AU2010201490A1

AU2010201490A1 - Anthelmintic formulation

Info

Publication number: AU2010201490A1
Application number: AU2010201490A
Authority: AU
Inventors: Kai Kin Lau
Original assignee: Jurox Pty Ltd
Current assignee: Zoetis Services LLC
Priority date: 2009-04-15
Filing date: 2010-04-14
Publication date: 2010-11-04
Anticipated expiration: 2030-04-14
Also published as: AU2010201490B2; AU2010100349B4; AU2010201490C1; AU2010100349A4; NZ584629A

Description

AUSTRALIA FB RICE & CO Patent and Trade Mark Attorneys Patents Act 1990 Jurox Pty Ltd Anthelmintic formulation 2 Anthelmintic formulation The disclosure of the present application relates to pesticidal compositions, their preparations and use. More particularly the invention relates to liquid anthelmintic compositions comprising multiple actives. 5 Parasites in farm animals are a widespread problem throughout Australia and New Zealand. Scientists are exploring many avenues in trying to develop new options for graziers to deal with parasites and the escalating dilemma of resistance in animals to drenches. 10 Drench is the common name for an anthelmintic, a chemical specifically designed to kill parasites such as worms. Drenches can be "broad spectrum" which means they are suitable for treating a wide range of internal parasites or can target multiple stages of the parasites lifecycle, or "narrow spectrum", which means that they treat a restricted 15 range of internal parasites. "Combination drenches" are mixes of two or more of these drench classes. Combinations of two or even three broad spectrum drenches can be used to control parasites. Examples of broad spectrum drenches that are available include benzimidazole 20 drenches or "white" drenches, and levamisole or "clear" drenches. Macrocyclic lactones drenches are the newest group of broad spectrum drenches. Combination drenches are generally broad-spectrum in activity. Examples of combinations include: 25 imidazothiazole plus benzimidazole; salicylanilide plus benzimidazole; macrocyclic lactone plus benzimidazole; and macrocyclic lactone plus benzimidazole plus imidazothiazole 30 Drenches are usually administered orally using a drenching gun. When drenching it has been found to be important to shake the drench container first as most combination drenches settle out, meaning that the active ingredients settle into various phases in the container in which they are stored. It is important that the animals 3 to which the drench is administered receive sufficient amounts of each of the active ingredients, otherwise there is an increased chance that the animals to which the drench is administered may develop resistance to one or more of the active ingredients. 5 Triton, registered trade mark of Merial (hereinafter Triton), is one example of a triple combination drench. In work leading to the development of Triton (as described in PCT/NZOO/00087) it was the intention of the inventors to address problems relating to stability and degradation, flocculation and curdling of the active ingredients. In one aspect of the composition described in PCT/NZOO/00087, the composition is a 10 partitioned composition comprising, in a first liquid phase (preferably organic) a first active ingredient and in a second liquid phase (preferably aqueous at acid pH) a second active ingredient, said active ingredient in said first liquid phase being unstable chemically in the conditions of said second liquid phase. The third active ingredient is suspended preferably in the aqueous phase. More specifically, according to Example 15 15 and the claims of PCT/NZ0O/00087, a macrocyclic lactone is carried in the organic liquid phase, levamisole is carried in the aqueous phase and albendazole is particulate and is at least in part in the aqueous phase, with the levamisole. The organic liquid carrier is preferably an oil, and more preferably includes a co-solvent. 20 According to PCT/NZOO/00087 the presence of an emulsifying agent and/or anti flocculant agent was found to be necessary to ensure stability of the two phases with the first phase with its first active ingredient as an emulsion within said second phase. The Triton formulation and the formulation described in PCT/NZOO/00084 is an 25 emulsion formulation, more particularly a suspo-emulsion. Emulsions consist of two immiscible phases, being an oil phase and an aqueous phase, which are generally considered to be thermodynamically unstable. After time or at elevated temperatures an emulsion becomes unstable and separates into two phases. As soon as phase separation occurs, the active which is protected in the oil phase of the emulsion will 30 start to contact with the aqueous phase and the active contained in the aqueous phase will start to contact with the oil phase. The degradation will be enhanced further once the emulsion is broken down. A known technique in slowing an emulsion from breaking down is the use of a viscosity modifier to increase the viscosity of the formulation. Although this will slow down the separation of the two phases, it also 35 gives the final formulation an undesirably high viscosity that makes the formulation extremely difficult to push through the drench gun at low temperature. A high 4 viscosity product also has the disadvantage of being difficult to redisperse. Since an emulsion will separate into phases with time, the user is required to "shake up" the product well before use to ensure that the animal receives the adequate dose of the active. 5 Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the 10 field relevant to the present invention as it existed before the priority date of each claim of this application. In work leading to the present disclosure, the inventors have surprisingly found that an effective anthelmintic composition comprising three active ingredients may be prepared 15 where the composition comprises a micellar solution. Accordingly the present disclosure relates to anthelmintic compositions comprising three active ingredients. Preferably the active ingredients have different spectrums of activity with respect to parasites and in particular nematodes. Examples of parasite 20 species for which the composition has activity are provided in the following table: Parasite Species Species Common Name Haemonchus contortus Barber's pole worm Haemonchus placei Large stomach worm Ostertagia circumcincta Small brown stomach worm Trichostrongylus axei Stomach hair worm Trichostrongylus colubriformis Trichostrongylus vitrinus Black scour worm Cooperia curticel Cooperia oncophera Small intestinal worm Nematodirus spathiger Nematodirusfilicollis Thin-necked intestinal worm Chabertia ovina Large mouthed bowel worm 5 Oesophagostomum columbianum Nodule worm Oesophagostomum venulosum Large bowel worm Trichuris ovis Whip worm Strongyloides papillosus Intestinal threadworm Bunostomum spp Hookworm Oestrus ovis Dictyocaulus viviparus Large lungworm Fasciola hepatica Monezia As used herein the term "anthelmintic" and derivatives thereof refer to a medication capable of expelling or destroying parasitic worms. Preferably the composition is particularly useful for administration to a non-human animal. The compositions 5 disclosed herein are effective when used in a variety of animals. For example, sheep, goats, ruminants (including cattle) and camelids. Throughout this specification, and unless it is stated to the contrary, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers 10 or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Accordingly in a first aspect the present disclosure relates to an anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective 15 amount of at least one compound selected from each of the following groups: macrocyclic lactones, benzimidazoles, and imidazothiazoles; the composition further comprising a therapeutically acceptable carrier and at least one surfactant. The composition does not comprise a separate organic liquid phase. In this way, the formulation now described is advantageous since the formulation is a single phase and 20 the actives can be protected from interacting. For example, the macrocyclic lactone is protected from interacting or reacting with the imidazothiazole by the formation of the micellar solution. The formulation of the present invention is more stable and is less prone to separation. This may help to provide a longer shelf life for the product. Furthermore, in comparison to prior art emulsion based compositions, this increased 25 stability means that the less thickening agent is required to maintain an adequate shelf 6 life for the product. This leads to a decrease in the viscosity of the formulation which has advantages in both manufacture and administration, especially administration at low temperature which can be particularly difficult with viscous emulsion based formulations. 5 In a second aspect, the present disclosure relates to a method of treating helminth or suspected helminth infections in an animal comprising administering an anthelmintically effective amount of a composition, which is a micellar solution and comprises at least one compound selected from each of the following groups: 10 macrocyclic lactones, benzimidazoles, and imidazothiazoles together with a therapeutically acceptable carrier and at least one surfactant, to an infected animal or an animal suspected to be infected with at least one helminth. As used herein the term "micellar solution" refers to a thermodynamically stable single 15 phase system. The therapeutically active compounds disclosed herein are preferably incorporated into formulations in the range of concentrations as follows (g/L): macrocyclic lactones: 0.1-20.0 g/L, preferably 0.5-1.5 g/L 20 benzimidazoles: 1-100 g/L, preferably 18-30 g/L imidazothiazoles: 1-100 g/L, preferably 30-50 g/L. The anthelmintic composition disclosed herein can be formulated and administered in a number of ways, including for example as a drench, a pour-on transdermal formulation, 25 a slow release bolus or an injectable formulation. Preferably the composition is a drench. More preferably the composition is an oral drench. Preferably the amount of surfactant present is in the range of less than 200 g/L, preferably about 5 to less than about 200 g/L, preferably in the range of about 120 30 165 g/L. Examples of suitable surfactants include, for example, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, and ethoxylated caster oil. Teric 380 (Teric is a registered trademark of Huntsman Corporation Australia Pty Ltd) is an example of an alcohol ethoxylate surfactant. Preferably the surfactant is polysorbate 80. Polysorbate 80 is a nonionic surfactant or emulsifier derived from polyethoxylated sorbitan and 35 oleic acid.

7 Most surprisingly, the inventors have found that a micellar solution can be formulated comprising at least one each of a macrocyclic lactone, benzimidazole, and imidazothiazole even when the concentration of surfactant is less than 200g/L. This is surprising and advantageous since the novel composition has an improved viscosity and 5 it is easy to keep and administer the composition to an animal in need. Preferably the viscosity is improved even at lower temperatures. An advantage for the manufacturer of having less surfactant is a decrease in cost of the ingredient. Therefore, the composition now disclosed is a single phase micellar solution and it 10 comprises lower amounts of surfactant than would be expected in a formulation comprising the three actives described here. The composition described here preferably comprises less than 200g/L surfactant. The composition has a low viscosity which makes the product easy to administrate to 15 the animal using a drench gun. The composition is not greatly affected by temperature. This micellar solution based formulation provides a product wherein the actives can be resuspended readily and remain in suspension for a long time during use without it being necessary to further shake the formulation. 20 Preferably the viscosity of the composition is in the range of less than about 300 cps, less than about 250 cps, less than about 200 cps, less than about 150 cps, about 50-300 cps, about 50-250 cps, about 50-200 cps, about 100-200 eps, about 50-150 cps, or about 100-150 cps, as determined by a Brookfield viscometer using a spindle 3 at a speed of 60 rpm at 25 degrees centigrade. 25 The micellar solution is thermodynamically stable and the macrocyclic lactone inside the micelles is well protected from reacting with other actives in the formulation. Stability results are provided in the Examples. 30 Preferably the therapeutic composition can comprise multiple combinations of actives to expand the spectrum of available treatments.

8 Preferred examples of each of the active ingredients are as follows: Macrocyclic lactone Benzimidazole Imidazothiazole abamectin albendazole levamisole ivermectin fenbendazole pyrantel pamoate doramectin thiabendazole butamisole moxidectin oxfenbendazole milbemycin febantel avermectin mebendazole parbendazole flubendazole oxibendazole I carbendazole In one preferred embodiment the macrocyclic lactone compound is selected from the group comprising abamectin, ivermectin, doramectin, moxidectin, milbemycin and 5 avermectin. In one example the macrocyclic lactone is abamectin. Abamectin is understood to be a mixture of avermectins. Preferably the macrocyclic lactone is present in an amount in a range of about 0.1-20.0 g/L, preferably 0.3-5 g/L, preferably 0.5-1.5 g/L, preferably about I g/L. In one 10 example the macrocyclic lactone is present in an amount of about Ig/L. In another preferred embodiment the benzimidazole is selected from the group comprising albendazole, fenbendazole, thiabendazole, oxfenbendazole, fenbantel, mebendazole, parbendazole, flubendazole, oxibendazole and carbendazole. 15 Preferably the benzimidazole is present in an amount in the range of about 1-100 g/L, preferably 10-50 g/L, preferably 18-30 g/L, preferably about 25 g/L. In one example the benzimidazole is present in an amount of about 25g/L. 20 In a preferred embodiment of the composition the benzimidazole is micronized. Preferably the particle size of the micronized material is substantially less than 10 microns, more preferably 80%, 90% or 100% of the micronized material is less than 10 9 microns. Micronization of the benzimidazole improves the bioavailability and suspendability of this ingredient. In a preferred embodiment of the invention the benzimidazole is albendazole. 5 Preferably albendazole is micronized. It is preferred that substantially all of the albendazole is micronized to less than 10 microns. Most preferably 80%, 90% or 100% albendazole is micronized to less than 10 microns. Generally, micronization will result in most particles being in the range of 5-10 microns. 10 In another preferred embodiment the imidazothiazole is selected from the group comprising levamisole, pyrantel pamoate and butamisole. Preferably the imidazothiazole is levamisole. Preferably the levamisole is present in 15 the form of a water soluble salt, more preferably the levamisole is present as a hydrochloride salt, that is levamisole hydrochloride. Preferably the imidazothiazole is present in an amount in the range of about 1-100 g/L, preferably 20-60 g/L preferably 30-50 g/L preferably about 40 g/L. In one example the 20 imidazothiazole is present in an amount of about 40g/L. Most preferably the composition comprises levamisole, albendazole and avermectin. The therapeutically active compounds used in the invention are preferably incorporated 25 into formulations in the range of concentrations as follows (g/L): avermectin: 0.1-20.0 g/L, preferably 0.3-5 g/L, preferably 0.5-1.5 g/L, preferably about 1 g/L; albendazole: 1-100 g/L, preferably 10-50 g/L, preferably 18-30 g/L, preferably about 25 g/L; 30 levamisole: 1-100 g/L, preferably 20-60 g/L preferably 30-50 g/L preferably about 40 g/L. According to a preferred embodiment of the present invention, avermectin is protected from interacting or reacting with levamisole by forming a stable micellar solution. A 35 stable micellar solution is formed by the presence of an amount of surfactant that is 10 suitable to form a micellar solution. Preferably the amount of surfactant is less than 200g/L. In a preferred embodiment the composition comprises surfactant at about 5 to less than 5 about 200 g/L, preferably, about 100-190g/L, preferably about 110-180g/L, preferably about 120-170 g/L, most preferably about 120g/L, 130g/L, 140g/L, 150g/L, 160g/L, or 170g/L. Most preferably the surfactant is polysorbate 80. 10 In the present invention the composition further comprises a solvent system, and one or more anti-caking agents. In a preferred embodiment of the composition, the macrocyclic lactone is in a solvent 15 system. The solvent system is preferably miscible with water to form a single phase. In one embodiment the solvent system includes one or more solvents selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol. 20 In one preferred embodiment the solvent system comprises an amount of benzyl alcohol. In another preferred embodiment the solvent system comprises an amount of propylene glycol. In yet another embodiment, the solvent system comprises amounts of benzyl alcohol (about 1 - 40 g/L) and propylene glycol ( about 5 - 400 g/L). 25 In one embodiment the solvent systems comprises: benzyl alcohol: 1-50 g/L, preferably 1-40 g/L, preferably 20-40 g/L; propylene glycol: 5-250 g/L, preferably 175-225 g/L. Preferably the composition comprises an anti-caking agent. Preferably the anti-caking 30 agent is present in an amount effective to prevent the micronized material from agglomeration or forming large particles or forming a hard "cake", particularly on the bottom surface of a container. In a preferred embodiment of the invention the anti caking agent is a kaolin and / or colloidal silicon dioxide. A variety of anti-caking agents are known. 35 1 Preferably the composition comprises a buffering system. A variety of buffer systems may be used. Preferably the pH of the composition is about 5.0 - 5.5. Examples of suitable buffering systems for the present invention include for example 5 phosphate buffers based on combinations of varying amounts of monobasic and dibasic sodium phosphate to achieve the desired pH. One example of a suitable phosphate buffer is monosodium phosphate anhydrous. In one example of the invention the composition comprises about 15-20g/L 10 monosodium phosphate anhydrous, more preferably about 18g/L monosodium phosphate anhydrous. Preferably the composition comprises an antifoaming agent. An antifoaming agent is used to minimise foaming during manufacturing and use of the composition. In one 15 embodiment the antifoaming agent is a silicone oil, for example a hydrophobic silicone oil antifoaming agent. For example, Antifoam AF. A preferred range of the antifoaming agent is about 0.01 - 1.0 g/L. Preferably the composition comprises a dispersing or suspending agent. Preferably the 20 dispersing or suspending agents are effective to suspend the benzimidazole. Preferably the dispersing or suspending agents can be selected from, for example, the group comprising glyceryl palmitostearate, bentonite, colloidal silica, xanthan gum and polymeric pyrrolidones. In a preferred example the dispersing/suspending agent is a colloidal silica. 25 The dispersing or suspending agent can also be used as viscosity agents. Preferred viscosity agents can be selected from, for example, colloidal silica, xanthan gum and polymeric pyrrolidones. 30 In a preferred embodiment of the composition described herein, the dispersing or suspending agent(s) / viscosity agent(s) are present in an amount of about 10 - 50 g/L, preferably about 15 - 45 g/L. In one example the composition comprises about 18, 20, 25, 30, 35, 40 or 45g/L dispersing or suspending agent. Examples of dispersing agents include, for example, Terasperse 2500 (polymeric dispersant) or Aerosil 200 35 (amorphous fumed silica, Aerosil is a registered trade mark of Evonik Industries).

12 Examples of viscosity agents include, for example, colloidal silica, xanthan gum and polymeric pyrrolidones. Methods of formulation 5 In another aspect, the present invention provides methods for formulating a product. In work leading to the formulation of the product, the inventors found that a superior product is formulated in a micellar solution. Furthermore, the inventors found that a superior product is formulated with lower amounts of surfactant than would be expected for this type of formulation. Furthermore, the inventors found that a superior 10 product is formulated if the benzimidazole is micronized. To ensure proper formation of a stable micelle it is most preferred that the macrocyclic lactone is first mixed with and dissolved in the surfactant and water miscible solvent. Preferably, water is then added slowly to the surfactant-macrocyclic lactone solution. 15 The inventors found that this method minimises an instant dilution effect of water which can cause instability of micelles. The inventors were able to keep the micelles stable even using smaller amounts of surfactant than would be expected. Benzimidazole will then be added to the micellar solution in small portions to minimise agglomeration to form large particles the pH of the formulation is preferably adjusted 20 before adding an imidazothiazole to ensure that it is buffered to remain as an acidic water soluble salt. In order to better understand the nature of the compositions described herein examples will now be described as follows: 25 Example 1 FORMULATION: NAMES OF SUBSTANCES QUANTITY (g/L) Monosodium Phosphate anhydrous 18 Antifoam AF 1 g Benzyl Alcohol 30 Polysorbate 80 150g Propylene Glycol 200 g Disodium Phosphate anhydrous 2 g Abamectin 1 Albendazole (micronized) 25 g 13 Aerosil 200 18 g Levamisole Hydrochloride 40 g Water q.s. to 1 L Example 2 NAMES OF SUBSTANCES QUANTITY (g/L Monosodium Phosphate anhydrous 18 g Antifoam AF 1 g Benzyl Alcohol 30g Polysorbate 80 120g Propylene Glycol 300g Disodium Phosphate anhydrous 2 g Abamectin I g Albendazole (micronized) 25 g Aerosil 200 40 g Levamisole Hydrochloride 40 g Water g.s. to 1 L 5 Method Examples I and 2 were prepared as follows: 1 . Dissolve avermectin in benzyl alcohol and propylene glycol. 2. Add polysorbate 80 to step 1. 3. Add water to the solution ftrm step 2 and mix until homogeneous. 10 4. Dissolve phosphate buffer salts in the solution from step 3. 5. Add albendazole and levamnisole hydrochloride. Mix until fully dispersed. 6. Add Aerosil to the suspension and mix until fully dispersed. 15 Trial I To determine the efficacy against adult liver fluke in sheep using RDO 190 (example 1). Twelve Merino sheep were sourced from the fluke infested mob available at the research station. These sheep were selected on the basis of similar body weights, good 20 health status and active fluke infection as determined by faecal egg count. Each animal had a uniquely numbered ear tag. A FEC was conducted for group allocation on Day 7. Sheep were weighed on Day 0 and the weights recorded. Six untreated control sheep were used to evaluate treatment efficacy. The other six sheep were oral dosed with example I at 0.2 mL/kg body weight. Individual faecal samples were collected on Days 25 7 and 14 and individual faecal egg counts were performed. Treatment efficacy was 14 determined by comparison of group arithmetic mean total fluke counts and liver fluke faecal egg counts with the untreated control group. The results showed good activity against resident adult fluke. At Day 14 post-treatment, the untreated control sheep had an arithmetic mean fluke count of 49.8 fluke. Sheep treated with example I had a post 5 treatment arithmetic mean total fluke count of 3.2 fluke, which corresponds to a 94 % reduction in fluke number. Average fluke egg counts at Day 14 following treatment were 2.3 eggs per gram (epg) in treated sheep and 90.2 epg in the controls, representing a reduction of 97.4 % due to treatment. 10 Trial 2 To determine the efficacy of RD0190 against intestinal parasites of sheep and to compare this to the efficacy of currently registered drench products, in the same population of parasites. 15 Yearling merino sheep were sourced and used in the trial. One group was used as control. One group was administered with example 1, seven groups were administrated currently registered sheep drench products. Eleven days after treatment, faecal samples were collected from ten animals in each group and submitted for faecal egg counting and larval differential cultures. The parasite burden of enrolled sheep was 20 predominately Haemonchus Contortus and the untreated control group mean faecal egg count was high enough to make accurate interpretations of anthelmintic resistance in the population. RD0190 was effective in this study, with a faecal egg count reduction of 98.4%. However, abamectin (53.2%), albendazole (88.2%), closantel (81.1%), levamisole (91.7%) and naphthalophos (88.6%) were ineffective in the study based on 25 the efficacy definition of a >95 % egg reduction. The stability of example 1 was evaluated at 30 "C with the following results: Initial 6 months Albendazole 25.0 g/L 24.8 g/L Levamisole HCl 41.1 g/L 39.2 g/L Abamectin 1.0 g/L 1.0 g/L 30 In addition, it was noted that after centrifugation of a sample of Example 1 at 4000 g for 1 hour, the sample did not separate but remained as a single phase.

15 It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the scope of the invention as broadly described. The present 5 embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. An anthelmintic composition in the form of a micellar solution, comprising an 5 anthelmintically effective amount of at least one compound selected from each of the following groups: macrocyclic lactones, benzimidazoles, and imidazothiazoles; the composition further comprising a therapeutically acceptable carrier and at least one surfactant. 10

2. The composition of claim 1 wherein the anthelmintically active compounds are present in the range of concentrations as follows (g/L): macrocyclic lactones: 0.1-20.0 g/L; benzimidazoles: 1-100 g/L; 15 imidazothiazoles: 1-100 g/L.

3. The composition of claim I wherein the anthelmintically active compounds are present in the range of concentrations as follows (g/L): 20 macrocyclic lactones: 0.5-1.5 g/L; benzimidazoles: 18-30 g/L; imidazothiazoles: 30-50 g/L.

4. The composition of any preceding claim wherein the composition is formulated 25 for administration as a drench, a pour-on transdermal formulation, a slow release bolus or an injectable formulation.

5. The composition of any preceding claim wherein the composition is a drench. 30

6. The composition of any preceding claim wherein the composition is an oral drench.

7. The composition of any preceding claim wherein the amount of surfactant is present in the range of less than about 200 g/l, about 5 to about 200 g/L, about 100 to 35 about 190g/L, about 110 to about 180g/L, about 120 to about 170 g/L, or about 120 to 17 about 165 g/L, about 120g/L, about 130g/L, about 140g/L, about 150g/L, about 160g/L, or about 170g/L.

8. The composition of any preceding claim wherein the surfactant is selected from 5 the group consisting of polyoxyethylene sorbitan fatty acid esters, sorbitan esters, alcohol ethoxylate surfactants, and ethoxylated caster oil.

9. The composition of any preceding claim wherein the surfactant is selected from Teric 380 or Polysorbate 80. 10

10. The composition of any preceding claim wherein the viscosity of the composition is in the range of less than about 300 cps, less than about 250 cps, less than about 200 cps, less than about 150 cps, about 50-300 cps, about 50-250 cps, about 50 200 cps, about 100-200 cps, about 50-150 cps, or about 100-150 cps, as determined by 15 a Brookfield viscometer using a spindle 3 at a speed of 60 rpm at 25 degrees centigrade.

11. The composition of any preceding claim wherein the micellar solution is a reverse micellar solution. 20

12. The composition of any preceding claim wherein the macrocyclic lactone is protected within the micelles.

13. The composition of any preceding claim wherein the macrocyclic lactone is 25 selected from one or more of the group consisting of: abamectin, ivermectin, doramectin, moxidectin, milbemycin and/or avermectin.

14. The composition of any preceding claim wherein the benzimidazole is selected from one or more of the group consisting of: albendazole, fenbendazole, thiabendazole, 30 oxfenbendazole, febantel, mebendazole, parbendazole, flubendazole, oxibendazole and/or carbendazole.

15. The composition of any preceding claim wherein the imidazothiazole is selected from one or more of the group consisting of: levamisole, pyrantel pamoate and/or 35 butamisole. 18

16. The composition of any preceding claim wherein the macrocyclic lactone is an avermectin.

17. The composition of any preceding claim wherein the macrocyclic lactone is 5 abamectin.

18. The composition of any preceding claim wherein the macrocyclic lactone is present in an amount in a range of about 0.1-20.0 g/L, about 0.3-5 g/L, about 0.5-1.5 g/L, or about I g/L. 10

19. The composition of any preceding claim wherein the benzimidazole is albendazole.

20. The composition of any preceding claim wherein the benzimidazole is present in 15 an amount in the range of about 1-100 g/L, about 10-50 g/L, about 18-30 g/L, or about 25 g/L.

21. The composition of any preceding claim wherein the benzimidazole is micronized. 20

22. The composition of claim 21 wherein about 80%, about 90% or about 100% of the micronized material is less than 10 microns.

23. The composition of claim 21 wherein about 80%, about 90% or about 100% of 25 the particles are in the range of 5-10 micron.

24. The composition of any preceding claim wherein the benzimidazole is suspended in the composition. 30

25. The composition of any preceding claim wherein the imidazothiazole is levamisole.

26. The composition of claim 25 wherein the levamisole is present in the form of a water soluble salt. 35 19

27. The composition of claim 25 wherein the levamisole is levamisole hydrochloride.

28. The composition of any preceding claim wherein the imidazothiazole is present 5 in an amount in the range of about 1-100 g/L, about 20-60 g/L about 30-50 g/L or about 40 g/L.

29. The composition of any preceding claim wherein the composition comprises levamisole, albendazole and avermectin. 10

30. The composition of any preceding claim wherein the composition comprises levamisole, albendazole and abamectin.

31. The composition of any preceding claim wherein the composition further 15 comprises a solvent system.

32. The composition of claim 31 wherein the macrocyclic lactone is in a solvent system. 20

33. The composition of claim 31 or 32 wherein the solvent system includes one or more solvents selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol.

34. The composition of any one of claims 31 to 33 wherein the solvent system 25 includes: benzyl alcohol: 1-40 g/L or 20-40 g/L; and propylene glycol: 5-250 g/L or 175-225 g/L.

35. The composition of any preceding claim wherein the composition further 30 comprises one or more anti-caking agents.

36. The composition of claim 35 wherein the anti-caking agent is a kaolin and/or colloidal silicon dioxide. 35

37. The composition of any preceding claim wherein the composition further comprises a buffering system. 20

38. The composition of claim 37 wherein the buffering system is a phosphate buffer based on combinations of varying amounts of monobasic and dibasic sodium phosphate. 5

39. The composition of any preceding claim wherein the composition comprises about 15-20g/L, or about 18g/L monosodium phosphate anhydrous.

40. The composition of any preceding claim wherein the pH of the composition is 10 about 5.0 - 5.5.

41. The composition of any preceding claim wherein the composition further comprises an antifoaming agent. 15

42. The composition of claim 41 wherein the antifoaming agent is a silicone oil, for example, Antifoam AF.

43. The composition of claim 41 wherein the antifoaming agent is present in an amount of about 0.01 - 1.0 g/L. 20

44. The composition of any preceding claim wherein the composition further comprises dispersing or suspending agent(s).

45. The composition of claim 44 wherein the dispersing or suspending agent(s) act 25 as viscosity agents.

46. The composition of claim 44 or claim 45 wherein the dispersing or suspending agent(s) are selected from the group comprising glyceryl palmitostearate, bentonite, colloidal silica, xanthan gum, polymeric pyrrolidones, Terasperse 250, or Aerosil 200. 30

47. The composition of claim 44 or claim 45 wherein the dispersing or suspending agent(s) are selected from the group comprising colloidal silica, xanthan gum, and polymeric pyrrolidones. 35

48. The composition of claim 44 or claim 45 wherein the dispersing/suspending agent is a colloidal silica. 21

49. The composition of any one of claims 44 to 48 wherein the dispersing or suspending agent(s) is present in an amount of about 10 - 50 g/L, about 15 -45 g/L, about 18, about 20, about 25, about 30, about 35, about 40 or about 45g/L. 5

50. A method of treating helminth or suspected helminth infection in an animal comprising administering a composition according to any one of claims 1 to 49 to an infected animal or an animal suspected to be infected with at least one helminth. 10

51. The method of claim 50 wherein the helminth is selected from the group consisting of: Haemonchus contortus (Barber's pole worm); Haemonchus placei (Large stomach worm); Ostertagia circumcincta (Small brown stomach worm); 15 Trichostrongylus axei (Stomach hair worm); Trichostrongylus colubriformis; Trichostrongylus vitrinus (Black scour worm); Cooperia curticel; Cooperia oncophera (Small intestinal worm); 20 Nematodirus spathiger; Nematodirusfilicollis (Thin-necked intestinal worm); Chabertia ovina (Large mouthed bowel worm); Oesophagostomum columbianum (Nodule worm); Oesophagostomum venulosum (Large bowel worm); 25 Trichuris ovis (Whip worm); Strongyloides papillosus (Intestinal threadworm); Bunostomum spp (Hookworm); Oestrus ovis; Dictyocaulus viviparus (Large lungworm); 30 Fasciola hepatica; and/or Monezia.

52. The method of any one of claims 50 to 51 wherein the method is a method of treating helminth or suspected helminth infections in an animal by parasites resistant to 35 at least one of the groups macrocyclic lactones, benzimidazoles, and imidazothiazoles. 22

53. The method of any one of claims 50 to 51 wherein the method is a method of treating helminth or suspected helminth infections in an animal by parasites resistant to at least two of the groups macrocyclic lactones, benzimidazoles, and imidazothiazoles. 5

54. The method of any one of claims 50 to 51 wherein the method is a method of treating helminth or suspected helminth infections in an animal by parasites resistant to all three of the groups macrocyclic lactones, benzimidazoles, and imidazothiazoles.

55. The method of any one of claims 50 to 54 wherein the animal is a non-human 10 animal.

56. The method of any one of claims 50 to 55 wherein the animal is selected from the group consisting of sheep, goats, ruminants (including cattle) and camelids. 15

57. Use of a composition according to any one of claims 1 to 49 in the treatment of helminth or suspected helminth infection in an animal.

58. Use of a composition according to any one of claims 1 to 49 in the manufacture of a medicament for the treatment of helminth or suspected helminth infection in an 20 animal.

59. The use of claim 57 or 58 wherein the helminth is selected from the group consisting of: Haemonchus contortus (Barber's pole worm); 25 Haemonchus placei (Large stomach worm); Ostertagia circumcincta (Small brown stomach worm); Trichostrongylus axei (Stomach hair worm); Trichostrongylus colubriformis; Trichostrongylus vitrinus (Black scour worm); 30 Cooperia curticel; Cooperia oncophera (Small intestinal worm); Nematodirus spathiger; Nematodirusfilicollis (Thin-necked intestinal worm); Chabertia ovina (Large mouthed bowel worm); 35 Oesophagostomum columbianum (Nodule worm); Oesophagostomum venulosum (Large bowel worm); 23 Trichuris ovis (Whip worm); Strongyloides papillosus (Intestinal threadworm); Bunostomum spp (Hookworm); Oestrus ovis; 5 Dictyocaulus viviparus (Large lungworm); Fasciola hepatica; and/or Monezia.

60. The use of any one of claims 57 to 59 wherein the method is a method of 10 treating helminth or suspected helminth infections in an animal by parasites resistant to at least one of the groups macrocyclic lactones, benzimidazoles, and imidazothiazoles.

61. The use of any one of claims 57 to 59 wherein the method is a method of treating helminth or suspected helminth infections in an animal by parasites resistant to 15 at least two of the groups macrocyclic lactones, benzimidazoles, and imidazothiazoles.

62. The use of any one of claims 57 to 59 wherein the method is a method of treating helminth or suspected helminth infections in an animal by parasites resistant to all three of the groups macrocyclic lactones, benzimidazoles, and imidazothiazoles. 20

63. The use of any one of claims 57 to 62 wherein the animal is a non-human animal.

64. The use of any one of claims 57 to 63 wherein the animal is selected from the 25 group consisting of sheep, goats, ruminants (including cattle) and camelids.

65. A method of forming an anthelmintic composition comprising: (a) dissolve a macrocyclic lactone in a solution of surfactant and water miscible solvent(s); 30 (b) slowly add water to the surfactant macrocyclic lactone solution then mix until homogenous; (c) add benzimidazole and imidazothiazole, having first adjusted the pH if necessary. (d) mix until fully dispersed 35

66. The method of claim 65 further comprising adding one or more dispersing or suspending agents before step (d).

67. The method of claim 65 or claim 66 wherein a buffer is added before step (c). 24

68. The method of any one of claims 65 to 67 wherein the macrocyclic lactone is dissolved in the water miscible solvent(s) followed by addition of the surfactant. 5

69. A composition, method or use substantially as hereinbefore described with reference to the accompanying examples.