AU2009201942B2 - Anthelmintic composition - Google Patents

Anthelmintic composition Download PDF

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AU2009201942B2
AU2009201942B2 AU2009201942A AU2009201942A AU2009201942B2 AU 2009201942 B2 AU2009201942 B2 AU 2009201942B2 AU 2009201942 A AU2009201942 A AU 2009201942A AU 2009201942 A AU2009201942 A AU 2009201942A AU 2009201942 B2 AU2009201942 B2 AU 2009201942B2
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composition
group
compound
animal
benzimidazoles
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AU2009201942C1 (en
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Brian Desmond Ford
Marcus Holdsworth
Kai Kin Lau
John James O'brien
Edward Lionel Bruce Whittem
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Jurox Pty Ltd
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

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Abstract

Abstract: The invention relates to the treatment of anthelmintic infections in animals, and more particularly to compositions that are effective against parasites that are resistant to a wide variety of drug treatments. In a first aspect, the invention provides a synergistic anthelmintically effective composition consisting of at least one compound selected from each of the following groups: macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles and a therapeutically acceptable carrier, In a second aspect, the invention provides a method for treating parasitic infections in an animal, comprising administering to the animal, a synergistic anthelmintically effective amount of a composition which consists of at least one compound selected from each of the following groups: macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles and a therapeutically acceptable carrier. In a third aspect, the invention provides the use of a synergistic anthelmintically effective amount of a composition which consists of at least one compound selected from each of the following groups: macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles and a therapeutically acceptable carrier in the treatment of a parasitic infection in an animal.

Description

AUSTRALIA FB RICE & CO Patent and Trade Mark Attorneys Patents Act 1990 JUROX PTY LTD COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Anthelmintic composition The following statement is a full description of this invention including the best method of performing it known to us:- ANTHELMINTIC COMPOSITION Field of the Invention 5 This invention relates to the treatment of anthelmintic infections in animals, and more particularly to compositions that are effective against parasites that are resistant to a wide variety of drug treatments, particularly in non-human animals.. Background to the Invention 10 Farm animals such as lambs, weaners and sheep may typically be infected by a wide variety of parasites. Such parasites include Haemonconchus spp., Ostertagia spp., Trichostrongylus spp., Cooperia spp., Nematodirus spp., Chabertia spp., Oesophagostomum spp., Trichuris spp., Strongyloides spp., Bunostonum spp., Oestrus 15 spp., Dictyocaulus spp., Fasciola spp. and Monezia spp. Specific examples of these parasites are set out in Table 1. For a variety of reasons, there is an increasing number of such parasites that have developed resistance to available drug treatments. Moreover, because of the infective 20 nature and ready transmission from animal to animal, the presence of resistant parasites will rapidly spread to infect a substantial number, if not all, of the animals in a flock or herd. One means by which such infection will rapidly spread is where new animals in which the presence of drug resistance is known or suspected are to be introduced onto a property. 25 There are a variety of drug substances that are used to treat parasitic infections. Amongst these broad groups of substances are macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles. Unfortunately, many of the parasites mentioned in Table 1 have developed resistance to these substances. 30 Although the problem of resistance has been tackled through the development of new substances, the time to develop, evaluate and demonstrate efficacy of such substances is substantial and expensive. Moreover for the reasons that resistance has developed against existing substances it is very likely that resistance will occur in relation to these 35 new substances.
2 Summary of the Invention Rather then tackling the problem of resistance through the development of new 5 substances, the present inventors have found that it is possible to circumvent resistance by combining specific classes of anthelmintics. The efficacy of this combination arises out of the finding that the combination is synergistic. Accordingly, the present invention provides in a first aspect, a synergistic 10 anthelmintically effective composition consisting of at least one compound selected from each of the following groups: macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles and a therapeutically acceptable carrier. Table 1 Parasite Species Species Common Name Comments Haemonchus contortus Barber's pole worm includes inhibited L4 stage Haemonchus placei Large stomach worm Ostertagia circumcincta Small brown stomach includes inhibited L4 stage worm Trichostronglus axei Stomach hair worm Trichostrongylus colubriformis Trichostrongylus vitrinus Black scour worm Cooperia curticel Cooperia oncophera Small intestinal worm Nematodirus spathiger Nematodirusflicollis Thin-necked intestinal worm Chabertia ovina Large mouthed bowel worm Oesophagostomum Nodule worm columbianum 3 Oesophagostomum Large bowel worm venulosum Trichuris ovis Whip worm Strongyloides papillosus Intestinal threadworm Bunostomum spp H ookworm Oestrus ovis Dictyocaulus viviparus Large lungworm Fasciola hepatica Monezia Includes head and segments In a second aspect, the present invention provides a method for treating parasitic infections in an animal, comprising administering to the animal, a synergistic anthelmintically effective amount of a composition which consists of at least one compound selected from each of the following -groups: macrocylic lactones, 5 benzimidazoles, salicylanilides and imidazothiazoles and a therapeutically acceptable carrier. In a third aspect, the present invention further provides the use of a synergistic anthelmintically effective amount of a composition which consists of at least one 10 compound selected from each of the following groups: macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles and a therapeutically acceptable carrier in the treatment of a parasitic infection in an animal. Throughout this specification the word "comprise", or variations such as "comprises" or 15 "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The aforementioned treatments may be desirably administered to animals prior to 20 introduction to a land area so as to prevent the land area from becoming infested with parasites which may or may not be resistant to one or more compounds selected from the groups consisting of macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles. Typically, animals such as sheep, will be isolated for at least 2 days after treatment before being placed on pasture.
4 Alternatively, animals may be treated at any time, as appropriate, particularly when it is suspected that the animal may be carrying at least one parasite which is resistant to at least one of the groups macrocylic lactones, benzimidazoles, salicylanilides and 5 imidazothiazoles. The compositions of this invention have application where the parasites are resistant to known drug treatments. In particular, the compositions are effective in situations where parasites are resistant to at least one of each of the groups macrocylic lactones, 10 benzimidazoles, salicylanilides and imidazothiazoles. Preferably, the compositions are effective in situations where parasites are resistant to at least two of each of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles. More preferably, the compositions are effective in situations where parasites are resistant to at least three of each of the groups macrocylic lactones, benzimidazoles, salicylanilides 15 and imidazothiazoles. Most preferably, the compositions are effective in situations where parasites are resistant to all of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles. In use, a preferred indication is the treatment of stock to eliminate adult gastro 20 intestinal worms and liver fluke. Typically, treatment results in the clearance of >95% of total worm count including worms resistant to at least one of each of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles. Compositions of this invention include at least one compound selected from each of the 25 groups: macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles. Representative examples of compounds from each of these group are set out in Table 2.
5 Table 2 Compounds Macrocyclic lactone Benzimidazole Salicylanilide Imidazothiazole abamectin albendazole closantel levamisole ivermectin fenbendazole niclosamide pyrantel pamoate doramectin thiabendazole butamisole moxidectin oxfenbendazole cydectin fenbantel milbemycin mebendazole parbendazole flubendazole oxibendazole carbendazole Of these combinations which include at least abamectin from the macrocylic lactone group together with one compound from each of the other three groups; at least albendazole from the benzimidazole group together with one compound from each of the other three groups; closantel together with one compound from each of the other 5 three groups and levamisole together with one compound from each of the other three groups are each preferred. Particularly preferred is the specific combination of abamectin, albendazole, closantel and levamisole. Most preferably, the levamisole is used in the form of a water soluble salt such as the hydrochloride. 10 The therapeutically active compounds used in the invention are preferably incorporated into formulations in the range of concentrations as follows (g/L) macrocylic lactones: 0.1-20.0 g/L, preferably 0.5-1.5 g/L benzimidazoles: 1-100 g/L, preferably 18-30 g/L 15 salicylanilides: 1-100 g/L, preferably 30-50 g/L imidazothiazoles: 1-100 g/L, preferably 30-50 g/L Although drenches are preferred dosage forms for the compositions of this invention, a number of alternative compositions may be used. These pour-on transdermals, slow 20 release boluses for rumenal deposition and injectable formulations.
6 Each dosage form requires a therapeutically effective carrier. In the case of drenches, typically a formulation will include a solvent system for the macrocylic lactones, one or more dispersing and suspending agents for the benzimidazoles and salicylanilides , one or more surfactants, one or more preservatives, a buffering system and water as a 5 carrier. The solvent system for the macrocyclic lactones includes at least one solvent selected from the group consisting of: polyethylene glycol, tetraglycol, ethanol, benzyl alcohol and propylene glycol. 10 The dispersing and suspending agents for the benzimidazoles and salicylanilides include at least one selected from the group consissting of: glyceryl palmitostearate, bentonite, colloidal silica, xanthan gum and polymeric pyrrolidones. 15 Surfactants that may be used include polysorbate 80 and ethoxylated castor oil. A variety of buffer systems may be used, particularly phosphate buffers based on combinations of varying amounts of monobasic and dibasic sodium phosphate to achieve the desired pH. 20 The compositions of the invention are effective when used in a variety of animals. For example, sheep, goats, ruminants (including cattle) and camelids.
7 Modes for Carrying Out the Invention In order to better understand the nature of the invention, a number of examples will now be described as follows: Example I Material Supplier Grade Amount (g) Abamectin Haiman Technical 94% 1.0 Albendazole Pacific Resource USP24 25.0 Closantel Pacific Resource Technical 98% 37.5 Levamisole Hydrochloride Pacific Resource BP 1998 40.0 Tetraglycol AGRAR Food Grade 400.0 Benzyl alcohol APS BP1998 80.0 Keltrol F (Xanthan Gum) USP24 10.0 Rhone-Poulenc Phenonip (Phenoxyethanol) Food 10.0 Bronson& Jacobs Glyceryl Palmitostearate (Precirol ATO 5) USP24 5.0 Bronson & Jacobs Veegum Regular (Magnesium USP24 Aluminium Silicate) RT Vanderbilt Co. PVP29/30 (Ethenyl-2- USP24 pyrrolidinone homopolymer) ISP PVPC15 ISP USP24 Polyethylene glycol (PEG 2000) BASF USP24 Cremophor (ethoxylated Castor USP24 Oil) BASF Propylene Glycol USP24 Sodium phosphate monobasic Bronson & Jacobs Technical Sodium phosphate dibasic Bronson & Jacobs Technical Polysorbate 80 Bronson & Jacobs USP24 Cab-O-Sil M5 (Colloidal Silicon USP24 Dioxide) Cabot Corp Water gs Ilitre 8 Example 2 Material Supplier Grade Amount (g) Abamectin Haiman Technical 94% 0.8 Albendazole Pacific Resource USP24 19.0 Closantel Pacific Resource Technical 98% 30.0 Levamisole Hydrochloride Pacific Resource BP 1998 35.5 Glycerol formal 30.0 Tetraglycol AGRAR Food Grade Ethanol 20.0 Benzyl alcohol APS BP1998 80.0 Keltrol F (Xanthan Gum) USP24 10.0 Rhone-Poulenc Phenonip (Phenoxyethanol) Food Bronson& Jacobs Potassium sorbate 10.0 Glyceryl Palmitostearate (Precirol ATO 5) USP24 Bronson & Jacobls Veegum Regular (Magnesium USP24 50.0 Aluminium Silicate) RT Vanderbilt Co PVP29/30 (Ethenyl-2- USP24 50.0 pyrrolidinone homopolymer) ISP PVP C15 ISP USP24 Polyethylene glycol (PEG 2000) BASF USP24 Cremophor (ethoxylated Castor USP24 Oil) BASF Propylene Glycol USP24 Sodium phosphate monobasic Bronson & Jacobs Technical Sodium phosphate dibasic Bronson & Jacobs Technical Polysorbate 80 Bronson & Jacobs USP24 Cab-O-Sil M5 (Colloidal Silicon USP24 Dioxide) Cabot Corp Water gs I litre 9 Example 3 Material Supplier Grade Amount (g) Abamectin Haiman Technical 94% 1.0 Albendazole Pacific Resource USP24 25.0 Closantel Pacific Resource Technical 98% 37.5 Levamisole Hydrochloride Pacific Resource BP 1998 40.0 Tetraglycol AGRAR Food Grade Benzyl alcohol APS BP1998 20.0 Keltrol F (Xanthan Gum) USP24 Rhone-Poulenc Phenonip (Phenoxyethanol) Food 20.0 Bronson& Jacobs Glyceryl Palmitostearate (Precirol ATO 5) USP24 Bronson & Jacobs Bentonite 20.0 Veegum Regular (Magnesium USP24 Aluminium Silicate) RT Vanderbilt Co. PVP29/30 (Ethenyl-2- USP24 pyrrolidinone homopolymer) ISP PVPC15 ISP USP24 100.0 Polyethylene glycol (PEG 2000) BASF USP24 Cremophor (ethoxylated Castor USP24 80.0 Oil) BASF Propylene Glycol USP24 Sodium phosphate monobasic Bronson & Jacobs Technical Sodium phosphate dibasic Bronson & Jacobs Technical Polysorbate 80 Bronson & Jacobs USP24 Cab-O-Sil M5 (Colloidal Silicon USP24 Dioxide) Cabot Corp Water qs Ilitre 10 Example 4 Material Supplier Grade Amount (g) Abamectin Haiman Technical 94% 1.0 Albendazole Pacific Resource USP24 25.0 Closantel Pacific Resource Technical 98% 37.5 Levamisole Hydrochloride Pacific Resource BP 1998 40.0 Tetraglycol AGRAR Food Grade Benzyl alcohol APS BP1998 80.0 Keltrol F (Xanthan Gum) USP24 Rhone-Poulenc Phenonip (Phenoxyethanol) Food Bronson& Jacobs Glyceryl Palmitostearate (Precirol ATO 5) USP24 Bronson & Jacobs Veegum Regular (Magnesium USP24 Aluminium Silicate) RT Vanderbilt Co. PVP29/30 (Ethenyl-2- USP24 pyrrolidinone homopolymer) ISP PVP ClI5 ISP USP24 Polyethylene glycol (PEG 2000) BASF USP24 Cremophor (ethoxylated Castor USP24 Oil) BASF Propylene Glycol USP24 300.0 Sodium phosphate monobasic Bronson & Jacobs Technical 9.0 Sodium phosphate dibasic Bronson & Jacobs Technical 1.0 Polysorbate 80 Bronson & Jacobs USP24 200.0 Cab-O-Sil M5 (Colloidal Silicon USP24 200.0 Dioxide) Cabot Corp Water qs I litre 11 Example 4 was prepared as follows: 1. Dissolve avermectin in benzyl alcohol and propylene glycol. 2. Add polysorbate 80 to step 1. 5 3. Add water to the solution from step 2 and mix until homogeneous. 4. Dissolve sodium phosphate dibasic and sodium phosphate monobasic in the solution from step 3. 5. Add closantel, albendazole and levamisole hydrochloride. Mix until fully dispersed. 10 6. Add Cab-O-Sil M5 to the suspension and homogenise until the thicken agent fully hydrated. Based on this disclosure, the person skilled in the art would appreciate the general approach to be taken in preparing the compositions of this invention. 15 In order evaluate the efficacy of the compositions of the invention, a number of trials were conducted using Example 4 as above. Trial RD0201-H002: A critical pen sacrifice study evaluating the therapeutic efficacy 20 of a combination abamectin. levamisole hydrochloride, albendazole and closantel anthelmintic formulation against resistant strains of Haemonchus contortus, Trichostronzylus colubriformis and Teladorsagia circumcincta in sheep. This study was conducted from the 25* of February to the 29* of August, 2002, with 25 the animal phase conducted from the 7 t* May to the 27th June 2002. Suitable sheep (18) were relocated to the University of New England Animal House Facility on the 70 May 2002 were weighed, identified with individually numbered ear tags and treated with twice the recommended dose rate of Ivomec (Liquid for Sheep, Merial Australia Pty Ltd), to remove any residual worm burden. 30 On 22 nd May 2002 (Day -26) faecal samples were collected from each trial animal to confirm individual zero faecal egg counts. Later that day trial sheep were infected with approximately 5000 Haemonchus contortus (macrocyclic lactone and closantel resistant strains), 6000 Trichostrongylus colubrformis (levamisole hydrochloride and 35 albendazole resistant strains) and 5000 Osteratagia circumcincta (macrocyclic and albendazole resistant strains) infective larvae.
12 Faecal samples were collected from each sheep on 14' June 2002 (Day -3) and individual faecal egg counts were conducted. Animals were ranked on the basis of decreasing faecal egg counts and blocked into eight blocks each of two animals and 5 randomly allocated to the treatment groups from these blocks. The 16 animals with the highest counts were selected for inclusion in the trial and the two animals with the lowest faecal .egg counts were selected as spare animals. On 17 th June 2002 (Day 0) all trial animals were weighed, faecal sampled and animals 10 in Group 2 were treated as follows. Animals were weighed and dosed according to individual live weight as outlined in Table 3. Table 3: Dosage regime qatmet Dosrate .Active ngredint Group 1 Untreated control - . Group 2 Example 4 1 mL/5 kg 37.5 g/L closantel g/L abamnectin 40 g/L levamisole hydrochloride 25 g/L albendazole The 18 trial sheep (including the 2 spare animals) were sacrificed on 27h June 2002 (Day 10) for collection of faecal samples, abomasal and small intestine contents. Individual faecal egg counts, treatment group coprocultures and total worm counts 15 were conducted for calculation of treatment efficacies. Drenchrites (CSIRO Research - Horizon Technology 1996) was performed between the 100 July and the 23d August 2002 to clarify that strains of Trichostrongylus colubriformis used were resistant to levamisole hydrochloride and albendazole and, 20 Osteratagia circumcincta were resistant to albendazole. Faecal samples were collected according to standard procedures and submitted to the Veterinary Health Research parasitological laboratory. Individual strongyle faecal egg counts and group bulk coproculture for larval differentiation were carried out. 25 Gastrointestinal tracts were recovered according to standard procedures and following gut washing were submitted to the parasitological laboratory. Individual total worm counts were conducted and results are summarised in the accompanying tables, 4-10 and figures 1-4.
13 Table 4: Group mean strongyle faecal egg counts. Group Treent Day 0 . Day 10 Arithmetic Means 1 Control 9320.0' 8568.9 2 Example 4 8177.81 22.2 Geomdtr Mean 1 Control 6754.5 6754.5' 2 Example 4 1.8 1.82 'Means with different superscripts within the same column are significantly different at p<0.05 Table 5: Percentage reduction of strongyle species (based on group mean strongyle faecal egg count data) Gr6up - ir'tmeni' DaviO 0 Arithie4?gEfficac 2 Example 4 99.7% - i $$metric E$$t~cy 2 Example 4 >99.9% 14 0 t-0 0 'A' I0 000 14 q) ch oN ch ) .~co * IM4 r4) 0'~ . 04A Q0o\4 o'.00 -000 15 JU, , 0 0 0 00 66N6 00 00 0. 2 C)- 0 000~ ~~c oCJ46' 16 (4-4 00 00 o ON) Cd 0 0 0 "1 t N~ N 17 Conclusion: Excellent control (>99.9% reduction) of a mixed gastrointestinal strongyle burden as assessed by geometric faecal egg counts was achieved by the use of the Example 4 formulation at the conclusion of the trial (Day 10),. 5 Excellent control (>99.9% reduction) was achieved by the Example 4 formulation against the major nematodes, macrocyclic lactone and closantel resistant strains of Haemonchus spp. (adult and immature stages - geometric .means), macrocyclic and albendazole resistant strains Ostertagia spp. (adult, immature and L4 stages - geometric means) and levamisole hydrochloride and albendazole resistant strains of 10 Trichostrongylus spp (adult and immature stages - geometric means) as assessed by geometric total worm counts. Trial JJA1240r: A property faecal egg count reduction study evaluating the therapeutic efficacy of the Example 4 formulation against field strains of mixed nematode 15 population of either Haemonchus contortus, Trichostrongylus colubriformis and/or Teladorsagia circumcincta in sheep. This study was conducted from the 16'b May 2002 to the 20th August 2002 with the animal phase conducted between the ls' July 2002 to the 17*h July 2002 and animal 20 phase 2 between 5t September 2002 to the 4t October 2002. A trial site was sought, containing a mob of Merino sheep that were known to be harbouring resistant strains of nematodes (including either closantel resistant and/or macrocyclic lactone resistant Haemonchus species, as well as either benzimidazole resistant and/or levamisole resistant Trichostrongylus colubriformis and/or Teladorsagia circumcincta.) Pre-trial 25 monitoring of the site confirmed that the intended trial animals carried a nematode burden of greater than 400 eggs/gram. A group coproculture was performed on these prospective trial sheep to establish the genera present. On Day -3 of the trial, a mob of approximately 300 Merino ewes was mustered into a 30 set of sheep yards. Eighty ewes were identified with uniquely numbered eartags and faecal sampled as they presented in the race. The faecal samples were returned to Veterinary Health Research for individual faecal egg counts and a bulk coproculture.
18 The sixty animals with the highest strongyle faecal egg counts, as determined by the Day -3 faecal egg counts, were selected for inclusion in the trial. These sheep were allocated to one (1) of six (6) treatment groups, on the basis of their faecal egg counts, such that each group had a similar arithmetic group mean faecal egg count. 5 On Day 0 (treatment day), each animal was weighed and treated according to the treatment schedule outlined in Table 11. Clinical observations were conducted one hour post-treatment to. determine whether any adverse reactions had occurred in relation to treatments. None were detected. 10 Table 11: Treatment table (phase 1) rgtmej Folnation-a region NniTbr of 1 Untreated control - 10 2 Example 4 1 mL/5 kg 10 3 Ivomec (Liquid for Sheep, 1 mL/4 kg 10 Merial Pty Ltd) 4 Sustain (Dover Laboratories 1 mL/5 kg 10 Pty Ltd) 5 Youngs Levanisole (Youngs 1 mL/4 kg 10 Animal Health Pty Ltd) 6 Valbazen (Coopers Animal 1 mL/4 kg 10 Health) _ The trial concluded on Day 13 when faecal samples were collected and returned to the 15 Veterinary Health Research Laboratory for individual faecal egg counts and group coprocultures. The entire mob was administered an effective broad-spectrum anthelmintic to remove any existing worm burden. The aim of this field study was to study and evaluate under field conditions, the 20 therapeutic efficacy of Example 4 when administered to sheep that are known to be harbouring resistant strains of nematodes. The selected trial site was known to harbour closantel resistant Haemonchus contortus. This however was not confirmed during the initial phase of the study as a full dose of closantel was administered (as stated in the 19 protocol). Standard industry practice for diagnosis of closantel resistance in the field involves either the administration of a full dose of closantel and sequential sampling of treated sheep over three to six weeks post treatment, or alternatively administration of a 1/3 dose and sampling at 10 tol4 days post treatment. 5 A second faecal egg count reduction study was conducted after consultation with the Study Sponsor to confirm the closantel resistance status at the trial site, "Kelvin East". The second phase of the study involved two groups of sheep each consisting of ten animals. Ten random faecal samples were collected prior to treatment from the mob of 10 wethers to confirm a nematode burden of greater than 400 eggs/gram, and a group coproculture that confirmed a very high percentage (91%) of Haemonchus contortus were present. On Treatment Day (Day 0), individual faecal samples were collected from twenty animals as they presented in the race. These animals were weighed and weights recorded and treatments administered in accordance to the treatment regime 15 (detailed in Table 12). Faecal samples were returned to Veterinary Health Research for individual faecal egg counts and group coprocultures. Animals were observed post treatment for adverse reactions. None were detected. Table 12: Treatment table (phase 2) 20 Treadie4 fSorm io - Dsag egim' ibe N I Untreated control - 10 2 Sustain (Dover Laboratories 1 mL/15 kg 10 Pty Ltd) The second phase of this trial concluded on Day 11, with the collection of individual faecal samples from all animals. These samples were returned to Veterinary Health Research for individualfaecal egg counts and group coprocultures. 25 Faecal samples for phase 1 were collected during pre trial monitoring, (Day -3), at treatment (Day 0) and at the conclusion of the trial (Day 13) and for phase 2 at treatment (Day 0) and at the conclusion of the trial (Day 11). Results from faecal egg counts, larval differentiation and calculated treatment efficacies are summarised in the accompanying tables 13-24 and figures 5 and 6. Note that in figures 5 and 6, "Jurox" 30 refers to example 4.
20 Table 13: Pre trial monitoring results. D te Group ien fa 1 egg Range. of faecal egg count (epg) counts (epg) 01 July 2002 (Day -3) 900 320-1880 Table 14: Group arithmetic mean faecal egg counts and body weights at Day 0. 5 Grup TGro min faec1 egg Oroup mean bodyweig count (epg .: (g 1 Untreated control 984' 49.30' 2 Example 4 584' 45.25' 3 Ivomec 588' 46.05' 4 Sustain 584' 49.45' 5 Levamisole 4521 46.35' 6 _ Valbazen 328' 48.25' ' Means in the same column with different superscripts are significantly different at p<0.05 Table 15: Group arithmetic and geometric mean faecal egg counts (epg). G Trial rDay 13 :irithmtic Means. 1 Untreated controls 892 984' 664' 2 Example 4 872 584' 44 3 Ivomec 940 588' 04 4 Sustain 924 584' 160',' 5 Levamisole 900 452' 12'-' 6 Valbazen 872 328' 682, 21 1 Untreated controls 823.0 691.5 340.3 2 Example 4 768.9 508.7 0.5 3 Ivomec 869.9 416.4 0 4 Sustain 860.1 450.1 97.4 5 Levamisole 834.1 379.7 2.1 6 Valbazen '818.9 179.7 14.9 Means in the same column with different superscripts are significantly different at p<0.05 Table 16: Overall percentage efficacy calculated using arithmetic and geometric group mean faecal egg counts. abroup Tieatment -Eficacy (%) 4rithrnetic Rifcacy< . 2 Example 4 99.4 3 Ivomec >99.9 4 Sustain 75.9 5 Levamisole 98.19 6 Valbazen 89.76 2 Example 4 99.87 3 Ivomec >99.9 4 Sustain 71.37 5 Levamisole 99.4 6 Valbazen 95.61 22 0 0 >n0C >C 0 0 0 DC )C 0i LIP 0 ... 0a Q) 4) ts 2) 4 -7I~ *,4 *- -8 c 0 ON 0 C.c t 0 A A A A A~ A! ) 4 _ _ _ _ _ _ Ittrn % 23 Phase 2 Table 19: Treatment day monitoring results. [Date 6f Sampling Oroup, Mean faecal Egg Eg Count (eggs/gre~) Counts Ieggs/graxn) 23 Sept 2002 (Day 0) 1428 80-3000 Table 20: Group arithmetic mean faecal egg counts and body weights at Day 0. Groxp Treatet Group Fae gg Gr Mean Count eggram) Weight &g 1 Untreated controls 16281 51.6' 2 Sustain 1228' 50.2' 'Means in the same column with different superscripts are significantly different at 5 p<0.05 Table 21: Group arithmetic and geometric mean faecal egg counts. Group Treatment Da Day 11 Arithmetic Means 1 Untreated controls 1628.0 3008.0' 2 Sustain 1228.0' 2088.0' Geometric Means 1 Untreated controls 1237.7 2041.1 2 Sustain 940.0 1511.9 'Means in the same column with different superscripts are significantly different at p<0.05 24 Table 22: Overall percentage efficacy (arithmetic and geometric means) op Treatment - Percentage Efficay (%) Arithmet c E/cay 2 1/3 Sustain 30.6 Geonetic Eficacy 2 1/3 Sustain 25.9 25 0 _ _ _> 0 00 0 oc 00 I co'. ~ f CA. J~jI F- E.
26 Conclusion: The second faecal egg count reduction test was to confirm the presence closantel resistant Haemonchus at the trial site. This was achieved by administering a one third dose of closantel to a group of ten (10) animals and the addition of another group of ten (10) animals retained as untreated controls. The use of a one third dose of closantel is standard industry practice for diagnosis of closantel resistance in the field. Reduced efficacy of closantel was observed against Haemonchus, confirming. The presence of closantel resistant Haenonchus at the trial site. The inclusion of the levamisole and benzimidazole groups confirmed the resistance status of Trichostrongylus. Excellent efficacy (> 99.0%) was attained by the Example 4 formulation against a mixed gastrointestinal population including closantel resistant Haemonchus as well as levamisole and benzimidazole resistant Trichostrongylus.
27 Trial JUA1273r: A property faecal egg count reduction study evaluating the therapeutic efficacy of the Example 4 formulation against field strains of mixed nematode populations, including closantel resistant strains of Haemonchus contortus in sheep. 5 This study was conducted from the 5h of September 2002 to the 23d of October 2002, with the animal phase conducted between 10* of September 2002 and the 14 of October 2002. Routine monitoring of a trial site known to harbour closantel resistant strains of Haemonchus contortus was conducted to identify a suitably infected group of sheep. Pre-trial monitoring confirmed that one group of sheep (270 Merino hoggets) 10 was suitably infected with a high burden of Haemonchus contortus. On Day -2 of the trial individual faecal samples were collected from ninety (90) potential trial sheep and individual strongyle faecal egg counts performed. Trial sheep had already been identified using uniquely numbered ear tags as part of standard 15 farming practice at the trial site. From the ninety (90) potential trial sheep sixty (60) sheep were selected and allocated (according to individual strongyle faecal egg counts) to six (6) groups of ten (10) sheep each, such that each group had a similar group arithmetic mean strongyle faecal egg count and range of faecal egg counts within the group. 20 On Day 0 of the trial (18L September 2002) selected trial sheep were weighed (see figure 7 for arithmetic mean body weights and note that the treatment "Jurox" refers to the treatment with Example 4), the weights recorded and individual faecal samples collected for individual strongyle faecal egg counts. Trial sheep in Group 2 were 25 treated according to individual body weight with the test formulation, trial sheep in Groups 3-6 were treated with the respective reference formulation and trial sheep in Group 1 were retained untreated as negative controls. Groups 2, 3, 5 and 6 were treated at the recommended dose rate for each active, while sheep in Group 4 were treated at one third the normal closantel dose rate, to determine and demonstrate the presence of 30 closantel resistance (Reference: Rolfe PF; Fourth International Congress for Sheep Veterinarians 1997, pg 55). Sheep were observed in the immediate post-treatment period for adverse reactions (none were observed). Individual strongyle faecal egg counts and group bulk coprocultures for larval differentiation were subsequently performed on the samples collected.
28 Trial sheep were returned to the sheep yards on Day 13 of the trial (1 October 2002) and individual faecal samples again collected. All trial sheep received a single therapeutic dose of Rycozole@ due to animal welfare concerns. Individual strongyle faecal egg counts and group bulk coprocultures for larval differentiation were 5 subsequently performed on the samples collected. Treatment efficacies were then calculated using group arithmetic and geometric strongyle faecal egg counts for the major strongyle species present (see figures 8 and 9 and note that the treatment "Jurox" refers to treatment with Example 4). Rycozole Oral Anthelmintic for Sheep and Cattle, Novartis Animal Health Australasia Pty Ltd 29 0000 - - - 0el 00 A AU C) 00 000 %~f -~N 00 0 0 Cf0 %- 1 I IVii 08 '2,~ L)~~- t- 00 %00 ' % enI -wN C4C4N C4e 000 0 '1 -~r C- en .- _ _ 30 - - - - 4) 14) 0 044 *14 4)) .4 0 -l C4) 4GO 93 (4.0 oO 31 t~ CO) - - - - - 14D m- 000 CA01 e~0e 0< ) N- 6 o vN *t % @' Q0 32 - 00>C 0(> C 0 0 00000 a Q0 Q00 a o0 00000 0 QC)00C>00 o D c)cC>ci>,Q(),0, ( . ~N 0WO__ _ Sr 404 (D 0 (D 0 n0 te 4) C>m()0 C .) -N0 nr 9 0O nC _ _ _ _ _ _ _ _ _ _ _ 33 Table 31: Overall treatment efficacies, against all strongyle species (apart from Nematodirus spp.) Grou Treatment Batch No Efficacy at Day 13 thmetic Means 2 Example 4 FS489 >99.9% 3 Ivomec@ 51983 95.6% 4 1/3 Sustain@ 13146 82.6% 5 Levamisole@ 6053 99.7% 6 Valbazen@ V03790/2 85.0% Geometric Means 2 Example 4 FS489 >99.9% 3 Ivomec® 51983 97.2% 4 1/3 Sustain@ 13146 97.2% 5 Levamisole@ 6053 >99.9% 6 Valbazen@ V03790/2 84.4% Table 32: Treatment efficacies against Haemonchus contortus. otearaet o E~fctcy at -1 2 Example 4 FS489 >99.9% 3 Ivomec@ 51983 96.1% 4 1/3 Sustain® 13146 83.0% 5 Levamisole@ 6053 99.8% 6 Valbazen@ V03790/2 85.5% Geometric Means 2 Example 4 FS489 >99.9% 3 Ivomec@ 51983 97.5% 4 1/3 Sustain® 13146 86.8% 5 Levamisole@ 6053 >99.9% 6 Valbazen@ V03790/2 84.9% 34 Conclusion: Excellent efficacy (greater than 99.9% based on group arithmetic and geometric means and larval differentiation results) was attained by the Example 4 formulation against a gastrointestinal strongyle population consisting almost exclusively of Haemonchus contortus. 5 Efficacies attained by the comparison formulations against this strain of Haemonchus contortus ranged from 85.5% for the albendazole formulation (Valbazen@D) through 96.1% for the ivermectin formulation (Ivomec@) to 99.8% for the levamisole formulation (Levamisole@), based on group arithmetic mean faecal egg counts and 10 larval differentiation. Efficacies attained against this strain based on geometric mean faecal egg counts and larval differentiation were 84.9%, 97.5% and >99.9% for these formulations respectively. These results indicate that this strain is moderately resistant to white drenches (benzinidazoles) and fully susceptible to levamisoles, with a slight but non-significant reduction in efficacy for ivermectin. Ivermectin was 96.1% 15 (arithmetic) and 97.5% (geometric) efficacious, which establishes that this strain could not be defined as macrocyclic lactone resistant at present. Treatment with a 1/3 dose of closantel resulted in a treatment efficacy of 83.0% based on arithmetic group mean faecal egg counts and a treatment efficacy of 86.8% based on 20 geometric group mean faecal egg counts, confirming the presence of moderate closantel resistance by this Haemonchus strain. Insufficient numbers of other gastrointestinal strongyles (Nenatodirus, Teolodorsagia and Trichostrongylus species) were present to draw any conclusions about efficacy of the test formulation against these strains.
35 Trial JUA1270r: A property faecal egg count reduction study evaluating the therapeutic efficacy of the Example 4 formulation against field strains of mixed nematode populations, including macrocyclic lactone resistant strains of Haemonchus contortus in sheep in sheep. 5 This study was conducted from the 5t of September 2002 to the 7f" of November 2002, with the animal phase conducted between 11 h and 25th of October 2002. Routine monitoring of a trial site known to harbour macrocyclic lactone resistant strains of Haemonchus contortus was conducted to identify a suitably infected group of sheep. 10 Pre-trial monitoring confirmed that one group of sheep (approximately 200 Merino wether hoggets) was suitably infected with a high burden of Haemonchus contortus. On Day 0 of the trial, ninety six (96) sheep were randomly selected from a larger mob as they appeared in the sheep handling facility, weighed (see figure 10 for arithmetic 15 mean body weights and note that the treatment "Jurox" refers to treatment with example 4) and individual faecal samples collected for subsequent individual strongyle faecal egg counts and group bulk coprocultures. Sheep had been previously allocated to six (6) treatment groups, one (1) of eleven (11) sheep to act as untreated (negative) controls and five (5) groups of seventeen (17) sheep, to be treated with the test 20 formulation and a range of registered reference formulations. Trial sheep in Group 1 were retained untreated, while sheep in Groups 2-6 were treated according to individual body weight with the test and reference formulations. Sheep were observed in the immediate post-treatment period for adverse reactions (none were observed). Trial sheep were then returned to their parent flock and maintained in open grazing 25 paddocks. On Day 13 of the trial sheep were returned to the sheep handling facilities. Individual faecal samples were collected from trial sheep and individual strongyle faecal egg counts and group bulk coprocultures for larval differentiation were subsequently 30 performed on the samples collected. Treatment efficacies were then calculated using group arithmetic and geometric strongyle faecal egg counts for the major strongyle species present (see figures 11 and 12 and note that the treatment "Jurox" refers to treatment with Example 4).
C (D = 0 0))0. n 2 .s EEEE U? ~ 0 U. E _ 'a C. 0 + 0 a), z ~ .r C a 4)) a)A -6- 0 C ( DU0O 0 L ->N T. 0 Nq -0 ' 4- C?) 75 )0 Ca ~ 0)0 l'(DN 0In T (D E W~ ~ -e E m C-.. ( 0 0 - p> U (D0 > cm-o E) -c 4) tm 0) 0) 0 m m0C _X ::] iii ::) In E~I c u o0 E _ E E E E _u EmtmCOC 0 C. 0)0C 0) 0) z co 0 co wo > 0) cicu 00 IT In I- CLL m E__ _ 0) 00000 0 (ni 0) 6 )6 i o~ 0 =.. 0)
N-
1 Nc 0EE 0 E CDo 0 0) 4) LO 0 C) 'a_ E EW * I>1 E E > cO z C to _r -n a)) E_ 6 c a) a o6 (D M~ _~j 0 0 0 N -0~E c 0) E 0) . -) C LL > m E cEEEC 4-~ CfW
)
CL in C ) L 0[f> 0) Nl C O n N 0 >I 0 a 0 C0n D
)
- CV E5 ___ tmc N C 0)C) CI a) (D 0 C x ma ci) Z) CXOUl.2 0 > 0 0 (DN r--- N- N Eu - cu '-) 0~) In (0H -Nm E -i ? -D -j > - 37 C- -oV o 60 Irti C>, en 00 0x o C4-b vW 38 "t r (40c) r- (71 e' IZ4 r- o oC4 \00 te4) .ON mO~o 00 4O v-)OO00 tr4) eN 0 0 __1NI L".l-rm-.- ' I - 39 - a-- --- * 0 0000 0 0 0 n )0. ) 0 0 0 0 0 0) 000 0) C 0 00000 0 000 I0 0 0 0o o0o o - oooo o 00 00 0 000 0 .00 * 0000.o0000 o _o 5. 00 00 0 co _ _ _ _ 3u 40 C) 4i C o0 C e o mf 000 - Clr 000 0 -n ro0 en0 t) 4) c 41 Conclusion: Efficacies attained by the formulations against this strain of Haemonchus contortus for the ivermectin formulation (Ivomec®), the albendazole formulation (Valbazen®), the closantel formulation (full dose Sustain®), the levamisole formulation (Levamisole Gold®) and for the test formulation, based on group geometric mean faecal egg counts and larval differentiation were negative, 3.0%, 65.3%, 78.9% and >95% respectively. While moderate efficacies were attained by the reference closantel formulation, a full (label) dose rate of this formulation was used in this case. In instances of moderate closantel resistance efficacies are still usually >95% for a full dose, with a reduction in initial efficacy only evident at a 1/3 normal dose rate. This particular strain is therefore severely resistant to closantel. These results indicate that this strain also has severe resistance to white drenches (benzimidazoles) and macrocyclic lactones and moderate resistance to levamisole. This strain of Haemonchus contortus is, therefore, moderately to severely resistant to all four drug families. Unexpectedly, the Example 4 formulation containing an example of all four of these families resulted in effective treatment of the infestation. 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 spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification 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 field relevant to the present invention as it existed before the priority date of each claim of this application.

Claims (28)

1. A synergistic anthelmintically effective composition consisting of at least one compound selected from each of the following groups: macrocylic lactones; benzimidazoles; salicylanilides; and imidazothiazoles; and a therapeutically acceptable carrier.
2. The composition of clyaim 1 wherein the macrocyclic lactone compound is at least one selected from the group consisting of abamectin, ivermectin, doramectin, moxidectin, cydectin and milbemycin.
3. The composition of claim I wherein the benzimidazole compound is at least one selected from the group consisting of albendazole, fenbendazole, thiabendazole, oxfenbendazole, fenbantel, mebendazole, parbendazole, flubendazole, oxibendazole and carbendazole.
4. The composition of claim I wherein the salicylanilide compound is at least one selected from the group consisting of closantel and niclosamide.
5. The composition of claim I wherein the imidazothiazole compound is at least one selected from the group consisting of levamisole, pyrantel pamoate and butamisole.
6. The composition of claim 2 wherein: the selected macrocyclic lactone compound is at least abamectin; the benzimidazole compound is at least one selected from the group consisting of albendazole, fenbendazole, thiabendazole, oxfenbendazole, fenbantel, mebendazole, parbendazole, flubendazole, oxibendazole and carbendazole; the salicylanilide compound is at least one selected from the group consisting of closantel and niclosamide; and the imidazothiazole compound is at least one selected from the group consisting of levamisole, pyrantel pamoate and butamisole.
7. The composition of claim 3 wherein: the benzimidazole compound is at least albendazole; the macrocyclic lactone compound is at least one selected from the group consisting of abamectin, ivermectin, doramectin, moxidectin, cydectin and milbemycin; 43 the salicylanilide compound is at least one selected from the group consisting of closantel and niclosamide; and the imidazothiazole compound is at least one selected from the group consisting of levamisole, pyrantel pamoate and butamisole.
8. The composition of claim 4 wherein: the salicylanilide compound is at least closantel; the macrocyclic lactone compound is at least one selected from the group consisting of abamectin, ivermectin, doramectin, moxidectin, cydectin and milbemycin; the benzimidazole compound is at least one selected from the group consisting of albendazole, fenbendazole, thiabendazole, oxfenbendazole, fenbantel, mebendazole, parbendazole, flubendazole, oxibendazole and carbendazole; and the imidazothiazole compound is at least one selected from the group consisting of levamisole, pyrantel pamoate and butamisole.
9. The composition of claim 5 wherein: the imidazothiazole compound as at least levamisole; the macrocyclic lactone compound is at least one selected from the group consisting of abamectin, ivermectin, doramectin, moxidectin, cydectin and milbemycin; the benzimidazole compound is at least one selected from the group consisting of albendazole, fenbendazole, thiabendazole, oxfenbendazole, fenbantel, mebendazole, parbendazole, flubendazole, oxibendazole and carbendazole; and the salicylanilide compound is at least one selected from the group consisting of closantel and niclosamide.
10. The composition of any one of claims 1 to 5 wherein the composition consists of at least abamectin, albendazole, closantel and levamisole.
11. The composition of any one of claims I to 10 wherein the composition comprises: macrocyclic lactone compounds in an amount of from 0.1-20.0 g/L; benzimidazole compounds in an amount of from l-1OOg/L; salicylanilide compounds in an amount of from 1-100 g/L; and imidazothiazole compounds in an amount of from 1-100 g/L.
12. The composition of any one of claims I to I1 wherein the composition comprises: macrocyclic lactone compounds in an amount of from 0.5- 1.5 g/L; 44 benzimidazole compounds in an amount of from 18-30 g/L; salicylanilide compounds in an amount of from 30-50 g/L; and imidazothiazole compounds in an amount of from 30-50 g/L.
13. The composition of any one of claims 1 to 12 wherein the composition is in the form of a drench, a pour-on transdermal formulation, a slow release bolus or an injectable formulation.
14. The composition of any one of claims I to 12 wherein the composition is in the form of a drench including a solvent system for the macrocylic lactones, one or more dispersing and suspending agents for the benzimidazoles and salicylanilides, one or more surfactants, one or more preservatives, a buffering system and water as a carrier.
15 The composition of claim 14 wherein the solvent system for the macrocyclic lactones includes at least one solvent selected from the group consisting of: polyethylene glycol, tetraglycol, ethanol, benzyl alcohol and propylene glycol.
16. The composition of claim 14 wherein the dispersing and suspending agents for the benzimidazoles and salicylanilides include at least one selected from the group consisting of: glyceryl palmitostearate, bentonite, colloidal silica, xanthan gum and polymeric pyrrolidones.
17. The composition of claim 14 wherein the surfactant is polysorbate 80 and/or ethoxylated castor oil.
18. The composition of claim 14 wherein the buffering system includes monobasic and dibasic sodium phosphate.
19. A method of treating parasitic infections in an animal comprising administering to the animal, a synergistic anthelmintically effective amount of a composition according to any one of claims 1-18.
20. The method of claim 19 wherein the method is a method of treating infection in an animal by at least one species of parasite selected from the group consisting of Haemonchus contorlus, Haemonchus place, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus vitrinus, Cooperia curticel, 45 Cooperia oncophera, Nematodirus spathiger, Nematodirus filicollis, Chabertia ovina, Oesophagostomum columbianum, Oesophagostomum venulosum, Trichuris ovis, Strongyloides papillosus, Bunostomum spp, Oestrus ovis, Dictyocaulus viviparus, Fasciola hepatica, and Monezia.
21. The method of claim 19 wherein the method is a method of treating infection in an animal by parasites resistant to at least one of each of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles.
22. The method of claim 19 wherein the method is a method of treating infection in an animal by parasites resistant to at least two of each of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles.
23. The method of claim 19 wherein the method is a method of treating infection in an animal by parasites resistant to at least three of each of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles.
24. The method of claim 19 wherein the method is a method of treating infection in an animal by parasites resistant to all of the groups macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles.
25. The method of claim 19 wherein the method is a method of treating infection in an animal by gastro-intestinal worms and liver fluke.
26. The method of any one of claims 19 to 25 wherein the composition is administered to an animal prior to introduction to a land area so as to prevent the land area from becoming infested with parasites which may or may not be resistant to one or more compounds selected from the groups consisting of macrocylic lactones, benzimidazoles, salicylanilides and imidazothiazoles.
27. The use of a synergistic anthelmintically effective amount of a composition according to any one of claims 1 to 18 and a therapeutically acceptable carrier, in the treatment of a parasitic infection in an animal.
28. The method of any one of claims 19 to 26 or the use of claim 27 wherein the animal is selected from the group consisting of sheep, goats, ruminants and camelids.
AU2009201942A 2003-02-05 2009-05-15 Anthelmintic composition Expired AU2009201942C1 (en)

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PCT/AU2004/000126 WO2004069242A1 (en) 2003-02-05 2004-02-04 Anthelmintic composition
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CN101686962B (en) * 2007-06-29 2012-05-23 辉瑞大药厂 Anthelmintic combination
CN101848710A (en) * 2007-11-09 2010-09-29 英特威国际有限公司 Anthelmintic combination
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ES2667026T3 (en) * 2009-09-07 2018-05-09 Argenta Manufacturing Limited Granulated anthelmintic preparations and administration systems
DK2568980T3 (en) * 2010-05-12 2015-11-30 Merial Inc INJECTABLE PARASITICIDE FORMULATIONS OF LEVAMISOL AND MACROCYCLIC LACTONS
RU2591082C2 (en) 2011-06-23 2016-07-10 Байер Нью Зиленд Лимитед Anti-parasitic composition containing macrocyclic lactone and levamisole, and method of treating parasitic infestation
NZ594610A (en) 2011-08-16 2013-03-28 Virbac New Zealand Ltd Injectable Anthelmintic Formulations cotaining levamisole and one or more macrocyclic lactones for controlling internal parasites in ruminants
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GB2413764A (en) 2005-11-09
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AU2009201942A1 (en) 2009-06-04
AU2004210461B2 (en) 2009-12-03
AU2004210461A1 (en) 2004-08-19
AU2004210461C1 (en) 2017-06-29
GB0516881D0 (en) 2005-09-28
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WO2004069242A1 (en) 2004-08-19
BRPI0407271A (en) 2006-01-31

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