AU2018101849B4 - Improved myiasis control - Google Patents

Abstract

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

Description

IMPROVED MYIASIS CONTROL

The present application is a divisional application of Australian patent application no. 2015230729,

the entirety of which is incorporated herein by reference.

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 of the 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 screw

worm fly (Cochliomyia hominivorax) and the Old World screw-worm fly (Chrysomya bezziana) have

both had wide distribution through tropical regions of the world and can infest livestock and

companion animals. The gray flesh fly (Wohfahrtia vigil) is found further from the tropics, in North

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

1 10879027_1(GHMatters) P100809.AU.2 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 Luciliastrike 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

2 10879027_1 (GHMatters) P100809.AU.2 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

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 low

volume 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

3 10879027_1 (GHMatters) P100809.AU.2 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 todicyclanil: 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 TM; 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 (Zappm ; 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

ZappT" 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.

4 10879027_1 (GHMatters) P100809.AU.2

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

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

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-{1-[(6-Chloro-3-pyridyl)methyl]

4,5-dihydroimidazol-2-yl}nitramide), as shown: HN'NO2

35C

5 108790271 (GHMatters) P100809.AU.2

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'TM; 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.

6 10879027_1 (GHMatters) P100809.AU.2

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

7 10879027_1 (GHMatters) P100809.AU.2 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,

8 10879027_1 (GHMatters) P100809.AU.2 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. (black

bottle 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 I 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

9 10879027_1 (GHMatters) P100809.AU.2 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 aboutmonths' 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

10 10879027_1 (GHMatters) P100809.AU.2 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 months' wool growth. In some

11 10879027_1 (GHMatters) P100809.AU.2 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

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

least about 1 months' wool growth. In some embodiments, the animal is a sheep with at least about

2 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

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 aboutmonths' 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 of the 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,

12 10879027_1 (GHMatters) P100809.AU.2 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 aries), 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 jetting

wand 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

13 10879027_1 (GHMatters) P100809.AU.2 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;

14 108790271 (GHMatters) P100809.AU.2

* emulsions and suspensions for dermal administration, semi-solid preparations, and pre

mixes;

* formulations in which the active compound is incorporated into a cream base or into an oil

in-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 ovine animal, the method comprising

administering to the animal an effective amount of a neonicotinoid, wherein said prevention of

myiasis does not include the use of triflumuron.

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

3. The method of item 1 or 2, wherein the neonicotinoid is administered at a dose-rate of 1 to 80

mg/kg by body weight of the animal.

4. The method of any one of items 1 to 3, wherein the neonicotinoid is imidacloprid.

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

more than 7 days after the animal has been sheared.

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.

15 12348485_1 (GHMatters) P100809.AU.2

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.

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.

16 108790271 (GHMatters) P100809.AU.2

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.

17 10879027_1 (GHMatters) P100809.AU.2

Table 1: Efficacy of a 3.5% (w/v) imidacloprid pour-on in Australian field trials Treatment Study Timing & Treatment Groups Fly Trap Ref. Dose per (No.ofSheep) Findings Sheep Numerous After 1.Untreated((150) Lucilia sp. 5.3% untreated sheep Efficacy to at 6111038 shearing; 2. Imidacloprid (373) present to 19 affected. Nil treated least 15 weeks 60mL 3. Dicyclanil (203) weeks after sheep affected. after treatment. treatment 8.7% untreated sheep Numerousaffected. 0.6% After 1. Untreated (150) Lucilia sp. Efficacy to at imidacloprid-treated 6111039 shearing; 2. Imidacloprid (333) present to 18 least 17 weeks sheep affected. Nil 60mL 3. Dicyclanil (334) weeks after after treatment. treatment dicyclanil-treated sheep affected. Numerous 2 months' Indicative of wool 1. Imidacloprid (196) Lucilia Nil treated sheep efficacy to 13 6111029 presentto 13 growth; 2. Dicyclanil (200) affected. weeks after weeks after 75mL treatment. treatment Numerous 3 months' 2.5% imidacloprid wool 1. Imidacloprid (197) Lucilia treated sheep affected. Efficacytoat 6111046 presentto17 least16 weeks growth; 2. Dicyclanil (198) weet 2.0% dicyclanil-treated aeatent. 50mL ~ ~ weeks after sepafcd.after treatment. treatment sheepaffected. Numerous 2 months' Indicative of wool 1. Imidacloprid (204) Lucilia p Nil treated sheep efficacy to 20 6111045 present to 20 growth; 2. Dicyclanil (206) affected. weeks after weeks after 60mL treatment. treatment

3 months' Numerous Indicative of wool 1. Imidacloprid (220) Lucilia p Nil treated sheep efficacy to 17 6111049 present to17 growth; 2. Dicyclanil (220) affected. weeks after weeks after 75mL treatment. treatment Numerous 3 months' 0.8% imidacloprid Lucilia sp. Efficacy to at wool 1. Imidacloprid (237) treated sheep affected. 6111047 presentto 20 least14 weeks growth; 2. Dicyclanil (235) weet 0.4% dicyclanil-treated aeatent. 60mL ~ ~ weeks after sepafcd.after treatment. 60mLsheafetd 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.

18 108790271 (GHMatters) P100809.AU.2

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.

19 10879027_1 (GHMatters) P100809.AU.2

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.

20 10879027_1 (GHMatters) P100809.AU.2

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.

21 10879027_1 (GHMatters) P100809.AU.2

Claims (5)

The claims defining the invention are as follows:

1. A method for the prevention of myiasis in an ovine animal, the method comprising

administering to the animal an effective amount of a neonicotinoid, wherein said prevention of

myiasis does not include the use of triflumuron.

2. The method as claimed in claim 1, for the prolonged prevention of myiasis in an animal.

3. The method as claimed in claim 1 or 2, wherein the neonicotinoid is administered at a dose-rate

of 1 to 80 mg/kg by body weight of the animal.

4. The method as claimed in any one of claims 1 to 3, wherein the neonicotinoid is imidacloprid.

5. The method as claimed in any one of claims 1 to 4, wherein the neonicotinoid is administered to

the animal more than 7 days after the animal has been sheared.