments of the present invention relate to on and all documents cited or referenced in the appin cited docu farm dilution allowing stable liquid formulations of ML ments, and all documents cited or referenced herein (“herein actives to be made available and for customisation at dilution cited documents”), and all documents cited or referenced in prior to administration. At the time of such dilution other herein cited documents, together with any manufacturer’s components can be added and with the relatively brief time instructions, descriptions, product specifications, and product between dilution and administration stability becomes less of sheets for any products mentioned herein or in any document an issue. Certainly extended shelflife of nML/BZ, ML/LEV incorporated by reference herein, are hereby incorporated and/or ML/BZ/LEV formulation can be rendered irrelevant herein by reference, and may be employed in the practice of while at the same time providing maximisation of customi the invention. sation. [0013] A further embodiment of the invention is to provide FIELD OF THE INVENTION for fine ML particles or a ML present in a micro-emulsion in [0003] The present invention relates to beneficial granules a final (and preferably customized) formulation including suitable as a platform technology for providing anthelmintic targeted on farm diluents(s) (whether water, aqueous, non agents to animals. aqueous or other) having substantial homogeneity of particle [0004] More particularly the present invention relates to spread and/or active spread. anthelmintic granules, kits involving packs of granules, meth [0014] A still further embodiment of the invention is to ods of treating an animal using such granules, and methods of provide a low volume liquid concentrate of at least one ML administering at least one anthelmintic active. anthelmintic active stable in that form for a satisfactory manufacture/supplier chain/user storage shelf life without BACKGROUND OF THE INVENTION substantial loss of ML and/or significant reduction in its dilutability. [0005] U.S. Pat. No. 6,013,636 relates to ML anthelmintic [0015] A further embodiment is to provide a liquid concen actives such as avermectins, ivermectin, , abam trate of an ML able to be added to levamisole and/or a benz ectin, and and discusses that they are imidazole in water or an aqueous composition or a non difficult to formulate. Reference is also made to injectable aqueous composition on farm just prior to administration. solutions, pour-on compositions and oral compositions for [0016] A further embodiment is to provide at least substan mulations requiring not only a vegetable oil (such as soya tially (and preferably) pyrrolidone free and/or glyceryl bean oil, sesame oil and corn oil) but also a co-solvent which acetate free formulations of at least one ML active. is an alcohol of 4 or more carbon atoms (eg benzyl alcohol). [0017| Citation or identification of any document in this [0006| WO 98/06407 (PCT/NZ97/00096) relates to an application is not an admission that such document is avail organic solvent able to dissolve both praziquanel and at least able as prior art to the present invention. one ML anthelmintic as a pathway to a mixed phase packaged composition for direct oral administration to warm-blooded non-human animals. Most examples at manufacture may SUMMARY OF THE INVENTION include an aqueous phase and a solvent phase. An example of [0018] Accordingly, in a first aspect the present invention a drench form without water has N-Methyl-2-Pyrrolidone relates to an anthelmintic composition in the form of a stable present as a solvent. granule comprising two or more anthelmintic actives selected [0007] WO 98/06407 relates to a nonaqueous injectable from but not limited to one or more imidazothiazoles, one or solution of abamectin and praziquantel used as manufactured more benzimidazoles, one or more macrocyclic lactones, one (i.e. without further dilution). or more salicylanilides, praziquantel, the stable granule being [0008] WO 2004/009080 relates to an animal deliverable readily dispersible in water to provide a homogenous mixture formulation capable of stably including avermectins or mil of the anthelmintic actives for administration to a non-human bemycins together with levamisole. In reference to stability it mammal, the granule further comprising a suspending agent is discussed that formulations have to be “stable” to be of if the anthelmintic actives comprise a , a wet commercial use. It is discussed that a commercially accept ting agent if the anthelmintic actives comprise a macrocyclic able anthelmintic formulation as one which is “stable” at lactone, a wetting agentifthe anthelmintic actives comprise a room temperature for a period of at least 6 months. It is and a suspending agent if the anthelmintic reported that there is great difficulty in formulating such a actives comprise praziquantel. combination product in order to achieve the required stability. [0019] Another aspect of the invention relates to a dosage [0009] Reference is also made to the content of New system for orally dosing animals with an anthelmintic agent, Zealand patent specification 336139 of Nufarm pointing to the system comprising US 2012/02385.16 A1 Sep. 20, 2012

[0020) (a) one or more packs of granules for addition into [0046] Another aspect of the invention relates to a method an aqueous liquid, the granules comprising offorming an anthelmintic composition comprising the steps [0021] (i) a benzimidazole and a suspending agent for of: the benzimidazole, [0047] providing an imidazothiazole, [0022] (ii) a macrocyclic lactone and a wetting agent, [0048] providing one or more anthelmintic actives [0023] (iii) a salicylanilide and a wetting agent, selected from benzimidazoles and macrocyclic lactones, [0024] (iv) praziquantel and a wetting agent, [0049) providing a suspending agent if the one or more anthelmintic active comprises a macrocyclic lactone [0025] (v) an imidazothiazole and one or more anthel [0050] providing a wetting agent if the one or more mintic agents selected from benzimidazoles, macro anthelmintic active comprises a benzimidazole cyclic lactones, salicylanilides, and praziquantel, and [0051] mixing the macrocylic lactone with the suspend optionally a suspending agent, ing agent if a macrocylic lactone is present, [0026] (b) a suspending agent if (i) the granules do not [0052] mixing the benzimidazole with the wetting agent comprise a suspending agent, or (ii) additional suspend if a benzimidazole is present, ing agent is required to suspend the anthelmintic actives [0053] combining the anthelmintic actives, and in the liquid. [0054] granulating the mixture of anthelmintic actives. [0027] Another aspect of the invention relates to a method [0055] The following embodiments may relate to any of the of preparing a stable liquid delivery formulation for treating above aspects. an animal comprising the steps of [0056] In some embodiments the imidazothiazole is [0028) (a) providing one or more packs of granules, the levamisole HCL. granules comprising [0057] In some embodiments the composition comprises [0029) (i) a benzimidazole and a suspending agent for levamisole and a macrocyclic lactone. In some embodiments the benzimidazole, the composition comprises levamisole and a benzimidazole. [0030) (ii) a macrocyclic lactone and a wetting agent, [0058] In some embodiments the composition comprises [0031] (iii) a salicylanilide and a wetting agent, levamisole, a benzimidazole and a macrocyclic lactone. [0032) (iv) praziquantel and a wetting agent, [0059] In some embodiments the composition comprises a [0033] (v) an imidazothiazole and one or more anthel particulate source of one or more minerals. Unless where mintic agents selected from benzimidazoles, macro specifically stated, reference to minerals in this specification cyclic lactones, salicylanilides, and praziquantel, and should be taken to be reference to any minerals required by optionally a suspending agent, the non-human animal to be treated, including but not limited [0034] (b) adding the granules from the one or more to selenium, cobalt, magnesium, zinc, iodine and any combi packs of granules to an aqueous liquid, nation of any two or more thereof. [0035) (c) adding a suspending agent if (i) the granules [0060] In some embodiments the granules comprises a sus do not comprise a suspending agent, or (ii) additional pending agent. suspending agentis required to suspend the anthelmintic [0061] In some embodiments the granules comprises a actives in the liquid. gum. Gums that may be useful in any embodiment described [0036] Another aspect of the invention relates to a method herein include but are not limited to agar, alginic acid, algi offorming an anthelmintic composition comprising the steps nate, sodium alginate, carrageenan, arabic, ghatti, tragacanth, of: karaya, guar, locust bean, beta-glucan, chicle, dammar, glu [0037] providing two or more anthelmintic actives comannan, mastic, psyllium seed husk, spruce, tara, gellan, selected from one or more imidazothiazoles, one or and xanthan gums and any combination of any two or more more benzimidazoles, one or more macrocyclic lac thereof. tones, and praziquantel, [0062] In some embodiments the granules comprises an [0038] providing a suspending agent if the anthelmintic anionic surfactant. actives comprise a macrocyclic lactone, [0063] In some embodiments the granules comprise about [0039) providing a wetting agent if the anthelmintic 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75,80, 85, 90 or 95% actives comprises a benzimidazole, w/w of anthelmintic active. [0040] mixing the macrocyclic lactone with the suspend [0064] In various embodiments, a composition useful ing agent if a macrocyclic lactone is present, 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, [0041) mixing the benzimidazole with the wetting agent 94, 95, 96, 97, 98 or 99% w/w of one or more anthelmintic if a benzimidazole is present, actives useful herein and useful ranges may be selected [0042] combining the anthelmintic actives, and between any of these values (for example, about 1 to about 10, [0043] granulating the anthelmintic actives. about 1 to about 20, about 1 to about 30, about 1 to about 40, [0044] In one embodiment the method further comprises a about 1 to about 50, about 1 to about 60, about 1 to about 70, step before the providing step of determining the treatment about 1 to about 80, about 1 to about 90, about 10 to about 20, needs of one or more animals. Determination of the treatment about 10 to about 30, about 10 to about 40, about 10 to about needs of one or more animals can be carried out by a skilled 50, about 10 to about 60, about 10 to about 70, about 10 to worker with regard to that skill and the teaching of this speci about 80, about 10 to about 90, about 20 to about 30, about 20 fication. to about 40, about 20 to about 50, about 20 to about 60, about [0045] In one embodiment the method further comprises 20 to about 70, about 20 to about 80, about 20 to about 90, administering the liquid to one or more animals. In another about 30 to about 40, about 30 to about 50, about 30 to about embodiment the method further comprises immediately 60, about 30 to about 70, about 30 to about 80, about 30 to administering the liquid to one or more animals. about 90, about 40 to about 50, about 40 to about 60, about 40 US 2012/02385.16 A1 Sep. 20, 2012

to about 70, about 40 to about 80, about 40 to about 90, about [0087] The present invention includes the use of dilutable 50 to about 60, about 50 to about 70, about 50 to about 80, powders, dilutable granules, and dilutable liquid concentrate about 50 to about 90, about 50 to about 60, about 50 to about (s) and/or semisolid concentrates to provide a multiactive 70, about 50 to about 80, about 50 to about 90, about 60 to anthelmintic formulation capable of oral, spray and/or topical about 70, about 60 to about 80, about 60 to about 90, about 70 delivery. to about 80, or about 70 to about 90). It should be understood [0088] Preferably the granules at least in respect of one that these values and ranges may relate to one anthelmintic anthelmintic active result from a fluidized bed granulation of active or a combination of anthelmintic actives. For example, anthelmintic particles. a composition useful herein may comprise one, two, three or [0089] Various aspects of the present invention will now be more anthelmintic actives and these values and ranges may described but not exclusively of other aspects as will be relate to each active individually or to the combination of apparent from process flow diagrams, use diagrams and other actives. Formulation of a particular combination of two or aspects disclosed herein. more actives can be carried out by a skilled worker with [0090] Optionally another anthelmintic (e.g. praziquantel) regard to that skill and the teaching of this specification. can be present in a granule, powder or liquid of the system. [0065] In some embodiments the granule comprises less [0091]. Various anthelmintic actives have been considered than 3, 2, 1% w/w water. for use in granules of the present invention. These include at [0066] In some embodiments the granules are free or at least, by way of example, least substantially free of pyrrolidones. [0092] benzimidazoles such as oxfendazole, albenda [0067] In some embodiments the composition comprises zole, fenbendazole, , , oxi [0068] from about 1 to about 40% w/w benzimidazole, bendazole, , netobimin, thiabendazole, and and febantel, [0069] from about 1 to about 70% w/w levamisole HCL. [0093] salicylanilide such as closantal, brotianide, cliox [0070] In some embodiments the composition comprises 1, anide, , oxyclozanide, rafoxanide, 5, 10, 15, 20, 25, 30, 35 or 40% w/w macrocyclic lactone. , disophenol, hexachlorophene, nitroxynil, [0071] In some embodiments the granules comprise a par diamfenetid, and niclofolan menichlophola, ticulate thixotrope, particulate rheology modifier and/or gum. [0094) imidazothiazoles such as levamisole HCL, [0072] In some embodiments the granules contain a sus levamisole base, pamoate, butamisole, and tet pending agent. ramisol, and [0073] In some embodiments the suspending agentis added [0095] macrocyclic lactones such as abamectin, aver to the liquid. mectin, moxidectin, doramectin, ivermectin, emamec [0074] In some embodiments the suspending agent is a tin, , , milbemycin, and cydec gum. tin. [0075] In some embodiments the suspending agent of (a)(i) [0096] A preferment is both granules and powder(s) rather is a non-colloidal agent. In some embodiments the non-col than just granules alone. loidal agent is silicon dioxide. In some embodiments the [0097] Preferably at least one benzimidazole is present in liquid is water. each granule. [0076] In some embodiments the liquid is an anthelmintic [0098] Preferably a levamisole is present in each granule or COncentrate. some granule(s). [0077] In some embodiments the liquid contains avermec [0099] The other inclusion preferably include a gum as a tin and/or milbemycin in a liquid concentrate form. athixotrope. [0078] In some embodiments the liquid delivery formula [0100] Preferably a gum is present as a suspending agent tion is suitable for administration to animals for up to one for at least the benzimidazole content whereby, when diluted, month after mixing. there will be substantial homogeneity of the resultant suspen [0079] In some embodiments the granules comprise S1011. [0080) from about 1 to about 40% w/w benzimidazole, [0101] Preferably the anthelmintic agent(s) of each granule and accounts for at least about 30% w/w (more preferably at least [0081] from about 1 to about 60% w/w levamisole HCL. about 40% w/w) (still more preferably at least about 50% [0082] Preferably the diluents is water or an aqueous com w/w) (and most preferably from about 40% w/w to about 70% position. w/w) of the granule weight. [0083) Preferably xanthan gum is the or a thixotrope and/or [0102] Preferably the granules have less than about 3% w/w suspending agent for a particulate BZ in the delivery liquid (more preferably less than about 2% w/w) of water. composition. [0103] Preferably the granules are free or at least substan [0084] Preferably granules of at least one BZ and also con tially free of water. taining LEV provide for a particulate BZ presence in the [0104] Preferably the granules are free or at least substan delivery liquid composition. tially free of pyrrolidones. [0085] In an aspect the invention is a diagnosis of the [0105] Preferably a non-aqueous liquid is present in the anthelmintic needs of a herd of warm-blooded non-human anthelmintic granules in the range up to about 20% w/w of the animals and the provision of a corresponding kit of (ii) and/or granule (preferably at least about 10% w/w). (iii) type packs for use in a method as aforesaid. [0106] Most preferably some water is present and some [0086) In another aspect the invention is a use of one or non-aqueous liquid is present in the anthelmintic granules. more pack of granules and/or a liquid concentrate to provide [0107] Preferably any alcohol (e.g. benzyl alcohol) is for one or more of LEV. BZ and/or ML actives in a delivery present in an amount less than that needed to dissolve all of liquid composition. any anthelmintic active present. US 2012/02385.16 A1 Sep. 20, 2012

[0108] Whilst they can be prepared by any granulation [01301 (c) the drenching device for its fixed dosage technique (these techniques include but are not limited to amounts or a calibratable variable dosage amount, single pot granulation, fluid bed top spray granulation, high [0131] will deliver, in use, an effective amount of the sheer granulation/fluid bed drying combination, continuous beneficial agent(s) to each drenched target animal. fluid bed granulation, spray drying, etc), preferably the gran [0132] In another aspect the invention is a dosage system ules, at least in respect of one anthelmintic active, result from for orally dosing animals with plural anthelmintic actives, a fluidized bed granulation reliant on spraying of a solids said system comprising or including stream that includes the anthelmintic particles. Dry compac [0133) (a) one or more packs of granules of at least one tion (dry granulation) and wet extrusion followed by drying anthelmintic active of the present invention, and and sizing may be used. [0134] (b) at least one container with an avermectin and/ [0109] By way of example only a preferred double anthel or milbemycin active in a liquid concentrate form mintic active granule can have: [0135] (c) [0136] (i) a drenching device and a mixing container, Or [0137) (ii) a drenching device having a mixing reser QUANTITY FUNCTIONALITY A PREFERENCE voir, 10 to 40% "/.. a benzimidazole Oxfendazole or albendazole [0138] when one or more of (A), (B) and/or (C) is in about 15 to about 25% ". physical association with instructions whereby use of 10 to 60% "/.. levamisole HCl about 30 to about 40% "/, [0139] (a) all of one or more pack content(s), [0140] (b) all of one or more container content(s), [0141] (c) the mixing container or mixing reservoir with [0110] A suitable levamisole is levamisole HC1. water or an aqueous carrier as instructed, and [0111] Suitable benzimidazole(s) include those sparingly [0142] (d) the drenching device for its fixed dosage soluble in water. amounts or its calibratable variable amount, [0112| Examples include but are not limited to oxfenda [0143] will deliver, in use, an effective amount of the zole, albendazole, fenbendazole, mebendazole, flubenda plural anthelmintic agents to each drenched target ani zole, , triclabendazole, netobimin, thiabenda mal. zole, febantel, etc. [0144] In another aspect the invention is the use of a pack or [0113] Most preferably the BZ is oxfendazole, albendazole quantity of anthelmintic granules to deliver a recommended or fenbendazole. dose orally per animal when diluted with water or other [0114] Praziquantel might also be included in granule(s) aqueous carrier as instructed, the granules being readily asso powder(s). ciable with the water or aqueous carrier. [0115] Preferably a benzimidazole active ingredient is sus [0145] In another aspect the invention is a method of treat pendable. ing an animal which comprises orincludes, in any order (A (i) [0116] Preferably the suspendable anthelmintic particles to A (iv)): are no larger than those of that anthelmintic actives starting [0146) (a)(i) providing or taking at least one volume of material particles. anthelmintic granules [preferably of substantial homo [0117] Preferably a levamisole active ingredient is present. geneity] able to be associated (eg, by dispersion) with [0118] Optionally granulation involves one or more sprays water or an aqueous composition to provide a (prefer of a solids stream on a fluidized bed. ably thixotropic or pseudoplastic) liquid composition [0119) A spray may involve a liquid antifoaming agent containing one or more anthelmintic actives, and/or minerals and/or vitamins. [0147] (optionally (ii) providing or taking a liquid [0120) A spray may involved a liquid in which the benz concentrate of at least one avermectin and/or at least imidazole is more soluble than it is in water but in insufficient one milbemycin), quantity to fully dissolve the benzimidazole starting material [0148] (iii) providing or taking a volume of water and/ (s). or an aqueous composition, and [012.1] A spray may involve a ML (Milbemycin). [0149] (iv) providing or taking apparatus able to [0122] In another aspect the invention is a dosage system administer a (preferably thixotropic) liquid composi for orally dosing animals with at least one beneficial agent tion to such an animal; and (preferably at least one anthelmintic active), said system [0150] (b) associating in any order (i) and (iii) or (i), (ii) requiring and (iii), whether in the apparatus of A(iv) or not; and [0123] (a) one or more packs of granules of the beneficial [0151] (c) using the apparatus of A(iv) to administer the agent(s) of the present invention, and (preferably thixotropic or pseudoplastic) aqueous com position resulting from (B) to such an animal. [012.4] (b) [0152] In another aspect the invention is a method of [01251 (i) a drenching device and a mixing container, administering a mix of anthelmintic actives to an animal Or which comprises [0126) (ii) a drenching device having a mixing reser [0153] (1) preparing an aqueous delivery composition Voir, [0154) (a) from a dry granular composition of at least [0127] when one or other, or both, (A) and/or (B) is in one anthelmintic active of the present invention, or physical association with instructions whereby use of [0155] (b) from both a dry composition of at least one [0128] (a) the one or more packs anthelmintic active of the present invention and a [0129] (b) a said mixing container or said mixing reser liquid concentrate of at least one other anthelmintic voir with water or a aqueous carrier as instructed in, and active, and US 2012/02385.16 A1 Sep. 20, 2012

[0156] (2) administering an effective amount of the [0171] and wherein at least one non ML anthelmintic agent aqueous delivery composition to the animal. and/or other beneficial component(s) may be present; [0157] In an aspect the invention is an on-farm preparation [0172] and wherein a gum or alginate, or both, is present; for administration to an animal, the preparation being an [0173] and wherein chelating agent(s), stabilizer(s), etc aqueous suspension of ML anthelmintic particles derived may be present; from a non-aqueous concentrate upon its aqueous dilution, [0174] and wherein the whole concentrate content of the the concentrate not necessarily (and preferably not) having container of the concentrate is for dilution prior to animal the ML antibiotic present in a particulate form. administration. [0158] Preferably a gum suspends the particles, the gum (0175] Preferably the concentrate is liquid. being derived from the concentrate. [0176] Preferably the concentrate is free of pyrrolidone [0159] Preferably the administration is to be by any of the solvent and/or is free of glyceryl acetate solvent. routes herein described. [0177] Aspects of the invention relate to both high gum and [0160] In another aspect the invention is an on-farm prepa low gum formulations, low gum being below 5% W/W, and ration as aforesaid that includes other components added in a high gum 5% w/w (e.g. 5-20% w/w) Gums can be Xanthan. substantially dry form. Alginates of different viscosity grades may be used. [0161] In yet another aspect the invention is an on-farm [0178] Preferably the gum provides a thixotropic mix when anthelmintic preparation prepared by dilution of a concen diluted. trate in a liquid or gel form of at least one ML anthelmintic [0179] Another prospect is a storage stable and contained active. liquid or gel formulation (eg a liquid concentrator a gelled [0162] Preferably the concentrate is as herein described. concentrate) of at least one ML anthelmintic active for dilu [0163] Optionally the dilution is with water, an aqueous tion in a diluent, to provide a deliverable composition, prior to composition or a non-aqueous liquid. administration (orally, as a pour on and/or as a spray or dip) to [0164] In another aspect the invention is at least one pack of a target species of animal: granules of at least one anthelmintic active for use in an, on [0180] wherein the ML active(s) is at least substantially farm, customisation of a liquid delivery formulation of ben stable in its concentrate liquid or gel environment. eficial agents to animals. [0181] The ML active(s) can be more stable in the concen [0165] In another aspect the invention is a webcast, web trate than were it to be already diluted with the intended site, blog, flyer, brochure, datasheet or other (substrated) diluents(s), yet is readily mixable with such a diluent prior to material(s) providing or extolling the ability or virtue of gran administration. ules (eg as defined herein) and/or liquid concentrate(s) (eg as [0182] Preferably the formulation is for a target diluent defined in our patent application(s) filed simultaneously here (includes a range of diluents) and the formulation is or with) and/or dispensing apparatus in respect of the adminis includes: tration of one or more beneficial agent (eg to a target species [0183) (i) at least one ML active, animal type). [0184] (ii) an organic solvent or organic solvents in [0166] Another choice of course are liquid or semisolid which the ML active(s) is (are) stable, and (e.g. gel) preparations (and particularly concentrates) for a [0185] (iii) at least one suspending agent, whereby, when targeted diluent type. In particular, although not solely, the in the or a targeted diluents(s), the at least one ML active, invention relates to stable liquid concentrates of at least one as a precipitate or as a microemulsion, will be sus ML active (i.e., Macrocyclic Lactone anthelmintic active(s)). pended. [0167] The present invention relates to a product, the whole [0186] The formulation is ideally at least almost totally content of which, is to be on farm diluted (e.g. water or oil non-aqueous. dilution) for animal administration. This may maximize [0187] Preferably where the diluent is, or is to be, water or shelf-life and availability of the active(s) as well as allowing an aqueous composition. customisation at the dilution stage of the active(s) and ben [0188] Preferably said solvent is water miscible. eficial agents to be administered. [0189] In other embodiments the diluent is, or is to be, an [0168] Applicants assert that on farm dilution allows stable organic vehicle such as one or more vegetable oil (e.g. soya liquid or semisolid formulations of ML actives to be made bean, sesame oil, corn oil, etc.) available with a shelf life or at least about 6 months and for [0190] Preferably said solvent is vegetable oil miscible. customisation at dilution prior to administration. At the time (0191] Preferably the ML active is selected from the group of such dilution other components can be added and with the consisting of avermectins and milbemycins eg more prefer relatively brief time between dilution and administration sta ably is one or more of abamectin, moxidectin, doramectin, bility becomes less of an issue. Certainly extended shelf life ivermectin, emamectin. ofan ML/BZ, ML/LEV and/or ML/BZ/LEV formulation can [0192] Preferably the concentrate is free of pyrrolidone be rendered irrelevant while at the same time providing maxi solvent and/or is free of glyceryl acetate solvent. misation of customisation. [0193] Further aspects of the invention also relate to a [0169] Aspects of the invention relate to providing a con stable liquid concentrate in a container or pack and intended tained stable anthelmintic liquid or semi solid concentrate for aqueous dilution to an anthelmintic delivery or dosage targeted for dilution prior to animal administration, the con form, the concentrate comprising orincluding at least one ML centrate being a solution, emulsion, microemulsion, micron anthelmintic active, ized suspension, nanonized suspension, or some combination [0194] an organic solvent of the ML active(s), and thereof. [0195] a suspending agent able to suspend the ML active [0170] wherein at least one ML anthelmintic is present in (s) in the aqueous diluents(s) (even if water rather than (i) a water miscible organic solvent and/or (ii) an oil or an aqueous composition); organic liquid miscible type solvent; [0196) and optionally a preservative; US 2012/02385.16 A1 Sep. 20, 2012

[0197) and optionally an antifoam agent to reduce foam [0227] Aspects of the invention relate to a container in ing on aqueous dilutions, which a liquid concentrate is a formulation as previously [0198] and optionally a bulking agent. defined, and associated with instructions as to dilution prior to [0199 Benzyl alcohol is a preferred preservative. administration to an animal. [0200) Polysorbate&0TM is a preferred surfactant/antifoam [0228) Aspects of the invention relate to an on-farm prepa agent. Sodium lauryl sulphate is another option. A molten ration for administration to an animal, the preparation being wax may also be present. an aqueous suspension of ML anthelmintic particles derived [0201] Fumed silicon dioxide is a preferred building agent. from a non-aqueous concentrate upon its aqueous dilution, [0202] Preferably the concentrate is free of pyrrolidone the concentrate not necessarily (and preferably not) having solvent and/or is free of glyceryl acetate solvent. the ML anthelmintic present in a particulate form. [0203] Another option is a stable liquid concentrate in a [0229] Preferably a gum suspends the particles, the gum container or pack and intended for non-aqueous dilution to an being derived from the concentrate. anthelmintic delivery or dosage form, the concentrate com [0230|| Preferably the administration is to be by any of the prising or including routes herein described. [0231] Aspects of the invention also relate to an on-farm [0204] at least one ML anthelmintic active, preparation as aforesaid that includes other components [0205] an organic solvent of the ML active(s), and added in a substantially dry form. [0206] a suspending agent able to suspend the ML active(s) [0232] Aspects of the invention relate to an on-farm anthel in the non-aqueous diluents. mintic preparation prepared by dilution of a concentrate in a [0207] Preferably the solvent is one or more glycol ether, liquid or gel form of at least one ML anthelmintic active. and/or one or more cyclic-ether. [0233] In another aspect the invention is a webcast, web [0208] A preferred solvent is glycerol formal, propylene site, blog, flyer, brochure, datasheet or other (substrated) glycol or glycerol formal and propylene glycol. Another materials providing or extolling the ability or virtue of gran water miscible solvent option (alone or with any other) is ules and/or granules and powders and/or liquid and/or semi glycerine. sold concentrate(s) and/or dispensing apparatus in respect of [0209] A particularly preferred solvent is glycerol formal. the administration of one or more beneficial agent (e.g. to a [0210] A preferred suspending agent for a non-aqueous target species animal type). diluent (e.g. a vegetable oil) is as mentioned above. [0234] As used herein “diluent”, “target diluents”, etc pref [0211] Preferably the concentrate is free of pyrrolidone erably (but not necessarily) refers to a diluent with which a solvent and/or is free of glyceryl acetate solvent. liquid content of the concentrate granule(s) is miscible. [0212] Yet another option is a liquid concentrate in the form [0235] As used herein “LEV” means a levamisole and of a solution, the solution having “BZ” means a benzimidazole. [0213] (a) at least one ML active [0236] As used herein “semisolid” envisages gelled or [0214) (b) at least one organic solvent in which the ML other such forms, as a mass whether pourable or not, able to active(s) is (are) stable, and be diluted with the target diluent type. [0215] (c) at least one gum as suspending agent, whereby [0237] As used herein “on-farm” or the equivalent can in water or an aqueous composition with which it is mean in close time proximity for use with the animals e.g. A suitable for dilution, the at least one ML active, as a veterinarian may dilute a customized selection of concentrate precipitate, will be suspended or be dispersed (e.g. as in (s), granules and/or powder(s) for a farmer. a fire emulsion) and the aqueous suspension, dispersion [0238] Reference to “animal(s)” preferably includes any or emulsion is suitable for administration to an animal suitable animal, warmblooded or not, farmed, domestic, com orally, as a pour-on or as a spray or dip formulation. panion or other (ruminant or otherwise and can include fish). [0216] Microemulsions are preferred as a pour-on. [0239) Reference to “beneficial agent(s)” includes but is [0217| Optionally the liquid concentrate includes a glycol not restricted to trace elements and vitamins. It can include ether or cyclic ether as the solubilizer and/or stabilizer, or at anti-bloat agents, digestion ads, growth promotants, etc. least one said organic solvent. [0240] As used herein the term “and/or” means “and” or [0218] A preferred solvent is glycerol formal, propylene “or”, or both. glycol or glycerol formal and propylene glycol. [0241] As used herein “(s)” following a noun means the [0219) Preferably said ML active is one or more of an plural and/or singular forms of the noun. abamectin, moxidectin, doramectin, ivermectin, emamectin [0242] Reference to “animal(s)” preferably includes any etc. suitable warm-blooded animal ruminant or otherwise. [0220) Preferably said solvent is one or more glycol ether [0243) Reference to “beneficial agent(s)” includes but is and/or cyclic ether. The solvent is preferably glycerol formal. not restricted to trace elements and vitamins. It can include [0221] Preferably the liquid concentrate includes an anti anti-bloat agents, digestion ads, growth promotants, etc. foam agent. [0244] It is intended that reference to a range of numbers [0222] Preferably a preservative and a bulking agent is also disclosed herein (for example, 1 to 10) also incorporates present. reference to all rational numbers within that range (for [0223) A preferred preservative is benzyl alcohol also able example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also to act as a co-solvent. any range of rational numbers within that range (for example, [0224] A preferred bulking agent is fumed silicon dioxide. 2 to 8, 1.5 to 5.5 and 3.1 to 4.7). [0225] A preferred suspending agent for a non-aqueous [0245] In this specification where reference has been made diluents (e.g. a vegetable oil) is as mentioned above. to patent specifications, other external documents, or other [0226] Preferably the concentrate is free of pyrrolidone sources of information, this is generally for the purpose of solvent and/or is free of glyceryl acetate solvent. providing a context for discussing the features of the inven US 2012/02385.16 A1 Sep. 20, 2012

tion. Unless specifically stated otherwise, reference to such [0258] FIG. 9 shows the stability of a concentrate as in external documents is not to be construed as an admission that Example 13 in a typical container. such documents, or such sources of information, in any juris diction, are prior art, or form part of the common general DETAILED DESCRIPTION knowledge in the art. [0246] Accordingly, it is an object of the invention to not [0259] The present invention recognizes that for many pur encompass within the invention any previously known prod poses animal health products are supplied in formulations uct, process of making the product, or method of using the that are greater than 80% water or other diluent. product such that Applicants reserve the right and hereby [0260] The present invention recognizes the advantage to disclose a disclaimer of any previously known product, pro be derived for many situations where anthelmintic and/or cess, or method. It is further noted that the invention does not beneficial agents are to be administered or self administered intend to encompass within the scope of the invention any (“administered”) to an animal (warmblooded or not farm product, process, or making of the product or method of using animals, companion animals, fish, etc.) to provide a platform the product, which does not meet the written description and that obviates the need of the provision through from manu enablement requirements of the USPTO (35 U.S.C. §112, facture to end user of unnecessary water and/or other liquid first paragraph) or the EPO (Article 83 of the EPC), such that carrier(s). Applicants reserve the right and hereby disclose a disclaimer [0261] The present invention in addition or instead recog of any previously described product, process of making the nizes that for some beneficial agents, there are advantages product, or method of using the product. insofar as transport, storage and inventory costs are con [0247] It is noted that in this disclosure and particularly in cerned of having beneficial agents provided in a form able to the claims and/or paragraphs, terms such as “comprises”, be readily associated with water or other diluent (without a “comprised”, “comprising” and the like can have the meaning requirement of specialist mixing equipment) prior to admin attributed to it in U.S. patent law; e.g., they can mean istration to an animal. “includes”, “included”, “including”, and the like; and that [0262] In many instances there are single or combinations terms such as “consisting essentially of and “consists essen of beneficial agents that advantageously can be maintained in tially of have the meaning ascribed to them in U.S. patent association in at least substantially fixed proportions without law, e.g., they allow for elements not explicitly recited, but the instability sometimes encountered in liquid formulations. exclude elements that are found in the prior art or that affect [0263] By way of example, the present invention recog a basic or novel characteristic of the invention. nizes how single or a combination or combinations of anthel [0248] These and other embodiments are disclosed or are mintic actives can be combined into a granular product obvious from and encompassed by, the following Detailed (whether in each individual granule or in blends of different Description. granules) advantageously (or both granules and powder forms) with respect to the advantages discussed as well as not BRIEF DESCRIPTION OF THE DRAWINGS being significantly detrimental to end usage and/or stability during storage. Indeed for some such formulations, prefer [0249] The following detailed description, given by way of ably in a simple or complex granular form, there are stability example, but not intended to limit the invention solely to the advantages over having one or more of the actives in a simple specific embodiments described, may best be understood in liquid formulations. conjunction with the accompanying drawings, in which: [0264] Such single or combined anthelmintic actives [0250] FIG. 1 is one of several flow diagrams able to pro (granulated, granulated and powder, and/or liquid concen duce granules as described, such a formulation being exem trate) can be directly or indirectly associated with mineral plified hereafter (NB Granulation Solution 1 may or may not supplements and vitamins eitherin the granule itself and/or in include a drug, anthelmintic and/or beneficial agent(s)), ancillary concentrated forms to be associated with the anthel [0251] FIG. 2 shows stability of the Example 6 formulation mintic active or actives when downstream (eg with the over time in months (M) and the temperatures shown in (c). farmer) in a delivery or dosage liquid formulation. [0265 Various anthelmintic actives have been considered [0252) FIG. 3 shows the stability of a concentrate as in for use in the platform technology of the present invention, Example 7 in a typical package being by way of example these include by way, of example, in granulated form benz aluminium foil (but it could be a plastic sachet), bottle eg. imidazole(s) typified by oxfendazole, albendazole, etc and HOPE or other), levamisole(s) typified by its variations including levamisole, [0253] FIG. 4 shows the stability of a concentrate as in base levamisole HC1 or any of its salts. Example 9, [0266] Praziquantel and MLs are another possibility. [0254] FIG. 5 shows the stability of a concentrate as in [0267] Typical of anthelmintic actives that lend themselves Example 10, and to a liquid concentrate are and milbemycins (eg [0255] FIG. 6 shows the stability of a concentrate of abamectin, ivermectin, etc). Example 11. [0268] Beneficial agents considered in respect of the plat [0256] FIG. 7 is one of several flow diagrams able to pro form technology and related aspects of the present invention duce a liquid concentrate as described, such a formulation include mineral supplements, vitamins, etc. being exemplified, by way of example, by Example 12 here [0269] Target species include farmed or unfarmed animals, after, domestic or companion animals (e.g. cattle, sheep, horses, [0257] FIG. 8 shows the stability of a concentrate as in deer, swine, dogs, cats, fish etc). The invention is preferably Example 12 in a typical bottle (by way of example, a glass or for use with target ruminants being farmed where significant plastic bottle (HDPE or other)), quantities can be diluted for serial animal administration. US 2012/02385.16 A1 Sep. 20, 2012

This enables on farm customisation of beneficial agents in a [0288] Addition of water miscible components can lower liquid mix (preferably aqueous) prepared immediately or the freezing point of the reconstituted formulation if water is soon prior to administration. to be used as a reconstituting medium. [0270| Such beneficial agents preferably include trace ele ment additions (e.g. selenium, magnesium, cobalt, zinc, 1. Multi-Active Granules iodine, etc) and/or vitamins or vitamin precursors. [0289. In some embodiments the invention consists in [0271] Suitable suspending agents include one or more of anthelmintic granules (preferably of substantial homogeneity [0272] gums (such as xanthan, guar, gellan, etc.) notwithstanding historical particles may still be manifest in part in the granules) able to be associated (e.g., by dispersion) [0273] fumed or colloidal silicon dioxides (eg AEROSIL with water or an aqueous composition to provide a [prefer R972R, AEROSIL 200 Mesh, etc) ably thixotropic or pseudoplastic] liquid composition able to [0274] THIXCIN R (a nonhydroscopic castorwax be administered (e.g. mechanically administered, or able to derivative of castor oil). be self administered), to an animal or to animals, the granules [0275] A most preferred suspending agent is particulate being of, or derived from, at least xanthan gum either in the dry mix to be granulated by any [0290] (a) from about 1 to about 70% w/w of at least one process or in the dry mix and/or granulating fluid of a fluid particulate anthelmintic active ized bed granulation process. [0291] (b) from about 0 to about 20% w/w of at least one [0276] Such beneficial agents can include or be added using particulate beneficial agent anthelmintic liquid concentrate additions. [0292] (c) from about 1 to about 10% w/w of a particulate [0277] Preparation of dual anthelmintic active granules and thixotrope, particulate rheology modifier and/or gum. with a cobalt and selenium source as further beneficial agents [0293] In another embodiment the composition is, or is can be prepared as in FIG. 1 which shows a fluidized bed top formulated as, an anthelmintic granules, preferably of sub spray granulation process using two sprays in series. stantial homogeneity notwithstanding historical particles [0278] A solids stream of particulate benzimidazole(s) may still be manifest in part in the granules, that is able to be (“BZ”), a levamisole (“LEV”), a cobaltsource (“Cobalt”) and associated (e.g. by dispersion) with water oran aqueous com xanthan gum (“XG”) is fed to the fluidized bed. position to provide a liquid composition able to be adminis [0279] First a granulating solution of Tween 80 and benzyl tered (e.g. mechanically administered, or able to be self alcohol (“BA”) is sprayed. This may or may not have any administered), to an animal or to animals, the granules being active in a fully or partially dissolved. Second a granulating of, or derived from, at least solution of a buffer and a selenium source (NaSe). [0294] (a) from about 1 to about 20% w/w of at least one [0280] This leads then the granules being formed and dried particulate anthelmintic active prior to sizing and packing e.g. in plastic, aluminium or like [0295] (b) from about 0 to about 20% w/w of at least one bags, containers, etc. particulate beneficial agent [0296] (c) from about 1 to about 10% w/w of a particulate [0281] Suitable applicators for administering the deliver thixotrope, particulate rheology modifier and/or gum. composition are those available from N J Phillips Pty Lim Preferably the composition is thixotropic orpseudoplas ited, Instrument Supplies Ltd, Simcrotech Ltd and PrimaTech tic. Ltd. Particularly preferred are backpack reservoired applica [0297] In another embodiment the composition is a granu tors of N J Phillips Pty Limited (e.g. with 2.5 litre backpack) lated product capable of dilution to a delivery composition and a variable dose capability. form to which other active(s) and/or beneficial agent(s) might [0282] Liquid impregnated granules optionally can be one also have been, be or are to be added, the product being of the following: [0298] (a) produced substantially as herein described or [0283] It can be mixture of a Liquid Surfactant and a analogously thereto, OR liquid preservative (e.g. Polysornate 80 and Benzyl [0299) (b) substantially as herein defined or exemplified, Alcohol) or analogous thereto, OR [0284] It can be a mixture of a Liquid surfactant/s+Sol [0300) (c) having a combined deliverable content of vent (usually water miscible type but not limited to e.g. anthelmintic active(s) postagglomeration or granulation glycerol formal, Propylene glycol)+Liquid or a solid from particles of at least 30% w/w (and preferably Preservative. higher). [0285] Usually below 10% w/w low liquid content granules [0301] In another embodiment the composition is an oral and above 10% w/w is regarded as high liquid content gran dosage aqueous composition having present one or both: ules. Liquid’s are described above. Usually these liquid [0302) (a) at least one or two anthelmintic actives derived impregnated granules contain a potent organic soluble drug/s from a pack of granules of such actives, and e.g. Abamectin not limited to ML can be any organic drug, [0303] (b) at least one anthelmintic active derived from a beneficial chemical agent. container of a liquid or semisolid [0286] The drugs may be in a solubilized state or a partially [0304] (c) concentrate of that anthelmintic active. solubilized state (which reduces the particle size of the drug). [0305] Preferred anthelmintic granules include able to be [0287] The aim of impregnating granules is to make the associated with water or an aqueous composition to provide a granules function as a liquid and as a solid. The liquid part liquid composition able to be administered (mechanical after coming in contact with the reconstitution medium either administered, or able to be self administered), to an animal or precipitates the drug as a fine suspension or may form a to animals, the granules being of at least micro-emulsion or even a coarse emulsion (i.e. thermody [0306] (a) from about 1 to about 30% w/w of at least one namically unstable). anthelmintic active, and US 2012/02385.16 A1 Sep. 20, 2012

[0307] (b) from about 0 to about 20% w/w of at least one at least most of the benzimidazole content if and when beneficial agent, and released into water oran aqueous diluent, and optionally with [0308] (c) Up to about 80% w/w of other inclusion(s). other inclusions; wherein all or some of the granules have an [0309] In another embodiment the composition consists in anthelmintic active content of from about 20 to about 80% granules, or a blend of granules, having one or more benz w/w. imidazole, a levamisole, or both, in individual granules [0332] In some embodiments the invention is anthelmintic wherein the granules can release into diluent water or an granules having an anthelmintic content (whether of one or aqueous diluent composition more anthelmintic actives) of at least about 30% w/w and [0310] (a) particles of said at least one benzimidazole, having been formed by a granulation process in which one or and more anthelmintic active(s) has (have) been presented as [0311] (b) sufficient suspending agent(s) to hold the ben particulate starting material(s): zimidazole particles at substantial homogeneity. [0333] wherein the granulation process has involved at [0312] In another embodiment the composition consists in least a suspending agent; anthelmintic granules able to be associated with water or an [0334] and wherein, upon delivery dilution prior to aqueous composition to provide a liquid composition able to administration to a warm-blooded animal, the suspend be administered (mechanical administered or able to be self ing agent will suspend particles of at least one granule administered), to an animal or to animals, the granules being included anthelmintic active ingredient. of at least [0335] Without wishing to be tied to a theory, anthelmintic [0313| (a) from 1 to 30% w/w of at least one anthelmintic actives in a granule or a mix of anthelmintic actives in a active, granule, where the matrix of the granule(s) includes carrier [0314] (b) from 0 to 20% w/w of at least one beneficial materials (which can be other beneficial agent(s)) not condu agent, and cive to chemical and/or physical instability of the anthelm [0315] (c) up to 80% w/w of other inclusion(s). intic active(s) reduces the within granule and/or granule to [0316] In another embodiment the anthelmintic granules granule interface of the different anthelmintic actives. Simi has at least both some liquid content and anthelmintic content larly where a pack (e.g. a sachet) might contain at least one and having an ability of being converted for liquid carried granule type whether with or without any other particulate animal administration with a diluent. content (e.g. powdered anthelmintic active, vitamins, miner [0317| In some embodiments the invention is, as a dilutable source of at least one anthelmintic active, are granules of at als, etc). least one anthelmintic agent (preferably two but optionally [0336] For benzimidazole(s) and levamisole a suspending three or more) optionally having other beneficial agent inclu agent such as a gum can be used in the matrix. Likewise other sions, or being in admixture with one or more powdered inclusions that can be conducive to performance post dilution and/or granulated source of other agent (e.g. anthelmintic, with a target or non-targeted diluent, and/or prior dilution beneficial or other); wherein one or more of the following with a targeted or non-targeted diluent, and/or to deliver other applies beneficial agents to the recipient(s). For example a suspend [0318] a benzimidazole is present, ing agent suitable in a diluent that is nonaqueous such as [0319) a levamisole is present castor oil or soya oil or other thick oil. For example a sus [0320] an ML anthelmintic is present pending agent suitable for aqueous dilution. [0321] a gum or other particle suspension agent effective [0337] In some embodiments the granules remainstable for upon aqueous dilution is present at least one month. [0322] an at least substantially homogeneous suspension [0338] In some embodiments the granules remainstable for of at least one anthelmintic agent can be created with at least 2, 3, 4, 5, or 6 months. aqueous dilution [0339] In some embodiments the granule comprises about [0323] an at least substantially homogeneous diluted 25 to about 50% imidazothiazoles. composition can be created by non-aqueous dilution [0340] In some embodiments the granule comprises about (e.g. with a suitable oil, alcohol and/or glycol). 15 to about 50% benzimidazole. [0324] a particulate source of one or more mineral is [0341] In some embodiments the granule comprises about present 10 to about 25% praziquantal. [0325] selenium particles are present [0342] In some embodiments the granule comprises about [0326) water is absent or below 3% w/w of the granules 0.10 to about 10% macrocyclic lactone. is present in the granules [0343] In some embodiments the benzimidazoles is [0327] a liquid other than water of from about 5 to about selected form one or more of oxfendazole, albendazole, fen 20% w/w (preferably about 10 to about 20% w/w) bendazole, mebendazole, flubendazole, oxibendazole, tricla [0328] an inclusion of the granules has been microencap bendazole, netobimin, thiabendazole, and febantel. sulated [0344] In some embodiments the salicylanilide is selected [0329] an anionic surfactant is present in the granules form one or more of closantal, brotianide, clioxanide, niclosa [0330] the granules, or granules and other powdered and/ mide, oxyclozanide, rafoxanide, bithionol, disophenol, or granulated material, is packed to a volume of from hexachlorophene, nitroxynil, diamfenetid, and niclofolan about 100 to about 600ml (more preferably about 200 to menichlophola. about 400 ml). [0345] In some embodiments the imidazothiazoles is [0331] In some embodiments the invention is an anthelm selected form one or more of levamisole HCL, levamisole intic granules or a blend of anthelmintic granules to provide a base, pyrantel pamoate, butamisole, and tetramisol benzimidazole active or both a benzimidazole active and a [0346) In some embodiments the macrocyclic lactones is levamisole active, the granules having a suspending agent for selected form one or more of abamectin, avermectin, mox US 2012/02385.16 A1 Sep. 20, 2012

idectin, doramectin, ivermectin, emamectin, eprinomectin, mixer. Essentially it is a mix of the other two types indicated selamectin, milbemycin, and cydectin. above. This helps in avoiding full batch granulation saving on processing costs. 2. Stable Liquid Delivery [0363] Other special cases: Microcapsules or pellets may be loaded to the granule platform if need arise. Relevant [0347] In some embodiments the invention is an agglom processes apply under those circumstances. eration of benzimidazole and levamisole particles without any substantial or full dissolution of either species of particle [0364] Note: The choice of process will depend on the type and in the presence of a suspending agent effective of formulation. [0348] (a) upon dilution with water or an aqueous com Formulation Presentation Notes position of suspending evolved benzimidazole particles, Or [0365] The final granule or powder formulation may be [0349] (b) upon dilution with a solvent for the benzimi sold as sachet pack/s or may be sold as capsules. Kit will dazole, to suspend the evolved levamisole particles, or contain items like spray guns/capsule delivery systems e.g. [0350] (c) upon dilution with an organic liquid to sus capsule gun. Incompatible drugs may be packed separately as pend any evolved particles in that organic liquid. sachets. [0351] Preferably, if (a), the suspending agentis a gum such [0366] Sachet pack (Liquid Product): Granules/powders as xanthan gum. etc discussed till now may be dispensed in one or more [0352] If (b) or (c), preferably an alcohol is present at sachets. The following are some of the options but not exhaus dilution, or, more preferably a vegetable oil is present at tive. dilution. [0367] Capsule type: The granules/powders may be filled in [0353] In some embodiments the packs of granules or gran hard capsules which may or may not contain drug contain. ules and powder(s) are emptied for dilution into a delivery They may include flavor enhancing chemicals. system reservoir dilution to a delivery system reservoir vol [0368] Indeed flavorenhancing chemical(s) can be added to ume. Likewise any liquid or semisolid concentrate. granules and/or powders of the invention. [0354] In some embodiments the invention is an anthelm [0369| A typical preferred liquid concentrate anthelmintic intic delivery liquid composition having BZ particles derived particularly suitable for water or aqueous dilution for use a from granules of at least one BZactive or both at least one BZ deliverable drench composition or for lesser dilution for active and a LEV active suspended in an aqueous carrier or delivery as a pour on composition can have or include: water, the suspension agent being at least in part derived from the granules. [0355] In some embodiments the composition also A preference Functionality Quantity (w/w) includes an ML active made available to the remainder of the Abamectin anthelmintic active 1-20% delivery liquid composition from a liquid concentrate of the preferably from 2-8% ML active. Glycerol formal organic solvent 4–85% [0356] In some embodiments the liquid concentrate has the preferably from 20-85% more preferably from 50-85% ML active carried (at least in part) in an organic liquid or in xanthan gum suspending agent, 0.1-20% organic liquids. rheology modifier preferably below 5% and/or gum preferably from 5-20% 3. Method of Manufacturing a Granule benzyl alcohol anti-microbial agent? 0-10% co-solvent preferably from 0.1-6% [0357] In some embodiments the granules for aqueous and/ Polysorbate 80 surfactant/antifoam 0-8% or nonaqueous dilution for oral dosing purposes(s), have been agent preferably 0.1-5% prepared by a process wherein: [0358] 1. a particulate anthelmintic agent or particulate [03701 Low gum formulations preferably are 5% w/w or anthelmintic agents (and optionally one or more other below and high gum formulations about 5 to about 20% w/w. particulate beneficial agent(s)) and at least one particu [0371] The gum can be xanthan. Alginates of different vis late suspending agent and/or rheology modifier and/or cosity grades may be used as well or instead. gum is provided on a fluidized bed, and [0372] Levamisole base may be added by the manufacturer [0359] 2. one or more liquid composition(s) adding to the or by the farmer prior to addition. Prior to use (i.e. at dilution) solids on the fluidized bed to provide the resultant gran any suitable form of levamisole (e.g. levamisole base, levami ules. sole HCl, etc) and any suitable BZ(s) can be added. [0360] Powder type: Mix the drug/s (bulky drugs) either in [0373] The formulation may contain a gum that can gel in a suitable mixer with other ingredients. In some cases the water for formulations to be made up using water or it might mixing might be done in a high shear mixer or a ball mill. The contain thickeners that thicken in oil phase like Aerosil 200 or powders may be compacted i.e. dry granulated if flow prob Thix.cin R or a combination of both for formulations intended lems arise. to be reconstituted interchangeably using water or oil. [0361] Granule type: a dry mix of powders will be granu [0374] Liquid content of the concentrate can be or include lated using one or more granulating fluids. In some cases ball water miscible solvents (eg glycerol formal, propylene gly milled powders may be used for granulation in a wet/dry col, glycerine, etc.). Non aqueous diluents(s) can be one or granulator. more of those or an oil. [0362] Hybrid type: Part of the formulation may be granu [0375] Drench formulations are preferably given at 1 ml per lated (wet or dry) and part of it may be mixed in a suitable 4 kg body weight or 1 ml per 5 kg body weight for sheep. US 2012/02385.16 A1 Sep. 20, 2012

[0376] For cattle it is 1 ml per 10 kg body weight if a drench [0396] (C) using the apparatus of A(iv) to administer the or 1 ml per 20 kg body weight if a pour on. Thus a need for (preferably thixotropic or pseudoplastic) aqueous and/ higher active in the pour on deliverable composition. or nonaqueous composition resulting from (B) to such [0377] All these are after dilution with water or a non an animal. aqueous diluent. [0397] In one embodiment the invention is a method of [0378] Pour-on dose volume is preferably a maximum 1 orally treating an animal which comprises or includes, in any ml/20 kg in current products. order (A (i) to A (iii)): [0379] For example about 50 to 70 ml of the concentrate [0398] (A) (i) providing or taking at least one volume of might be needed to make up a litre of Abamectin drench. A granules containing at least one beneficial agent able to greater 150 to 200 ml of the concentrate might be required to be dispersed into water or an aqueous composition to make 1 litre of pour on. provide a liquid dispersion of at least substantial homo [0380] The ratios will vary depending upon the drug used. geneity, [0381] An example as produced by the process of FIG. 7 is [0399) (ii) providing or taking a volume of water and/ that of Example 0. or an aqueous composition, and [0382] In FIG. 7 there is a high shear mixer used to provide [0400] (iii) providing or taking apparatus able to a solution of glycerol formal (“GF’’), benzyl alcohol (“BA”), administera thixotropic liquid composition to such an Tween80TM and abamectin (“ABA”). To this is added a mix of animal; and the xanthan gum (“XG”), colloidal or fumed silicon dioxide [0401] (B) associating in any order (i) and (ii), whetherin (“silica”), and the antifoam agent (“A/foam”). the apparatus of A(iv) or not; and [0383] This mixture of a solution/suspension leads to a [0402) (C) using the apparatus of A(iii) to administer storage stable liquid concentrate in the form of a suspension orally aqueous composition resulting from (B) to such but with the ML active in solution. an animal. [0403] In one embodiment the invention is a method of 4. Use of a Granule administering a mix of anthelmintic actives to an animal [0384] In one embodiment the invention is a method of which comprises co-administration of anthelmintic actives to warm-blooded [0404] (A) preparing an aqueous delivery composition non-human animals which comprises [0405] (i) from a dry granular composition of at least [0385) (A) preparing a delivery liquid composition con one anthelmintic active, or taining [0406] (ii) from both a dry composition of at least one [0386] (i) a diluent, anthelmintic active and a liquid concentrate of at least [0387] (ii) a liquid or semisolid concentrate of an ML one other anthelmintic active, and active, and [0407] (B) administering an effective amount of the [0388] (iii)(a) powdered and/or granulated materials) aqueous delivery composition to the animal. having an LEV active, (b) powdered and/or granu [0408] In one embodiment the invention is a dosage system lated material(s) having a BZactive, and/or (c) granu for orally dosing animals with at least one beneficial agent lated material(s) having both an LEV active and a BZ (preferably at least one anthelmintic active), said system active, said delivery liquid including, as a conse requiring quence of (ii) and/or a (iii) presence, sufficient sus [0409] (a) one or more packs of granules of the beneficial pending agent for at least one particulate active from agent(s), and (ii) and/or (iii) in the deliver liquid composition to [0410] (b) ensure a disperse consistency, and [0411] (ii) a drenching device and a mixing container, [0389) (B) administering such delivery liquid composi Or tion in a dosage amount to each said animal. (iii) a drenching device having a mixing reser [0390] In one embodiment the invention is a method of [0412] treating an animal which comprises or includes, in any order voir, (A (i) to A (iv)): [0413] when one or other, or both, (A) and/or (B) is in [0391] (A) (i) providing or taking at least one volume of physical association with instructions whereby use of anthelmintic granules [preferably of substantial homo [0414] the one or more packs geneity] able to be associated (eg, by dispersion) with [0415] (A) a said mixing container or said mixing reser water or an aqueous composition or with a nonaqueous voir with water ora aqueous carrier and/or a nonaqueous liquid or liquid system to provide a (preferably thixotro liquid or liquid system as instructed in, and pic or pseudoplastic) liquid composition containing one [0416] (B) the drenching device for its fixed dosage or more anthelmintic actives, amounts or a calibratable variable dosage amount, [0392] (optionally (ii) providing or taking a liquid [0417] (C) will deliver, in use, an effective amount of the concentrate of at least one avermectin and/or at least beneficial agent(s) to each drenched target animal. one milbemycin), [0418] In one embodiment the invention is a dosage system [0393] (iii) providing or taking a volume of water and/ for orally dosing animals with plural anthelmintic actives, or an aqueous composition and/or nonaqueous liquid said system comprising or including and/or liquid system, and [0419) (A) one or more packs of granules and/or gran [0394) (iv) providing or taking apparatus able to ules and powder(s) of at least one anthelmintic active, administer a (preferably thixotropic) liquid composi and tion to such an animal; and [0420] (B) at least one container with an avermectin and/ [0395] (B) associating in any order (i) and (iii) or (i), (ii) or milbemycin active in a liquid and/or semisolid con and (iii), whether in the apparatus of A(iv) or not; and centrate form US 2012/02385.16 A1 Sep. 20, 2012

[0421) (C) [0440] The fill weight is about 50 g/L of formulation. The [0422) (i) a drenching device and a mixing container, adjuvant quantities may be optimized later. The delivery dose Or is 0.2 ml/kg (sheep). [0423] (ii) a drenching device having a mixing reser [0441] In some embodiments minerals are additionally voir, added. [0424] when one or more of (A), (B) and/or (C) is in [0442] Other adjuvants such as a buffer, suspending agents physical association with instructions whereby use of like xanthan gum, guar gum, or alginates may be added. [0425] (a) all of one or more pack content(s), [0443) Wet granulation may be used using electrolyte solu [0426] (b) all of one or more container content(s), tions, buffers, and minerals, whereby the ingredients are [0427] (c) the mixing container or mixing reservoir with sprayed on to the bulking agent. water or a aqueous carrier and/or a [0444] Dual active formulations (e.g. including abamec [0428] (d) nonaqueous liquid or liquid system as tin), may also include a wetting solution. The wetting agent instructed, and can be a low or high liquid containing impregnated granule. [0429] 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 drenched target animal. Ingredient name % (w/w) [0430] The granules offer an ability to hold in storage for Triclabendazole 62.5 farm/veterinary customization mixing/assessment of needs. Aerosil 200 25 [0431] One or more packs and optionally one or more vol SLS (solid) or Polysorbate 80 (liq) or other surfactant 12.5 (SLS) umes of an ML liquid concentrate and/or other beneficial contents can be diluted into a drench gun for animal admin istration. [0445] The fill weight is about 160 g/L of formulation. [0432] The present invention includes the use of dilutable [0446] A ball milling step may be used prior to the fluidized powders, dilutable granules, and diluatable liquid concentrate bed system for aggregate forming drugs. (s) and/or semisolid concentrates to provide a multiactive [0447] In some embodiments if a liquid surfactant is used, anthelmintic formulation capable of oral, spray and/or purion such as polysorbate 80, the surfactant remains in the granules. delivery. [0448] Granulation can be used to add potent drugs or ben eficial agents (present below 5%) or in general to incorporate [0433] Preferably packs of granules or granules and pow very dense (i.e. denser than 1 bulk density) materials (formu der(s) are emptied for dilution to a delivery system reservoir lation ingredients) like metal salts where there is a perceived dilution to a delivery system reservoir volume. Likewise the risk of segregation either in the granules or in the reconsti liquid or semisolid concentrate(s). tuted product. Granulation will also be used if a flow problem [0434] As a kit packs and/or containers as modularamounts is perceived in general or if the formulation tends to lump on for combination or not would be provided of granules (single storage (making it non user friendly or may cause difficulty active, dual active, etc and optionally with trace elements and/or vitamins) and of a liquid concentrate of at least one ML during reconstitution). (optionally with additives). Example 2 [0435] Preferably packs of granules or granules and pow der(s) are emptied for dilution to a delivery system reservoir Dual Active Powder Formulations (Low Surfactant) dilution to a delivery system reservoir volume. Likewise the liquid or semisolid concentrate(s). [0449] 2.1 Levamisole and Albendazole [0436] In another aspect the invention is a drench gun (or like apparatus) dosing a delivery liquid composition as pre viously defined. Ingredient name % (w/w) [0437] Analysis or experience can allow on farm customi zation of each mix at dilution for animal administration. Levamisole HCl 35.4 Albendazole 22.12 [0438] The invention will now be further described by way Cobalt EDTA 15.93 of the following non-limiting examples. Aerosil 200 17.7 SLS (Solid) or Polysorbate 80 (Liq) or other surfactant 8.8 (SLS) EXAMPLES (may be liq or solid) Example 1 [0450] The composition is reconstituted at 117 g/L and Single Active Powder Formulations administered at 0.2 ml/kg. [0451] In some embodiments a mineral can be added along [0439) 1.1 Praziquantel with other adjuvants like buffers or suspending agents like xanthan gum, guar gum, and alginates. [0452] 2.2 Levamisole and Praziquantal Ingredient name % (w/w) Praziquantel 38.7 Aerosil 200 40.82 Ingredient name % (w/w) SLS (solid) or Polysorbate 80 (liq) or other 20.4 (SLS) surfactant (solid or liq) Levamisole HCl 37.4 Praziquantel 17.75 US 2012/02385.16 A1 Sep. 20, 2012

-continued -continued Ingredient name % (w/w) Ingredient name % (w/w) Cobalt EDTA 16.8 NaOH 0.2 Aerosil 200 18.7 Abamectin - SLS (Solid) or Polysorbate 80 (Liq) or other surfactant 9.35 (SLS) Benzyl Alcohol - (Liq or Solid) Colloidal Silicon dioxide -

[0453] The composition is reconstituted at 107 g/L and [0461] The composition is reconstituted at 171.5 g/L. The administered at 0.2 ml/kg. same comments made for 3.2 apply. The stability data for this [0454] 2.3 Levamisole and Triclabendazole composition is shown in FIG. 3. Example 4 Ingredient name % (w/w) Levamisole HCl 29 Dual Active Granule Formulation (High Surfactant) Triclabendazole 36.23 Cobalt EDTA 13.04 [0462] 4.1 Levamisole and Oxfendazole Aerosil 200 14.4 SLS (Solid) or Polysorbate 80 (Liq) or other surfactant 7.2 (SLS)

Excipient Class [0455] The composition is reconstituted at 138 g/L. Function (% Dry Wt) Ingredient Example 3 Actives Drugs Total (57.5%) Levamisole HCl (36.7%) & oxfendazole (20.8) Dual Active Granule Formulations (Low Surfactant) Suspending Agent Gum (1.4%) Xanthan Gum Rheology Modifier [0456) 3.1 Levamisole and Albendazole Anti-microbial Preservative (2.8%) Benzyl Alcohol preservative Wetting Agent Surfactant (13.8%) Polysorbate 80 pH Stabilizer Buffer (1.6%) Citric Acid & NaOH Ingredient name % (w/w) Adsorbent, Flow Bulking Agent (5.7%) Colloidal SiO, modifier, Bulking Levamisole HCl 43.20 Agt; Gum & Drug Albendazole 27.42 Dispersant; Cobalt EDTA 19.2 Disintegrating Agt Xanthan Gum 3.3 Mineral Supplements Minerals (17.2%) Cobalt EDTA & Na Polysorbate 80 (Other surfactant) 1.6 Selenate Sodium selenate 1.32 Citric Acid 3.3 NaOH 0.625 [0463] The composition is reconstituted at 220 g/L to L) Abamectin - Benzyl Alcohol - and administered at 0.1 ml/Kg. This formulation exhibits Colloidal Silicon dioxide - good stability (e.g. as for the triple high surfactant example). [0464] This formulation is a dual active formulation utilis [0457] The composition is reconstituted at 91 g/L and ing the high surfactant polysorbate 80 (above 10% is high), a administered at 0.2 ml/Kg. potent mineral (sodium selenate) and a bulky mineral (Cobalt [0458] This formulation is a dual active formulation com EDTA). This can be used as a dual standalone. prising a low surfactant polysorbate 80 (below 10% is less), a [0465] In some embodiments ball milling is used prior to mineral (sodium selenate), and a bulk mineral (cobalt EDTA). charging in to the fluidized bed system, such as aggregate In some embodiments a preservative can also be added. The forming drugs (e.g. albendazole). stability of this formulation is shown in FIG. 2. [0466] In-Use Suspendability [0459] In some embodiments ball milling is used prior to charging in to the fluidized bed system, such as aggregate [0467] The concentration of the reconstituted granule in forming drugs (e.g. albendazole). water was 1.1 kg/5 L. Oxfendazole was chosen as a marker [0460) 3.2 Levamisole and Oxfendazole compound for drug suspension stability. [0468] (Levamisole Fully Soluble) [0469] Initial: 100 mg/g Ingredient name % (w/w) [0470] 2 h; At the top was 96 mg/g and at the bottom was 105.2 mg/g Levamisole HCl 46.65 Oxfendazole 26.42 [0471] 4 h. At the top was 98 mg/g and at the bottom was 99 Cobalt EDTA 20.4 mg/g Xanthan Gum 1.2 [0472] 4 days: At the top was 95.7 mg/g and at the bottom Polysorbate 80 (Other surfactant) 3 Sodium selenate 1.4 was 98 mg/g Citric Acid 0.9 [0473] These results demonstrated that the reconstituted suspension is physically stable up to 4 days. US 2012/02385.16 A1 Sep. 20, 2012

[0474] In-Use Stability—Physico-Chemical [0486) 6.1 Levamisole, Oxfendazole and Abamectin [0475] 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 benzimi dazole and less than 2% degradation of Levamisole. It was Ingredient name % (w/w) additionally found that there was no significant change in the Levamisole HCl 35.42 pH or viscosity of the reconsitituted granule formulation. Oxfendazole 20 Cobalt EDTA 15.5 [0476] In-Use Flow Testing Xanthan Gum 1.77 [0477] Using a standard drench gun it was found that the Polysorbate 80 (Other surfactant) 15.5 in-use flow testing was excellent. Antifoam AF Emulsion - [0478] The dual and triple active granule formulations are Sodium selenate 1.06 thixotropic (shearthinning) with a viscosity of 500-900 cp at Citric Acid 1.32 20° C. NaOH 0.25 Abamectin (microfine) 0.93 [0479] Little change was observed when the formulation Benzyl Alcohol 2.66 was combined with a liquid concentrate of an ML active. Colloidal Silicon dioxide 5.53 Example 5 [0487] The abamectin was first dissolved in glyceryl formal Triple Active Granule Formulations (Low Surfac and polysorbate 80 mixture (Glyceryl formal 88% and tant) polysorbate 80 3.6%). The percentage indicates the compo [0480] In the low surfactant methods abamectin is first sition ratio used, and is not related to the formulation. The micronized, precipitated and then reconstituted and sprayed. abamectin is then precipitated out in water under agitation [0481] 5.1 Levamisole, Oxfendazole (Silverson). [0488] The fine precipitated abamectin is obtained from the dispersion by centrifuging (4200 rpm for 5 min) the disper sion after decanting the supernatant layer (i.e. glyceryl formal Ingredient name % (w/w) and polysorbate 80 is removed during centrifuging followed Levamisole HCl 45.82 by decanting). The microfine abamectin was then reconsti Oxfendazole 25.95 tuted quantitatively using wetting solution made up of water Cobalt EDTA 20 and polysorbate 80. Xanthan Gum 1.43 Polysorbate 80 (Other surfactant) 2.9 [0489] It is envisaged that the stability of labile drugs will Antifoam AF Emulsion 0.3 be further improved if separate granulation of actives occurs. Sodium selenate 1.4 For example, the contents in a sachet may be a mixture of two Citric Acid 0.9 granules to prevent intimate contact of the labile drugs. In NaOH 0.16 Abamectin ** - some embodiments the granules may be packed in two sepa Benzyl Alcohol - rate sachet packs. Colloidal Silicon dioxide - [0490] The composition is reconstituted at 175 g/L and administered at 0.1 ml/Kg. The stability is shown in FIG. 6. [0482] The composition is reconstituted at a concentration [0491] Chemical and Physical Stability—Abamectin of 175 g/L. The stability is shown in FIG. 4. [0492] When reconstituted with water, the sstability of abamectin in the reconstituted triple active formulation was [0483) 5.2 Levamisole, Albendazole investigated after storage at 30 and 40°C. for 1 month. It was observed that abamectin had less than 2% degradation and there was no physical change in pH or viscosity. Ingredient name % (w/w) [0493] In-Use Flow Testing—Reconstituted Drug Products Levamisole HCl 42.4 [0494] Using a standard drench gun it was found that the Albendazole 26.51 in-use flow testing was excellent. Cobalt EDTA 18.6 [0495] The dual and triple active granule formulations are Xanthan Gum 3.2 thixotropic (shearthinning) with a viscosity of 500-900 cp at Polysorbate 80 (Other surfactant) 2.65 Antifoam AF Emulsion 0.53 20° C. Sodium selenate 1.27 Citric Acid 3.2 Example 7 NaOH 0.6 Abamectin ** - Triple Active Granule Manufacture Benzyl Alcohol - Colloidal Silicon dioxide - [0496] A triple active granule was prepared in accordance with the table below. [0484] The composition is reconstituted at 94 g/L and administered at 0.2 ml/Kg. The stability is shown in FIG. 5. Example 6 Name of ingredient Qty per L (g) Qty 9% (w/w) Triple Active Granule Formulations (High Surfac Levamisole HCL 80 36.4 Oxfendazole 45.3 20.6 tant) Cobalt EDTA 35 15.9 [0485] In the high surfactant methods abamectin is incor Sodium Selenate 2.4 1.09 porated as a fine dispersion after dispersal in benzyl alcohol. US 2012/02385.16 A1 Sep. 20, 2012 15

-continued -continued Name of ingredient Qty per L (g) Qty 9% (w/w) Raw Material Percentage Batch Abamectin 2.1 0.96 Distilled Water (0-35% w/w) (0-700 g) Xanthan Gum 3 1.36 Citric Acid Anhydrous 1.31.5% w/w 19.73 g Colloidal Silicon Dioxide 12.5 5.69 Sodium Hydroxide 0.250% w/w 3.75 g Polysorbate 80 30 13.64 Distilled Water (14.667% w/w) (220 g) Benzyl Alcohol 6 2.73 Citric Acid 3 1.36 Total 100% w/w 1,499.99 g Sodium Hydroxide 0.57 0.26 Water (1) 76.2–114.3 - (for ABA) [0509] The granules were produced using the following Water (2) 25-42 ml - process: (formineral) Water (3) 2-3 ml - [0510) 1. sodium selenate was dissolved in purified (to flush lines) water, citric acid anhydrous and sodium hydroxide were added to the solution and mixed well to produce the Se TOTAL 219.87 100% solution, [0511] 2. abamectin was dissolved in benzyl alcohol, [0497] The manufacturing process for the triple granule polysorbate 80 was added to the solution and mixed well, and then a variable quantity of water (0-700 g) was comprises the steps of: added to the solution and mixed well to produce the ABA [0498] 1. dry mixing levamisole HCL, cobalt EDTA and solution, xanthan gum, [0512] 3. levamisole HCL, cobalt EDTA and xanthan [0499] 2. mixing oxfendazole and the aerosil in a poly gun were passed through a 40-mesh screen and mixed, bag and passing it through a 0.8-1 mm sieve, [0513] 4 oxfendazole and colloidal silicon dioxide 200 [0500) 3. dissolving the abamectin in benzyl alcohol and were passed through a 40-mesh screen and mixed, [0514] 5. the powder mixtures of (3) and 94) were placed adding polysorbate 80 to it while under agitation, in glatt granulator/dryer insert, [0501] 4 adding water to the abamectin while under [0515] 6. the powder mixtures of (5) were fluidized and agitation until a hazy white colored dispersion is pro warmed up, duced which is free from particulates (particulates [0516] 7, the ABA solution was sprayed onto the powder which are observed visually), mixtures at a variable spray rate (20-40 g/minute) with a [0502] 5. loading the powders from steps 1 and 2 into the variable inlet air temperature (30-60° C.) with suitable FBP bowl and mixing for five minutes, fluidising, 6. spraying the step 3 dispersion, [0517] 8. the Se solution was sprayed onto the powder [0503] mixtures with a spray rate of 15 g/minute and an inlet air [0504] 7, prepare a solution of citric acid, sodium temperature of 50°C. with suitable fluidising, hydroxide and sodium selenate in water, [0518] 9. the granule formed was dried with an inlet air [0505] 8. spraying the step 7 solution and keeping the temperature of 50° C. until the product temperature fluidized bed warm (40–55°C.), and reached 50° C., [0506] 9. drying the granules till the moisture content of [0519) 10, the granule was cooled to 25°C., 2-3% is achieved (KF method). [0520) 11, the dried granule was passed through a [0507] The granule produced by this method had good sta 18-mesh (850 pum) sieve, grinding up any lumps too big bility and dispersed well in water. to pass through, [0521) 12. the granule was tested for Loss on Drying (LoD), Mean Particle Diameter (MPD) and density Example 8 (bulk and tapped). [0522] 8.1 Stability Study Triple Active Granule Efficacy Study [0523] The study was conducted to review the quantity of spray solution, spray rate and inlet air temperature. Statistical [0508) A triple active granule was prepared in accordance analysis of the response data including flow-ability, dispers with the table below. ing-ability in water and sedimentation speed will be used to identify the optimal level of quantity of spray solution, spray rate and inlet air temperature. Raw Material Percentage Batch [0524] The quantity of spray solution (0, 350, 700 g), spray rate (20-40 g/min) and inlet air temperature (30-60° C.) was Levamisole Hydrochloride 35.071% w/w 526.06 g Oxfendazole 19.859% w/w 297.88 g varied in an attempt to understand the effect of changing these Abamectin 95% 0.969% w/w 14.54 g variables, individually and in combination, to identify an Cobalt EDTA 15.34.3% w/w 230.15g optimal combination of quantity of spray solution and pro Sodium Selenate 1.052% w/w 15.78 g cess parameters to produce suitable granule. Xanthan Gum 1.97.3% w/w 29.59 g [0525] 8.2 Efficacy Study Colloidal Silicone 8.386% w/w 125.79 g Dioxide 200 (CSD) [0526] A cross-over study was performed to determine the Benzyl Alcohol 2.630% w/w 39.45 g blood plasma concentrations of abamectin, oxfendazole and Polysorbate 80 13.15.2% w/w 197.27 g levamisole following oral treatment with reconstituted gran ule product containing these three . The efficacy

US 2012/02385.16 A1 Sep. 20, 2012

[0557] It is envisaged that it is diluted with water, an aque maTech Ltd. Particularly preferred are backpack reservoired ous composition or a non-aqueous liquid or composition, for applicators of N J Phillips Pty Limited (e.g. with 2.5 litre example, a pour on type concentrate (which will form water backpack) and a variable dose capability. based pour ons upon reconstitution). The final product is [0567] The invention is further described by the following administered at 1 ml/kg. For example, about 150 or 200 ml is numbered paragraphs: required to make up a litre of pour on with high gum/abam 1. An anthelmintic composition in the form of a stable granule ectin concentrate. This volume will vary depending upon the comprising two or more anthelmintic actives selected from drug used in addition to the ML anthelmintic. one or more imidazothiazoles, one or more benzimidazoles, [0558] For example, for levamisole mase (used in a pour on one or more macrocyclic lactones, one or more salicylanil concentrate owing to its penetration properties) about 600 to ides, praziquantel, the stable granule being readily dispersible about 700 ml/L for 200 g of base). Levamisole base (200 g) in water to provide a homogenous mixture of the anthelmintic needs glyceryl formal (200 g); Polysorbate 80 (about 400 g) actives for administration to a non-human mammal, to microemulsify the base. the granule further comprising a suspending agent if the anthelmintic actives comprise a benzimidazole, a wetting [0559] Stability Trial Post Mix agent if the anthelmintic actives comprise a macrocyclic lac [0560] The stability of the reconstituted abamectin was tone, a wetting agent if the anthelmintic actives comprise a investigated after storage at 20-25° C. for 4 days. It was salicylanilide and a suspending agent if the anthelmintic observed that there was no degradation of the abamectin and actives comprise praziquantel. some degradation of the benzyl alcohol to aldehyde. The 2. A composition of paragraph 1 comprisinglevamisole HCL reconstituted formulation remained suspended with no set and a macrocyclic lactone. tling 3. A composition of paragraph 1 comprisinglevamisole HCL and a benzimidazole. Example 10 4. A composition of paragraph 1 comprisinglevamisole HCL, Single Active Oil-Based Liquid Concentrate a benzimidazole and a macrocyclic lactone. 5. A composition of paragraph 1 comprising a benzimidazole [0561] An oil based liquid concentrate formulation and a macrocyclic lactone. example suitable for water or oil dilution: 6. A composition of paragraph 1 comprising praziquantel and one or more anthelmintic actives selected from one or more imidazothiazoles, one or more benzimidazoles, one or more macrocyclic lactones, one or more imidazothiazoles Ingredient Function w/w 7. A composition of any one of paragraphs 1 to 6 wherein the Abamectin active 10.3%, macrocyclic lactone is selected from avermectin, ivermectin Xanthan Gum suspending agent and abamectin. Thix.cin R protective colloid Aerosil 200 or R 972 rheology modifier 8. A composition of any one of paragraphs 1 to 6 wherein the Benzyl Alcohol benzimidazole is selected from oxfendazole, albendazole or Anti-Microbial Agent 67% fenbendazole. Solvent Particle size modifier If in water based reconstitution 9. A composition of any one or more of paragraphs 1 to 8 Propylene Glycol (optional) Solvent - especially if water is comprising a particulate source of one or more minerals. used for reconstitution) 10. A composition of any one or more of paragraphs 1 to 9 Polysorbate 80 Wetting agent - dispersing agent 22.45%, wherein the granules comprise a suspending agent or rheol as prevents aggregation of drug Colloidal silicon dioxide Antical;ing agent - needed if 0.6%, ogy modifier. xanthan is used as a thickener. 11. A composition of paragraph 10 wherein the suspending If aerosil is used as a thickener agent or rheology modifier is a gum. may not use it again as an 12. A composition of any one or more of paragraphs 1 to 11 anticabing agent. Antifoam Agent (optional) May be an emulsion or free wherein the granules comprise an anionic surfactant or wet flowing powder ting agent. 13. A composition of paragraph 12 wherein the wetting agent is polysorbate 80. [0562] The formulation should be diluted to 12-15 ml/L. 14. A composition of any one of paragraphs 1 to 13 wherein The concentration of the abamectin may be reduced to below the granules comprise a dispersant. 5% w/w if needed by increasing the quantity of benzyl alco 15. A composition of paragraph 14 wherein the dispersant is hol and polysorbate in the above ratio. colloidal silicon dioxide. [0563] Other surfactants (cationic, anionic or non ionics), 16. A composition of any one or more of paragraphs 1 to 15 gums, buffering systems may be added. wherein the granules comprise about 30, 35, 40, 45, 50, 55, [0564] The stability is shown in FIG. 9. 60, 65 or 70% w/w of the anthelmintic actives. [0565] Whilst the liquid concentrate is preferably in a con 17. A composition of any one or more of paragraph 1 to 16 tainer such as a bottle (glass or plastic) in some aspects the wherein the granule comprises less than 3, 2, or 1% w/w concentrate can be in capsules (e.g. hard or soft gelatine— Water. with or without drug or flavor enhancing agents). This is 18. A composition of any one of paragraphs 1 to 17 wherein particularly so if any added beneficial agent is malodorous. If the granules are free of pyrrolidones. for example in that form they can be still diluted prior to 19. A composition of any one of paragraphs 3 to 18 compris administration or be administered as is. ing [0566] Suitable applicators for administering and of the [0568] from about 1 to about 40% w/w benzimidazole, delivery composition are those available from NJPhillips Pty [0569] optionally a suspending agent, and Limited, Instrument Supplies Ltd, Simcrotech Ltd and Pri [0570) from about 1 to about 70% w/w levamisole HCL. US 2012/02385.16 A1 Sep. 20, 2012

20. A composition of paragraph 19 comprising 1, 5, 10, 15, 36. A dosage system of any one of paragraphs 22 to 35 20, 25, 30, 35 or 40% w/w macrocyclic lactone. wherein the granules comprise about 30, 35, 40, 45, 50, 55, 21. A composition of any one of paragraphs 1 to 20 wherein 60, 65 or 70% w/w anthelmintic actives. the granules comprise one or more of 37. A dosage system of any one of paragraphs 22 to 36 [0571] a particulate thixotrope, comprising 2, 3, 4, 5 or six anthelmintics [0572] a particulate rheology modifier 38. A dosage system of any one of paragraphs 22 to 36 [0573] a suspending agent, comprising a benzimidazole, levamisole and a macrocylic lactone. [0574] a wetting agent, and 39. A method of preparing a stable liquid delivery formulation (0575] a anti-colloidal, for treating an animal comprising the steps of [0576] or any combination of any two or more thereof. (a) providing one or more packs of granules, the granules 22. A dosage system for orally dosing animals with an anthel comprising mintic agent, the system comprising (i) a benzimidazole and a suspending agent for the benzimi (a) one or more packs of granules for addition into an aqueous dazole, liquid, the granules comprising (ii) a macrocylic lactone and a wetting agent, (i) a benzimidazole and a suspending agent for the benzimi (iii) a salicylanilide and a wetting agent, dazole, (iv) praziquantel and a wetting agent, (ii) a macrocylic lactone and a wetting agent, (v) an imidazothiazole and one or more anthelmintic agents (iii) a salicylanilide and a wetting agent, selected from benzimidazoles, macrocylic lactones, salicyla (iv) praziquantel and a wetting agent, nilides, and praziquantel, and optionally a suspending agent, (v) an imidazothiazole and one or more anthelmintic agents (b) adding the granules from the one or more packs of gran selected from benzimidazoles, macrocylic lactones, salicyla ules to an aqueous liquid, nilides, and praziquantel, and optionally a suspending agent, (c) adding a suspending agent if (i) the granules do not com (b) a suspending agent if (i) the granules do not comprise a prise a suspending agent, or (ii) additional suspending agent suspending agent, or (ii) additional suspending agent is is required to suspend the anthelmintic actives in the liquid. required to suspend the anthelmintic actives in the liquid. 40. A method of paragraph 39 wherein the granules contain a 23. A dosage system of paragraph 22 further comprising (i) a suspending agent. drenching device and a mixing container, or (ii) a drenching 41. A method of paragraph 39 or 40 wherein a suspending device having a mixing reservoir, when in use the one or more agent is added to the aqueous liquid. packs are used with a mixing container or mixing reservoir 42. A method of any one of paragraphs 39 to 41 wherein the with water or an aqueous carrier or a drenching device for its Suspending agent is a gum. fixed dosage amounts or a calibrated variable dosage amount 43. A method of any one of paragraphs 39 to 42 wherein the to deliver an effective amount of the anthelmintic actives to an suspending agent of (a)(i) is a non-colloidal agent. animal. 44. A method of paragraph 43 wherein the non-colloidal 24. A dosage system of paragraph 22 or 23 wherein the agent is silicon dioxide. granules contain a suspending agent. 45. A method of any one of paragraphs 39 to 44 wherein the 25. A dosage system of paragraph 24 wherein suspending aqueous liquid is water. agent is added to the liquid. 46. A method of any one of paragraphs 39 to 45 wherein the 26. A dosage system of paragraph 22 to 25 wherein the aqueous liquid is an anthelmintic concentrate. suspending agent is a gum. 47. A method of any one of paragraphs 39 to 46 wherein the aqueous liquid contains avermectin and/or Milbemycin in a 27. A dosage system of paragraph 22 to 26 wherein the liquid concentrate form. suspending agent of (a)(i) is a non-colloidal agent. 48. A method of any one of paragraphs 39 to 47 wherein the 28. A dosage system of paragraph 27 wherein the non-colloi liquid delivery formulation is suitable for administration to dal agent is silicon dioxide. animals for up to one month after mixing. 29. A dosage system of any one of paragraphs 22 to 28 49. A method of any one of paragraphs 39 to 48 wherein the wherein the liquid is water. mixing of the granules with the aqueous liquid is performed 30. A dosage system of any one of paragraphs 22 to 28 at, or near, the site of animal administration. wherein the liquid is an anthelmintic concentrate. 50. The method of any one of paragraphs 39 to 49 further 31. A dosage system of any one of paragraphs 22 to 28 comprising a step before the providing step of determining wherein the liquid contains ivermectin, avermectin and/or the treatment needs of one or more animals. milbemycin in a liquid concentrate form. 51. The method of any one of paragraphs 39 to 50 further 32. A dosage system of any one of paragraphs 22 to 31 comprising administering the liquid to one or more animals. wherein the liquid is suitable for administration to animals for 52. A method of any one of paragraphs 39 to 51 wherein the up to one month after mixing. granules comprise 33. A dosage system of any one of paragraphs 22 to 32 [0579) from about 10 to about 40% w/w benzimidazole, wherein the granules comprise and [0577] from about 10 to about 40% w/w benzimidazole, [0580) from about 10 to about 60% w/w levamisole and HCL. [0578] from about 10 to about 60% w/w levamisole 53. A method of any one of paragraphs 39 to 52 wherein the HCL. granules comprise 15, 20, 25, 30, 35 or 40% w/w macrocyclic 34. A dosage system of any one of paragraphs 22 to 33 lactone. wherein the granules comprise 15, 20, 25, 30, 35 or 40% w/w 54. A method of any one of paragraphs 39 to 53 wherein the macrocyclic lactone. granules comprise a particulate source of one or more min 35. A dosage system of any one of paragraphs 22 to 34 erals. wherein the granules comprise a particulate source of one or 55. A method of any one of paragraphs 39 to 54 wherein the more minerals. granules comprises a suspending agent. US 2012/02385.16 A1 Sep. 20, 2012

56. A method of any one of paragraphs 39 to 55 wherein the comprising levamisole HCL, a benzimidazole and a mac granules comprise a gum. rocyclic lactone; or 57. A method of any one of paragraphs 39 to 56 wherein the comprising a benzimidazole and a macrocyclic lactone; or granules comprise an anionic surfactant. comprising praziquantel and one or more anthelmintic 58. A method of any one of paragraphs 17 to 52 wherein the actives selected from one or more imidazothiazoles, one granules comprise about 30, 35, 40, 45, 50, 55, 60, 65 or 70% or more benzimidazoles, one or more macrocyclic lac w/w of the anthelmintic agents. 59. A method of forming an anthelmintic composition com tones, one or more imidazothiazoles; or prising the steps of providing two or more anthelmintic comprising a particulate source of one or more minerals. actives selected from one or more imidazothiazoles, 3. A composition of claim 1, wherein the macrocyclic one or more benzimidazoles, one or more macrocyclic lac lactone is selected from the group consisting of avermectin, tones, and praziquantel, ivermectin and abamectin; or providing a suspending agentifthe anthelmintic actives com wherein the benzimidazole is selected from the group con prise a macrocyclic lactone, providing a wetting agent if the sisting of oxfendazole, albendazole and fenbendazole; anthelmintic actives comprises a benzimidazole, mixing the Or macrocylic lactone with the suspending agent if a macrocylic wherein the granule(s) comprises about 30, 35, 40, 45, 50, lactone is present, 55, 60, 65 or 70% w/w of the anthelmintic actives; or mixing the benzimidazole with the wetting agent if a benz wherein the granule(s) comprises less than 3, 2, or 1% w/w imidazole is present, combining the anthelmintic actives, and water; or granulating the anthelmintic actives. wherein the granule(s) are free of pyrrolidones; or 60. A method of paragraph 59 wherein a stabilising agent is wherein the granule(s) comprises one or more of combined with the anthelmintic actives prior to granulation. a particulate thixotrope, 61. A method of paragraph 59 wherein the stabilising agentis a gum. a particulate rheology modifier 62. A method of any one of paragraphs 59 to 61 wherein the a suspending agent, granules further comprise a particulate source of one or more a wetting agent, and minerals. a anti-colloidal, 63. A method of any one of paragraphs 59 to 62 wherein the or any combination of any two or more thereof. granules comprise a suspending agent or rheology modifier. 4. A composition of claim 1 wherein the granule(s) com 64. A method of paragraph 63 wherein the suspending agent prises a suspending agent or rheology modifier; or or rheology modifier is a gum. wherein the granule(s) comprises an anionic surfactant or 65. A method of any one of paragraphs 59 to 64 wherein the wetting agent; or granules comprise an anionic surfactant or wetting agent. wherein the granule(s) comprises a dispersant. 66. A method of paragraph 65 wherein the wetting agent is polysorbate 80. 5. A composition of claim 4 wherein the suspending agent 67. A method of any one of paragraphs 59 to 66 wherein the or rheology modifier is a gum; or granules comprise a dispersant. wherein the wetting agent is polysorbate 80; or 68. A method of paragraph 67 wherein the dispersant is col wherein the dispersant is colloidal silicon dioxide. loidal silicon dioxide. 6. A composition of claim 1 comprising 69. A method of any one of paragraphs 59 to 68 wherein the from about 1 to about 40% w/w benzimidazole, granules comprise about 30, 35, 40, 45, 50, 55, 60, 65 or 70% optionally a suspending agent, and w/w of the anthelmintic actives. from about 1 to about 70% w/w levamisole HCL. [0581] Having thus described in detail preferred embodi 7. A composition of claim 6 comprising 1, 5, 10, 15, 20, 25, ments of the present invention, it is to be understood that the 30, 35 or 40% w/w macrocyclic lactone. invention defined by the above paragraphs is not to be limited 8. A dosage system for orally dosing animals with an to particular details set forth in the above description as many anthelmintic agent, the system comprising apparent variations thereof are possible without departing (a) one or more packs of granules for addition into an from the spirit or scope of the present invention. aqueous liquid, the granules comprising What is claimed is: (i) a benzimidazole and a suspending agent for the ben 1. An anthelmintic composition in the form of a stable zimidazole, granule(s) comprising two or more anthelmintic actives (ii) a macrocylic lactone and a wetting agent, selected from one or more imidazothiazoles, one or more (iii) a salicylanilide and a wetting agent, benzimidazoles, one or more macrocyclic lactones, one or (iv) praziquantel and a wetting agent, more salicylanilides, praziquantel, the stable granule being (v) an imidazothiazole and one or more anthelmintic readily dispersible in water to provide a homogenous mixture agents selected from benzimidazoles, macrocylic lac of the anthelmintic actives for administration to a non-human tones, salicylanilides, and praziquantel, and option mammal, ally a suspending agent, the granule further comprising a suspending agent if the (b) a suspending agentif (i) the granules do not comprise a anthelmintic actives comprise a benzimidazole, a wet suspending agent, or (ii) additional suspending agent is ting agent if the anthelmintic actives comprise a macro required to suspend the anthelmintic actives in the liq cyclic lactone, a wetting agentifthe anthelmintic actives uid. comprise a salicylanilide and a suspending agent if the 9. A dosage system of claim 8 further comprising (i) a anthelmintic actives comprise praziquantel. drenching device and a mixing container, or (ii) a drenching 2. A composition of claim 1 comprising levamisole HCL device having a mixing reservoir, when in use the one or more and a macrocyclic lactone; or packs are used with a mixing container or mixing reservoir comprising levamisole HCL and a benzimidazole; or with water or an aqueous carrier or a drenching device for its US 2012/02385.16 A1 Sep. 20, 2012 20 fixed dosage amounts or a calibrated variable dosage amount wherein the liquid delivery formulation is suitable for to deliver an effective amount of the anthelmintic actives to an administration to animals for up to one month after animal. mixing; or 10. A dosage system of claim 8, wherein the granules wherein the mixing of the granules with the aqueous liquid contain a suspending agent; or is performed at, or near, the site of animal administra wherein the suspending agent is added to the liquid; or tion; or wherein the suspending agent is a gum; or further comprising a step before the providing step of determining the treatment needs ofc.ne or more animals; wherein the liquid is water; or Or wherein the liquid is an anthelmintic concentrate; or further comprising administering the liquid to one or more wherein the liquid contains ivermectin, avermectin and/or animals; or milbemycin in a liquid concentrate form; or wherein the granules comprise wherein the liquid is suitable for administration to animals from about 10 to about 40% w/w benzimidazole, and for up to one month after mixing; or from about 10 to about 60% w/w levamisole HCL; or wherein the granules comprise wherein the granules comprise 15, 20, 25, 30, 35 or 40% from about 10 to about 40% w/w benzimidazole, and w/w macrocyclic lactone; or from about 10 to about 60% w/w levamisole HCL; or wherein the granules comprise a particulate source of one wherein the granules comprise 15, 20, 25, 30, 35 or 40% or more minerals; or w/w macrocyclic lactone; or wherein the granules comprises a suspending agent; or wherein the granules comprise a gum; or wherein the granules comprise a particulate source of one wherein the granules comprise an anionic surfactant; or or more minerals; or wherein the granules comprise about 30, 35, 40, 45, 50, 55, wherein the granules comprise about 30, 35, 40, 45, 50, 55, 60, 65 or 70% w/w of the anthelmintic agents. 60, 65 or 70% w/w anthelmintic actives; or 15. A method of claim 13 wherein the suspending agent of comprising 2, 3, 4, 5 or six anthelmintics; or (a)(i) is a non-colloidal agent. comprising a benzimidazole, levamisole and a macrocylic 16. A method of claim 15 wherein the non-colloidal agent lactone. is silicon dioxide. 11. A dosage system of claim 8 wherein the suspending 17. A method of forming an anthelmintic composition agent of (a)(i) is a non-colloidal agent. comprising the steps of: 12. A dosage system of claim 11 wherein the non-colloidal providing two or more anthelmintic actives selected from agent is silicon dioxide. one or more imidazothiazoles, one or more benzimida 13. A method of preparing a stable liquid delivery formu zoles, one or more macrocyclic lactones, and praziqu lation for treating an animal comprising the steps of antel, providing a suspending agent if the anthelmintic (a) providing one or more packs of granules, the granules actives comprise a macrocyclic lactone, comprising providing a wetting agent if the anthelmintic actives com (i) a benzimidazole and a suspending agent for the ben prises a benzimidazole, mixing the macrocylic lactone zimidazole, with the suspending agent if a macrocylic lactone is (ii) a macrocylic lactone and a wetting agent, present, (iii) a salicylanilide and a wetting agent, mixing the benzimidazole with the wetting agent if a (iv) praziquantel and a wetting agent, benzimidazole is present, combining the anthelmintic (v) an imidazothiazole and one or more anthelmintic actives, and agents selected from benzimidazoles, macrocylic lac granulating the anthelmintic actives. tones, salicylanilides, and praziquantel, and option 18. A method of claim 17, wherein a stabilizing agent is ally a suspending agent, combined with the anthelmintic actives prior to granulation; Or (b) adding the granules from the one or more packs of wherein the stabilizing agent is a gum; or granules to an aqueous liquid, wherein the granules further comprise a particulate source (c) adding a suspending agent if (i) the granules do not of one or more minerals; or comprise a suspending agent, or (ii) additional suspend wherein the granules comprise about 30, 35, 40, 45, 50, 55, ing agent is required to suspend the anthelmintic actives 60, 65 or 70% w/w of the anthelmintic actives. in the liquid. 19. A method of claim 17 wherein the granules comprise a 14. A method of claim 13, wherein the granules contain a suspending agent or rheology modifier; or suspending agent; or wherein the granules comprise an anionic surfactant or wherein a suspending agent is added to the aqueous liquid; wetting agent; or Or wherein the granules comprise a dispersant. wherein the suspending agent is a gum; or 20. A method of claim 19 wherein the suspending agent or wherein the aqueous liquid is water; or rheology modifier is a gum; or wherein the aqueous liquid is an anthelmintic concentrate; wherein the wetting agent is polysorbate 80; or Or wherein the dispersant is colloidal silicon dioxide. wherein the aqueous liquid contains avermectin and/or milbemycin in a liquid concentrate form; or sk sk sk sk sk