AU2018101849A4

AU2018101849A4 - Improved myiasis control

Info

Publication number: AU2018101849A4
Application number: AU2018101849A
Authority: AU
Inventors: Warwick Mitchell SMITH; Andreas Turberg
Original assignee: Bayer Australia Ltd
Current assignee: TROY LABORATORIES Pty Ltd
Priority date: 2014-09-22
Filing date: 2018-11-28
Publication date: 2019-01-03
Anticipated expiration: 2023-09-22
Also published as: AU2015230729B2; AU2018101849B4; AU2019201320A1; AU2018101848A4; ZA201507068B; AU2015230729A1; AU2018101848B4

Abstract

Abstract Disclosed are methods, uses and compositions for preventing myiasis in animals. 10879027_1 (GHMatters) P100809.AU.2

Description

Technical Field

The present invention relates to the use of neonicotinoids for the control of myiasis in animals.

Background

Myiasis is the term used to describe the infestation ofthe tissues of a living vertebrate host with fly larvae. All such flies belong to the order Diptera and are typically from the families Oestridae, Calliphoridae or Sarcophagidae. Individual species belong largely to the genera Lucilia, Calliphora,

Chrysomya, Phormia and Sarcophaga.

Myiasis-causing flies can be categorised on the basis of their dependence upon a living vertebrate host for larval development. The obligate parasites within this group cannot complete their lifecycle without a living host (i.e. specific myiasis). Other species, referred to as facultative parasites, typically lay their eggs in decomposing animal tissue or vegetable matter but can also lay their eggs on living hosts (i.e. semi-specific myiasis). A third category comprises a diverse collection of flies that do not require a host, nor do they seek decaying animal tissue, for larval development but rather become accidental parasites due to entry of eggs into a host, for example, via ingestion or inhalation (i.e. accidental myiasis).

There are numerous myiasis-causing fly species of veterinary importance. The New World screwworm fly (Cochliomyia hominivorax) and the Old World screw-worm fly (Chrysomya bezziana) have both had wide distribution through tropical regions ofthe world and can infest livestock and companion animals. The gray flesh fly (Wohlfahrtia vigil) is found further from the tropics, in North 30 America, and can cause myiasis in animals.

In Africa, the tumbu fly (Cordylobia anthropophaga) causes a similar furuncular lesion in humans and animals. Warble flies consist of numerous species belonging to the genus Hypoderma. These species are widespread in the northern hemisphere and their hosts include cattle, deer and horses. Oestrus

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2018101849 28 Nov 2018 ovis, the sheep bot fly, is widely distributed in sheep populations around the world. The larvae of this fly develop in the nasal cavity where it can result in severe irritation to the sheep.

Cutaneous ovine myiasis is a significant problem in sheep-producing regions of the world. The lesion caused by the developing larvae is typically referred to as a 'strike'. Facultatively-parasitic flies capable of initiating a strike lesion are known as primary species. Those species that colonise existing strike lesions only are known as secondary (and tertiary) species. Lucilia sericata and L. cuprina are primary species of particular importance in causing fly strike in sheep around the world.

In Australia, L. cuprina is known as the sheep blowfly and is responsible for initiation of over 90% of ovine strike lesions. As such, it is a major source of economic loss to the sheep industry and a significant threat to animal welfare. As of 2014, the annual costs associated with treatment and lost production are estimated to exceed $280 million (http://www.flyboss.org.au/). Other species, including Calliphora stygia and C. augur, may also be involved in fly strike in Australia but are considered to be of less importance than L. cuprina.

In New Zealand, L. sericata and C. stygia are considered to be primary agents of ovine myiasis but L. cuprina is also of increasing importance. Both species of Lucilia are found in South Africa but there L. cuprina is considered to be responsible for almost all primary strikes. L. sericata is of greater importance as a primary strike fly throughout most of Europe but towards the east, and extending into China, Wohlfahrtia magnifica is of increasing importance.

The adult female Lucilia strike flies are attracted to sheep with damp or soiled wool, or 'fleece rot' (infection with Pseudomonas aeruginosa) and they lay their eggs in the fleece. After hatching, the first instar larvae rely on moisture and nutrients within the fleece to survive. As they moult to second and third instar stages, the larvae feed at the skin surface. Secretion of proteolytic enzymes and abrasion with their mouth hooks causes damage and irritation to the skin. This irritation induces exudate which provides the larvae access to additional moisture and nutrients. The larvae move about the skin surface feeding on exudate, dead tissue, secretions and other debris. They do not feed directly on living tissue but the presence and feeding activity of the larvae progressively destroys layers of the skin leaving an open, raw wound.

The expansion and severity of the wound can progress extremely rapidly, especially when numerous larvae are present. Eggs typically hatch 12-24 hours after oviposition and the larvae develop rapidly

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2018101849 28 Nov 2018 through the larval stages to readiness for pupation in the soil approximately 3-4 days later. An active strike lesion presents a strong olfactory attractant to female flies (including secondary and tertiary species) as an ideal environment in which to lay their eggs. Continuing colonisation and expansion of the wound can result in death of the sheep after only several days (e.g. due to shock, toxicity or infection).

The susceptibility of sheep to myiasis by primary flies such as L. cuprina can be reduced by selective breeding, 'mulesing' of young lambs (a surgical operation to improve conformity of the skin around the rump), shearing away wool contaminated with urine and faeces (referred to as 'crutching') and 10 chemical treatment. In Australia, chemical treatment is critical to prevention of myiasis during the warmer and more humid times of the year when the adult flies are most active.

Methods of treatment with chemicals to prevent strike can be broadly categorised into high-volume application of diluted chemical (i.e. in water) or low-volume delivery of concentrated chemical formulations. High-volume application methods have included plunge dips, shower dips, jetting races and hand jetting. Low-volume application methods have become very popular due to their convenience and are typically ready-to-use spray-on formulations. Some restrictions on the suitability of different application methods can depend upon the length of wool on the sheep to be treated. In general, the low-volume application methods are more likely to be suitable for treatment of sheep with either short or long wool.

In recent years, chemical groups that have been used for prevention of strike in Australia include the spinosyns, macrocyclic lactones (MLs), insect growth regulators (IGRs), synthetic pyrethroids (SPs) and organophosphates (OPs). An important consideration for the sheep producer selecting a product to treat sheep is the persistency of the preventative effect. In many areas, flies may be intermittently active over a period of up to 6 months. It is a labour-intensive, and often expensive, exercise for producers to muster sheep for chemical treatments. For these reasons, products with prolonged periods of efficacy are an invaluable tool for producers to manage fly strike in their flock.

Currently, the only commercial products that provide greater than several weeks protection against myiasis in Australian sheep contain chemicals of the IGR group. The IGR Dicyclanil, applied as a lowvolume spray-on, has a registered label claim in Australia for up to 18-24 weeks protection against fly strike. Another IGR Cyromazine, applied as a low-volume spray-on or as a high-volume jetting fluid, can protect sheep for up to 11 and 14 weeks, respectively. Both these chemicals inhibit

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2018101849 28 Nov 2018 moulting of the blowfly larvae and thus prevent their growth and development. The prolonged efficacy of these products is due to persistence of the chemical in the fleece of the sheep.

In 2012, an Australian field isolate of Lucilia cuprina was shown to be resistant to cyromazine. Upon further investigation, these flies were also shown to possess cross-resistance to dicyclanil: GW Levot, 2012 'Cyromazine resistance detected in Australian sheep blowfly', Australian Veterinary Journal, Volume 90, No 11, November 2012. This emergence of potential field resistance to both important IGR chemicals in Australia highlights the risk of current commercial products reducing in effectiveness in the future. Consequently, new products containing active ingredients from different chemical classes that provide prolonged periods of protection will be critically important to maintain adequate control of ovine myiasis.

In New Zealand, a low-volume pour-on product containing 3.0% w/v imidacloprid and 2.5% w/v triflumuron (Zapp Encore™; Bayer NZ Ltd) is marketed for treatment and prevention of ovine myiasis. Triflumuron is a member of the IGR chemical group and, although there is widespread parasite resistance in Australia, it continues to be effective against strike flies in New Zealand. This combination product is registered with the same claims for prevention of myiasis as the predecessor product, a 2.5% w/v triflumuron pour-on (Zapp™; Bayer NZ Ltd). Specifically, protection against flystrike for 8 weeks, but in some cases may be longer.

Triflumuron, as an IGR, is a relatively slow acting insecticide that kills the insect by preventing moulting, which take several days for a larvae. Accordingly, imidacloprid was added to the original Zapp™ product for the purpose of providing rapid knockdown of parasites, while the triflumuron provides the long-term protection against flies and lice.

There is a clear need for a product that provides prolonged protection against myiasis for sheep based on an active ingredient from an alternative class of chemicals. Such a new product would provide for:

1) Effective treatment in areas where IGR resistance has emerged,

2) Effective rotation between chemical classes in areas where IGR resistance has not yet emerged to delay resistance and prolong the effective life of all products.

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2018101849 28 Nov 2018

It would be advantageous to address the foregoing problems or at least to provide the public with a useful choice.

All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in 10 New Zealand or in any other country.

Throughout this specification, the word comprise, or variations thereof such as comprises or 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 15 of elements, integers or steps.

Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only.

Summary of the Invention

The inventors have discovered that the use of neonicotinoids is surprisingly effective in the control of myiasis in an animal.

The neonicotinoids are a preferred class of chemical compounds that are agonists and antagonists of the acetylcholine receptors in insects. Suitable neonicotinoid compounds include but are not limited to the agonists or antagonists of the nicotinergic acetylcholine receptors in insects as described in the patent publication NZ 272141 which is incorporated herein by reference. Preferred neonicotinoids are imidacloprid and thiacloprid.

An especially preferred neonicotinoid compound is imidacloprid, (N-{l-[(6-Chloro-3-pyridyl)methyl]4,5-dihydroimidazol-2-yl}nitramide), as shown:

Hn-^N°2

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2018101849 28 Nov 2018

In Australia, a low-volume ready-to-use product containing 3.5% w/v imidacloprid was approved for control of sheep lice (Bovicola ovis) in 2009 (Avenge™; Bayer Australia Ltd). This product is preferably applied within 24 hours of shearing, but is also effective when applied off-shears up to 7 days after shearing, and effectively kills sheep lice for a period of four weeks after application. Following this period, treated sheep can be re-infested if they are exposed to a new source of lice. The relatively short period of lousicidal efficacy is likely due to the rapid decline in imidacloprid concentrations in the fleece.

It has now been surprisingly found by the inventors that despite the rapid decline in fleece concentrations responsible for the relatively short period of lousicidal efficacy, a neonicotinoid such as imidacloprid can exert a prolonged protective effect against myiasis when applied to susceptible sheep. This result is contrary to previous expectations regarding the activity of neonicotinoid compounds. The inventors have further found that a neonicotinoid can exert a prolonged protective effect against myiasis even when applied to a sheep more than 7 days after shearing. The inventors have even more surprisingly found that the protective effect is exerted when the neonicotinoid is applied to sheep with even longer wool, e.g. sheep with 1, 2, 3 or more months of wool growth.

One aspect of the invention broadly consists in the use of a neonicotinoid for the control of myiasis in an animal. Preferably the neonicotinoid is used for control of myiasis caused by diptera. Preferably the neonicotinoid is used for control of myiasis on an animal selected from the group consisting of bovine, ovine and caprid. Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the neonicotinoid is administered to the animal as a topical application. Preferably the neonicotinoid is administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the treated animal.

Preferably the use of the neonicotinoid provides prolonged control of myiasis in an animal. Preferably the prolonged control is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More preferably the prolonged control is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged control is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal.

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2018101849 28 Nov 2018

Another aspect of the invention broadly consists in a method of controlling myiasis in an animal, the method comprising administering to the animal an effective amount of a neonicotinoid. Preferably the neonicotinoid is administered as a topical application. In some embodiments, the neonicotinoid is administered by localised topical application, that is, by topical application to part of the exterior (e.g. the skin, fleece or fur) of the animal. Preferably the method is for control of myiasis caused by diptera. Preferably the method is for an animal selected from the group consisting of bovine, ovine and caprid. Preferably the method uses a neonicotinoid selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam.

More preferably the neonicotinoid used in the method is imidacloprid. Preferably the method uses the neonicotinoid administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the animal.

Preferably the method is for long-term control of myiasis. Preferably the method provides prolonged control of myiasis in an animal. Preferably the prolonged control is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More preferably the prolonged control is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged control is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal.

Another aspect of the invention broadly consists in a composition comprising a neonicotinoid and a pharmacologically acceptable carrier, when used for the control of myiasis in an animal. Another aspect of the invention broadly consists in a composition comprising a neonicotinoid and a pharmacologically acceptable carrier, for use in the control of myiasis in an animal. Preferably the neonicotinoid is present in a concentration of between 0.1 and 30% w/v. More preferably the neonicotinoid is present in a concentration of between 3 and 10% w/v, e.g. 3 to 9% w/v, 3 to 8% w/v, 3 to 7% w/v, 3 to 6% w/v, 3 to 5% w/v, or 3 to 4% w/v. Preferably the composition does not include triflumuron and/or other IGRs.

Another aspect of the invention broadly consists in the use of a neonicotinoid in the manufacture of a medicament for the control of myiasis in an animal. Preferably the medicament is for the control of myiasis caused by diptera. Preferably the medicament is for the control of myiasis on an animal selected from the group consisting of bovine, ovine and caprid. Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the medicament is for

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2018101849 28 Nov 2018 topical application to the animal. Preferably the medicament contains neonicotinoid in an amount of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the animal.

Preferably the medicament is for prolonged control of myiasis in an animal. Preferably the prolonged control is provided by the neonicotinoid having an effect more than 4 weeks after administration of the medicament. More preferably the prolonged control is provided by the neonicotinoid having an effect more than 8 weeks after administration of the medicament. Even more preferably the prolonged control is provided by the neonicotinoid having an effect more than 12 weeks after administration of the medicament.

Compared to prior art mysiasis controls that use IGRs such as dicyclanil, a neonicotinoid provides rapid knock-down by killing insects through the action on the nicotinergic acetylcholine receptor. An IGR has a delayed response with no knock-down, relying on the next life-cycle stage of a juvenile insect to have a lethal effect.

The use of a neonicotinoid in controlling myiasis in animals may provide the advantage of both lice control and fly control with only one active that can be administered as a single treatment. This can advantageously reduce the significant labour required to administer separate lice control and fly control treatments.

The use of a single active in a single treatment can be manufactured at a lower cost than treatments containing multiple-actives, with further benefits of easier formulation development, and potentially fewer residues and lower overall toxicity in the treated animals and lower impact on the environment due to fewer active chemicals.

Compared to a triflumuron and imidacloprid combination in particular, the use of imidacloprid without triflumuron avoids the issues with resistance associated with triflumuron in some areas, such as Australia.

Studies have surprisingly shown that neonicotinoids are effective in preventing myiasis for up to 20 weeks and possibly longer.

The present invention is suitable for controlling myiasis in humans and other animals. Suitable animals include but are not limited to productive livestock and breeding animals, including mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits,

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2018101849 28 Nov 2018 fallow deer, reindeer, fur-bearing animals, such as, for example, mink, chinchilla, racoon; birds such as, for example, chickens, geese, turkeys and ducks; laboratory and experimental animals including mice, rats, guinea pigs, golden hamsters; and pets such as dogs and cats.

Preferred animals for use with the invention include cattle, sheep and goats, which when referred to herein more generally signify the bovine, ovine and caprid families respectively.

The present invention is suitable for the control of myiasis caused or potentially caused by species, including but not limited to Dermatobia hominis (human botfly), Cordylobia anthropophaga (tumbu fly), Oestrus ovis (sheep botfly), Hypoderma spp. (cattle botflies or ox warbles), Gasterophilus spp. (horse botfly), Cochliomyia hominivorax (new world screwworm fly), Chrysomya bezziana (old world screwworm fly), Auchmeromyia senegalensis (Congo floor maggot), Cuterebra spp. (rodent and rabbit botfly), Lucilia spp. (green-bottle fly), Cochliomyia spp. (blue-bottle fly), Phormia spp. (blackbottle fly), Calliphora spp. (blowfly), Sarcophaga spp. (flesh fly or sarcophagids), Musca domestica (housefly), Fannia spp. (latrine flies), Eristalis tenax (rat-tailed maggots), Muscina spp.

As used herein, controlling myiasis or control of myiasis encompasses preventing myiasis, hindering the development of myiasis, and/or alleviating or reversing the symptoms of myiasis.

Thus, in one aspect, the present invention provides a method of preventing myiasis in an animal comprising administering to the animal an effective amount of a neonicotinoid. In another aspect, the present invention provides a method for the prolonged prevention of myiasis in an animal comprising administering to the animal an effective amount of a neonicotinoid. In some embodiments, the myiasis is myiasis caused by diptera. Preferably the animal is selected from the group consisting of bovine, ovine and caprid. More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at least about 1 months' wool growth (that is, the neonicotinoid is applied to the sheep 1 or more months after shearing). In some embodiments, the animal is a sheep with at least about 2 or 3 months' wool growth (that is, the neonicotinoid is applied to the sheep 2 or 3 or more months after shearing). Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the neonicotinoid is administered to the animal as a topical application. Preferably the neonicotinoid is administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the treated animal. Preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More

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2018101849 28 Nov 2018 preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal. In some embodiments, an IGR (e.g. triflumuron) is not co-administered with the neonicotinoid.

In another aspect, the present invention provides the use of a neonicotinoid for preventing myiasis in an animal. In another aspect, the present invention provides the use of a neonicotinoid for the prolonged prevention of myiasis in an animal. In some embodiments, the myiasis is myiasis caused by diptera. Preferably the animal is selected from the group consisting of bovine, ovine and caprid.

More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at least about 1 months' wool growth. In some embodiments, the animal is a sheep with at least about 2 or 3 months' wool growth. Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the neonicotinoid is administered to the animal as a topical application. Preferably the neonicotinoid is administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the treated animal. Preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal. In some embodiments, an IGR (e.g. triflumuron) is not co-administered with the neonicotinoid.

In another aspect, the present invention provides the use of a neonicotinoid in the manufacture of a medicament for preventing myiasis in an animal. In another aspect, the present invention provides the use of a neonicotinoid in the manufacture of a medicament for the prolonged prevention of myiasis in an animal. In some embodiments, the myiasis is myiasis caused by diptera. Preferably the animal is selected from the group consisting of bovine, ovine and caprid. More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at least about 1 months' wool growth.

In some embodiments, the animal is a sheep with at least about 2 or 3 months' wool growth. Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the neonicotinoid is administered to the animal as a topical application. Preferably the neonicotinoid is administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the treated animal. Preferably the prolonged

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2018101849 28 Nov 2018 prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal. In some embodiments, an IGR (e.g. triflumuron) is not co-administered with the neonicotinoid. In some embodiments, the medicament does not include an IGR (e.g. triflumuron).

In another aspect, the present invention provides a composition comprising a neonicotinoid and a pharmacologically acceptable carrier, when used for preventing myiasis in an animal. In another aspect, the present invention provides a composition comprising a neonicotinoid and a pharmacologically acceptable carrier, when used for the prolonged prevention of myiasis in an animal. In some embodiments, the myiasis is myiasis caused by diptera. Preferably the animal is selected from the group consisting of bovine, ovine and caprid. More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at least about 1 months' wool growth. In some embodiments, the animal is a sheep with at least about 2 or 3 months' wool growth. Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the neonicotinoid is administered to the animal as a topical application. Preferably the neonicotinoid is administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the treated animal. Preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal. In some embodiments, the composition does not include an IGR (e.g. triflumuron).

In another aspect, the present invention provides a composition comprising a neonicotinoid and a pharmacologically acceptable carrier, for use in preventing myiasis in an animal. In another aspect, the present invention provides a composition comprising a neonicotinoid and a pharmacologically acceptable carrier, for use in the prolonged prevention of myiasis in an animal. In some embodiments, the myiasis is myiasis caused by diptera. Preferably the animal is selected from the group consisting of bovine, ovine and caprid. More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at least about 1 months' wool growth. In some

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2018101849 28 Nov 2018 embodiments, the animal is a sheep with at least about 2 or 3 months' wool growth. Preferably the neonicotinoid is selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. More preferably the neonicotinoid is imidacloprid. Preferably the neonicotinoid is administered to the animal as a topical application. Preferably the neonicotinoid is administered at a dose-rate of between 1 and 80 mg/kg (e.g. between 1 and 50 mg/kg or between 5 and 50 mg/kg) by body weight of the treated animal. Preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. More preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 8 weeks after administration to an animal. Even more preferably the prolonged prevention is provided by the neonicotinoid having an effect more than 12 weeks after administration to an animal. In some embodiments, the composition does not include an IGR (e.g. triflumuron).

In one embodiment, the present invention provides a method for the prolonged prevention of myiasis in an animal, the method comprising administering an effective amount of a neonicotinoid 15 to the animal (e.g. an amount of 1 to 80 mg/kg by body weight of the animal), wherein the prolonged prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal. Preferably an IGR (e.g. triflumuron) is not co-administered with the neonicotinoid. Preferably the animal is selected from the group consisting of bovine, ovine and caprid. More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at 20 least about 1 months' wool growth. In some embodiments, the animal is a sheep with at least about or 3 months' wool growth.

In one particular embodiment, the present invention provides a method for the prolonged prevention of myiasis in an animal, the method comprising administering imidacloprid to the animal 25 in an amount of 1 to 80 mg/kg by body weight of the animal, wherein the prolonged prevention is provided by the imidacloprid having an effect more than 4 weeks after administration to an animal. Preferably an IGR (e.g. triflumuron) is not co-administered with the neonicotinoid. Preferably the animal is selected from the group consisting of bovine, ovine and caprid. More preferably the animal is a sheep. In some embodiments, the animal is a sheep with at least about 1 months' wool growth.

In some embodiments, the animal is a sheep with at least about 2 or 3 months' wool growth.

The preferred method of administration ofthe neonicotinoid compound is topical administration.

The most suitable method of administration may depend on the type and condition of the animal to which the treatment is applied. Examples of topical administration include administering the neonicotinoid dropwise, brushing on, rubbing in, spraying on, splashing on; and applying by dipping,

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2018101849 28 Nov 2018 bathing, washing, shampooing, jetting, pouring on, spotting on, pouring over or dusting. Another example of topical administration is the use of a dermal-contacting device, such as a collar, containing the neonicotinoid.

The present invention is particularly relevant to sheep farming, due to the considerable economic and animal-welfare issues caused by flystrike (myiasis) of sheep (Ovis dries), especially in Australia and New Zealand. Accordingly, methods are described with particular reference to administration to sheep; however one skilled in the art will be aware of suitable adaptations and means for administering to other animals.

The present invention advantageously provides control of myiasis in sheep with a broad range of wool length, the range including sheep that have been newly shorn (off-shears), extending to sheep with long wool, such as 6 months of wool growth.

The preferred administration methods for treating sheep in accordance with the present invention include backlining, dipping, and jetting.

A traditional form of dipping for sheep is known as plunge dipping, wherein the sheep are mustered through a deep trough containing the treatment liquid. The sheep swim though the liquid allowing the liquid to penetrate into the fleece. The sheep may also be completely submerged into the liquid by a handler immersing the head of each sheep into the liquid.

An alternative method of dipping is known as shower dipping, wherein the sheep are sprayed with the treatment liquid from overhead nozzles and optionally from side spraying nozzles. A typical arrangement uses a circular treatment enclosure with a rotating boom arm with downwards spraying nozzles mounted above the enclosure. The treatment time is approximately 12 minutes for the sheep to be sufficiently wetted with the treatment liquid.

The jetting procedure involves the use of a high pressure stream or jet of treatment fluid being directed onto the animal. The application technique includes manual hand-jetting and the use of an automated jetting race. Manual hand-jetting uses a pump to supply treatment fluid to a jettingwand held by an operator, who administers the treatment to the sheep. The jetting-wand includes a spray head with a nozzle or nozzles for directing the liquid into the fleece of the sheep, which helps saturate areas of the fleece and provide skin contact with the liquid. The operator uses the jetting wand to apply the liquid as onto different areas of the animal's body. The areas for administration may be chosen by the operator depending on the circumstances, such as wool length, the

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2018101849 28 Nov 2018 prevalence of fly-strike on certain areas and the requirements for different animals such as rams and wethers. The pressure of the jets is typically around 700 kPa, and the minimum volume of treatment liquid is around 0.5 L per month of wool growth.

An automated jetting race is a less laborious method of jetting compared to hand-jetting, using apparatus that applies treatment liquid to the back of an animal as it passes under a series of nozzles while traveling through the apparatus. Generally a higher volume and lower pressure of treatment liquid is used, compared to hand jetting.

The backlining technique, otherwise referred to as pour-on or spray-on, is the application of a relatively small amount of liquid to the back of an animal. The liquid may be applied as a spray or a stream or jet of liquid, using manual applicators or power assisted applicators. The volume, concentration, viscosity and other properties of the treatment liquid may vary depending on the requirements. Typically a pour-on is administered in two or more bands along either side of the spine of the sheep.

For example, for a ready-to-use product containing 3.5% w/v imidacloprid, the following dosing may be used for application to sheep:

Bodyweight of sheep (kg)	Dose (mL)	Method of application
Below 6kg	8	Single stripe along the back of the sheep
6.0-8.0	12	Single stripe along the back of the sheep
8.1-10.0	15	Single stripe along the back of the sheep
10.1-12.5	20	Single stripe along the back of the sheep
12.6-15	25	Single stripe along the back of the sheep
15.1-20	30	Single stripe along the back of the sheep
20.1-30	40	Single stripe along the back of the sheep
30.1-55	60	Double stripe along the back of the sheep
55.1-80	80	Double stripe along the back of the sheep
80.1-100	90	Double stripe along the back of the sheep

Suitable preparations of neonicotinoid for use with the present invention include:

• solutions or concentrates for administration after dilution, solutions for use on the skin, pour-on and spot-on formulations, gels;

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2018101849 28 Nov 2018 • emulsions and suspensions for dermal administration, semi-solid preparations, and premixes;

• formulations in which the active compound is incorporated into a cream base or into an oilin-water or water-in-oil emulsion base;

· powder preparations for dusting;

• solid preparations such as powders, or shaped articles containing an active compound.

The present invention as claimed herein is described in the following items 1 to 5:

1. A method for the prevention of myiasis in an animal, the method comprising administering to the animal an effective amount of a neonicotinoid.

2. The method of item 1, for the prolonged prevention of myiasis in an animal.

3. The method of item 1 or 2, wherein triflumuron is not co-administered with the neonicotinoid.

4. The method of any one of items 1 to 3, wherein the neonicotinoid is administered at a doserate of 1 to 80 mg/kg by body weight of the animal.

5. The method of any one of items 1 to 4, wherein the neonicotinoid is imidacloprid.

Aspects of the present invention will now be described by way of example only with reference to various experiments and trials conducted by the applicant.

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BEST MODES FOR CARRYING OUT THE INVENTION

The following examples illustrate the invention. In particular, Examples 1 and 2 present suitable neonicotinoid-containing formulations for use with the invention. Examples 3 and 4 present the results of animal trials.

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Example 1
Ingredients	Proportion
Imidacloprid	3.5% (w/v)	active
DMA (Dimethyl acetamide)	40% (w/v)	solvent
BHT (butylated hydroxytoluene)	0.2% (w/v)	antioxidant
Dipropylene glycol methyl ether	q.s. to 100%	co-solvent

Example 2
Ingredients	Proportion
Imidacloprid	3.5% (w/v)	active
DMA (Dimethyl acetamide)	50% (w/v)	solvent
BHT (butylated hydroxytoluene)	0.2% (w/v)	antioxidant
DMI (Dimethyl isosorbide)	q.s. to 100%	co-solvent

Example 3

Two studies utilising a method of artificially inducing myiasis with L. cuprina (i.e. a larval implant model) were undertaken in Australia to assess the protective effect of imidacloprid when applied as low-volume pour-on formulations. Both studies used similar active ingredient dose rates and application methods. The initial study utilised a 4% (w/v) imidacloprid formulation and demonstrated a significant level of efficacy to 10 weeks after treatment of sheep with 6 months' wool growth [BAL 014/02], The second study utilised a 3.5% (w/v) imidacloprid formulation and demonstrated a significant level of efficacy to 10 weeks after treatment of sheep with 3 months' wool growth [6108030], In this second study, exposure to samples of treated wool did not have an effect on adult L. cuprina flies.

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Example 4

A 3.5% (w/v) imidacloprid formulation was then tested in a series of field trials (on commercial

Australian sheep properties) to determine efficacy against naturally-occurring myiasis in susceptible Merino sheep. The product was applied as a pour-on (backlining) either immediately after shearing or to sheep with at least two months' wool growth. The positive control groups in the studies were treated similarly with an IGR product containing 5% dicyclanil (50g/L). The average weight of the sheep in the trials was about 50 kg.

Blowfly traps were regularly assessed to confirm exposure of sheep to Lucilia spp. during the conduct of the studies. This was particularly important to demonstrate the potential for myiasis where no untreated sheep were included at the trial site.

A summary of the field trials are shown in Table 1. It can be seen from the results of both the previous mentioned larval implant studies and the larger scale field trials of Table 1 that the application of imidacloprid has had a surprisingly long-lasting effect in preventing myiasis in susceptible Merino sheep.

The inventive control of myiasis in the field using neonicotinoids may be greater than that expected from controlled studies, due to the repellent effect of the neonicotinoid. Artificial studies that rely on larval implants or sensitivity of flies to residues in fleece may not be able to predict any additional control of myiasis due to flies avoiding animals that have been treated with neonicotinoids.

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Table 1: Efficacy of a 3.5% (w/v) imidacloprid pour-on in Australian field trials

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Study Ref.	Treatment Timing & Dose per Sheep	Treatment Groups (No.of Sheep)	Fly Trap Findings	Myiasis Findings	Conclusions
6111038	After shearing; 60mL	1. Untreated((150) 2. Imidacloprid (373) 3. Dicyclanil (203)	Numerous Lucilia sp. present to 19 weeks after treatment	5.3% untreated sheep affected. Nil treated sheep affected.	Efficacy to at least 15 weeks after treatment.
6111039	After shearing; 60mL	1. Untreated (150) 2. Imidacloprid (333) 3. Dicyclanil (334)	Numerous Lucilia sp. present to 18 weeks after treatment	8.7% untreated sheep affected. 0.6% imidacloprid-treated sheep affected. Nil dicyclanil-treated sheep affected.	Efficacy to at least 17 weeks after treatment.
6111029	2 months' wool growth; 75mL	1. Imidacloprid (196) 2. Dicyclanil (200)	Numerous Lucilia sp. present to 13 weeks after treatment	Nil treated sheep affected.	Indicative of efficacy to 13 weeks after treatment.
6111046	3 months' wool growth; 50mL	1. Imidacloprid (197) 2. Dicyclanil (198)	Numerous Lucilia sp. present to 17 weeks after treatment	2.5% imidaclopridtreated sheep affected. 2.0% dicyclanil-treated sheep affected.	Efficacy to at least 16 weeks after treatment.
6111045	2 months' wool growth; 60mL	1. Imidacloprid (204) 2. Dicyclanil (206)	Numerous Lucilia sp. present to 20 weeks after treatment	Nil treated sheep affected.	Indicative of efficacy to 20 weeks after treatment.
6111049	3 months' wool growth; 75mL	1. Imidacloprid (220) 2. Dicyclanil (220)	Numerous Lucilia sp. present to 17 weeks after treatment	Nil treated sheep affected.	Indicative of efficacy to 17 weeks after treatment.
6111047	3 months' wool growth; 60mL	1. Imidacloprid (237) 2. Dicyclanil (235)	Numerous Lucilia sp. present to 20 weeks after treatment	0.8% imidaclopridtreated sheep affected. 0.4% dicyclanil-treated sheep affected.	Efficacy to at least 14 weeks after treatment.

Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims.

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Also described herein are the following items 1 to 42:

1. The use of a neonicotinoid for the control of myiasis in an animal.

2. The use of item 1 for the prolonged control of myiasis in an animal.

3. The use of item 1 or 2 for control of myiasis caused by diptera.

4. The use of any one of items 1 to 3 wherein the animal is selected from the group consisting of bovine, ovine and caprid.

5. The use of any one of items 1 to 4 wherein the neonicotinoid is imidacloprid.

6. The use of any one of items 1 to 5 wherein the neonicotinoid is administered to the animal as a topical application.

7. The use of any one of items 1 to 6 wherein the neonicotinoid is administered at a dose-rate of between 1 and 50 mg/kg by body weight of the animal.

8. A method of controlling myiasis in an animal, the method comprising administering to the animal an effective amount of a neonicotinoid.

9. The method of item 8 wherein the neonicotinoid is administered as a topical application.

10. The method of item 8 or 9 for prolonged control of myiasis in an animal.

11. The method of any one of items 8 to 10 for control of myiasis caused by diptera.

12. The method of any one of items 8 to 11 wherein the animal is selected from the group consisting of bovine, ovine and caprid.

13. The method of any one of items 8 to 12 wherein the neonicotinoid is imidacloprid.

14. The method of any one of items 8 to 13 wherein the neonicotinoid is administered at a dose-rate of between 1 and 50 mg/kg.

15. A composition comprising a neonicotinoid and a pharmacologically acceptable carrier, when used for the control of myiasis in an animal.

16. A composition comprising a neonicotinoid and a pharmacologically acceptable carrier, for use in the control of myiasis in an animal.

17. The composition of item 15 or 16 wherein the neonicotinoid is present in a concentration of between 0.1 and 10% w/v.

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18. The composition of any one of items 15 to 17 wherein the neonicotinoid is present in a concentration of between 3 and 10% w/v.

19. The composition of any one of items 15 to 18 wherein the composition does not include triflumuron.

20. The use of a neonicotinoid for preventing myiasis in an animal.

21. The use of a neonicotinoid for the prolonged prevention of myiasis in an animal.

22. The use of a neonicotinoid in the manufacture of a medicament for preventing myiasis in an animal.

23. The use of a neonicotinoid in the manufacture of a medicament for the prolonged prevention of myiasis in an animal.

24. A method of preventing myiasis in an animal comprising administering to the animal an effective amount of a neonicotinoid.

25. A method for the prolonged prevention of myiasis in an animal comprising administering to the animal an effective amount of a neonicotinoid.

26. A composition comprising a neonicotinoid and a pharmacologically acceptable carrier, when used for preventing myiasis in an animal.

27. A composition comprising a neonicotinoid and a pharmacologically acceptable carrier, when used for the prolonged prevention of myiasis in an animal.

28. A composition comprising a neonicotinoid and a pharmacologically acceptable carrier, for use in preventing myiasis in an animal.

29. A composition comprising a neonicotinoid and a pharmacologically acceptable carrier, for use in the prolonged prevention of myiasis in an animal.

30. The use of any one of items 20 to 23, the method of item 24 or 25, or the composition of any one of items 26 to 29, wherein the myiasis is myiasis caused by diptera.

31. The use of any one of items 20 to 23, the method of item 24 or 25, or the composition of any one of items 26 to 29, wherein the animal is selected from the group consisting of bovine, ovine and caprid.

32. The use of any one of items 20 to 23, the method of item 24 or 25, or the composition of any one of items 26 to 29, wherein the neonicotinoid is imidacloprid.

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33. The use of any one of items 20 to 23, the method of item 24 or 25, or the composition of any one of items 26 to 29, wherein the neonicotinoid is administered to the animal as a topical application.

34. The use of any one of items 20 to 23, the method of item 24 or 25, or the composition of any one of items 26 to 29, wherein the neonicotinoid is administered at a dose-rate of between 1 and 50 mg/kg by body weight of the animal.

35. The use of any one of items 20 to 23, or the method of item 24 or 25, wherein an insect growth regulator (IGR) is not co-administered with the neonicotinoid.

36. The use of item 22 or 23, wherein the medicament does not include an insect growth regulator (IGR).

37. The composition of any one of items 26 to 29, wherein the composition does not include an insect growth regulator (IGR).

38. The use of item 21 or 23; the method of item 25; the composition of item 27 or 29; the use, method or composition of any one of items 30 to 34 when dependent on any one of items 21,

23, 25, 27 or 29; the use or method of item 35 when dependent on any one of items 21, 23 and

25; the use of item 36 when dependent on item 23; or the composition of item 37 when dependent on item 27 or 29; wherein the prolonged prevention is provided by the neonicotinoid having an effect more than 4 weeks after administration to an animal.

39. The use, method or composition of item 38, wherein the animal is a sheep with at least about 1 months' wool growth.

40. The use, method or composition of item 39, wherein the animal is a sheep with at least about 2 months' wool growth.

41. The use, method or composition of item 40, wherein the animal is a sheep with at least about 3 months' wool growth.

42. The use, method or composition of item 41, wherein the animal is a sheep with about 6 months' wool growth.

Claims

The claims defining the invention are as follows:

1. A method for the prevention of myiasis in an animal, the method comprising administering to the animal an effective amount of a neonicotinoid.
2. The method as claimed in claim 1, for the prolonged prevention of myiasis in an animal.

5
3. The method as claimed in claim 1 or 2, wherein triflumuron is not co-administered with the neonicotinoid.
4. The method as claimed in any one of claims 1 to 3, wherein the neonicotinoid is administered at a dose-rate of 1 to 80 mg/kg by body weight of the animal.
5. The method as claimed in any one of claims 1 to 4, wherein the neonicotinoid is imidacloprid.