AU2013204134B2 - Ectoparasitic Treatment Method and Composition - Google Patents

Abstract

Abstract: The present invention relates to a method for treating ectoparasitic infestation in an animal with a composition comprising a pharmaceutically effective amount of neonicotinoid.

Description

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013

ECTOPARASITIC TREATMENT METHOD AND COMPOSITION TECHNICAL FIELD

This invention relates to an ectoparasitic treatment method and composition. 5 In particular, the present invention relates to the treatment of biting lice on sheep, although it should be appreciated that aspects of the present invention can be extended to related matters.

BACKGROUND ART

Ectoparasites are a significant animal health concern as well as significantly affecting o production and increasing labour and capital costs.

In general, there are many ways to treat ectoparasites, but it is a continual battle to find new and more effective treatments.

Referring now to a specific problem the inventors seek to address, lice and blowflies are the two most significant external parasite problems experienced by sheep in Australia. Both 5 parasite groups cause extensive production losses and serious animal welfare concerns. Of these two ectoparasite groups only the lice are obligate and permanent sheep parasites. That is, they are dependent on spending their entire life cycle on sheep. The most prevalent and most important of the sheep lice is the biting louse, Bovicola (formerly Damalinia) ovis.

Lice are typically categorised into those that feed directly on the blood of the host, i.e. sucking !0 lice, and those that feed on the skin surface (e.g. on secretions and skin debris), i.e. biting (or chewing) lice. Three species of sucking louse are known to occur on sheep but are rarely identified or implicated in production losses or disease in Australia. These are Linognathus ovillus (the face louse) and Linognathus pedalis (the foot louse) and Linognathus africanus (O’Callaghan et al., 1989). 25 In Australia, lice have been estimated to cost the wool industry more than $120 million per year.1 Such costs include expenditure on treatment and control of infestations as well as production losses. Significant reductions in fleece value (e.g. up to 30%), greasy fleece weight and clean fleece weight have all been demonstrated in lice-infested flocks (Wilkinson et al., 1982; Niven & Pritchard, 1985; Elliott et al., 1986; Cleland et al., 1989). Lice infestation has also 30 been shown to detrimentally affect the colour of the fleece, i.e. making it less bright and more 1 hitp://www.wool.corn/Grow liceBoss.htm Accessed on: 3rd May 2012. 1

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 yellow (Kettle and Lukies, 1982), and can result in the downgrading of skins due to ‘cockle’ (Heath, 1995a).

The impacts on animal welfare and production due to sheep lice (i.e. B. ovis) are a consequence of the irritation experienced by infested sheep. Primarily, the sheep show signs of 5 pruritus (itchiness) such as rubbing, biting and scratching and these behaviours damage the integrity of the fleece (e.g. causing ‘pulled’ or cotted wool). In some sheep the pruritus can be intense and the irritation can manifest as changes to the skin, including increased scurf and thickening of the epidermis and overlying lipid layer (Britt et al. 1986; Heath et al. 1995b). There is variation between individual sheep susceptibility to lice and this may be linked to an immune o response to infestation (James 1999; James et al. 2002). B. ovis are recognised as feeding on “skin scurf, lipids, loose stratum corneum squames and bacteria” (James, Moon & Brown, 1998). Although most lice (particularly adults) have been observed in the fleece, away from the skin surface, they are quite mobile and are likely to feed on substrates other than just the loose debris present at that location (Sinclair, Butler & Picton, 5 1989). The feeding behaviour of B. ovis at skin level appears to occur only on the surface of the epidermis and does not bring it into direct contact with the internal tissues or blood of the host. Observations have determined that B. ovis “does not ingest nucleated keratinocytes and apparently does not penetrate deeper than the outer layers of the stratum corneum” (James, Moon & Brown, 1998). io Lice are transmitted between sheep via direct contact. Lice control relies upon effective chemical treatment of an entire flock and subsequent biosecurity measures to prevent reinfestation (i.e. exclusion of lice-infested sheep). Due to the surface-feeding habits of B. ovis, all successful chemical treatments previously used have involved topical delivery of the lousicidal chemical. The methods used can be broadly categorised into high-volume application of diluted 25 chemical (i.e. in water) or low-volume delivery of concentrated chemical formulations.

High-volume application methods used in the past have included plunge dips, shower dips, jetting races and hand jetting. These methods require prolonged wetting of the animal or high-pressure jets to ensure adequate penetration or saturation of the fleece with the chemical solution (Rothwell, 2005). Although they have often proven to be very reliable some 30 disadvantages of these methods of application include the capital expenditure on equipment, additional labour required, exposure of operators to chemical (Anon., 2006), stress to animals, secondary disease problems (e.g. transmission of infections), in-use maintenance of adequate chemical concentrations (Levot, 1995) and the safe disposal of left-over chemical solution (Levot, Lund & Black, 2004; Beynon, 2012). 35 Low-volume application methods have become very popular due to their convenience and include pour-on and spray-on formulations. These products are generally ready-to-use and the 2

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 operator applies them to individual sheep using a manual or gas-powered applicator. There is inevitably a high concentration of chemical at the sites of application but its subsequent distribution through the fleece and over the skin is uneven. Persistent chemical residues from some of these products have been identified as a potential environmental risk when the wool is 5 processed at scouring plants (Anon., 2006). Furthermore, the uneven distribution and persistence of sub-lethal concentrations of chemicals in the fleece have been implicated in accelerating the development of insecticide resistance within sheep lice populations (Johnson, Boray & Dawson, 1992; Rothwell, 2005).

Insecticide resistance within sheep lice populations in Australia has become a significant o problem. Reports of synthetic pyrethroid (SP)-based lousicide failures became frequent in the mid-1980s and resistance to the insect growth regulator (benzoylphenyl urea) pour-on products emerged around 2003-2004 (Levot & Sales, 2008). Chemical groups to which sheep lice in Australia are generally regarded as susceptible include the organophosphates (OPs), macrocyclic lactones (MLs), neonicotinoids and spinosyns. However, the limited number of 5 different product formulations containing these chemicals restricts the ability of sheep producers to choose between different methods of application.

It is evident that an ideal lousicide will: 1) Incorporate an active ingredient to which sheep lice are known to be susceptible 2) Deliver a high level of lousicidal efficacy !0 25 3) Be safe for administration to sheep 4) Rapidly deliver lethal insecticide concentrations to all areas of skin where the lice reside 5) Be convenient for the operator to apply 6) Minimise operator exposure to the chemical 7) Ensure minimal chemical residues persist in the fleece 8) Not require disposal of used or excess chemical into the environment

It can therefore be seen why there is continued research to find effective ways to treat ectoparasites - biting ones in particular. An ideal treatment would achieve a high insect mortality rate (via even exposure of the parasites to lethal chemical concentrations), have no detrimental effects on the host animal, be cost effective and not labour intensive, and it would 30 be safe for operators and the environment.

It is an object of the present invention 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 35 discussion of the references states what their authors assert, and the applicants reserve the 3

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 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. 5 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 o ensuing description which is given by way of example only.

DISCLOSURE OF THE INVENTION

According to one aspect of the present invention there is provided a method of treating an animal infested with biting lice 5 characterised by the step of administering internally to the animal a pharmaceutically effective amount of neonicotinoid such that the neonicotinoid is present systemically within the animal.

According to a further aspect of the present invention there is provided a composition for internal administration to an animal including a neonicotinoid in the order of 2% to 80% w/v. !0 According to yet another aspect of the present invention there is provided a dosage regime to treat biting lice on an animal characterised by the step of administering a neonicotinoid internally with a dosage of 40 milligrams per kilogram or less.

Throughout the specification, the use of the present invention will be described in relation to the treatment of biting lice on sheep (Bovicola ovis). It should be appreciated however that the 25 principles in the present invention could apply to and be useful in other situations - for example treating biting insects on other ruminant and camelid species. Many of the problems associated with sheep are also present in, for example, goats (e.g. due to Bovicola caprae) and alpacas (e.g. due to Bovicola brevis).

The medicament can be administered to the animal by a variety of means. 30 For example, in one embodiment the medicament may be administered orally, for example with a drench gun such as that used for other medicaments. 4

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013

Alternatively, an injectable liquid may be used and delivered via an injector - for example such as that used to deliver antibiotics.

However other methods may be incorporated, for example solid dose forms (e.g. tablets, pellets, boluses, implants) or other routes of administration/absorption (e.g. transcutaneous, 5 transmucosal). A critical aspect of the invention however is that regardless of the mode of administration, the neonicotinoid is present systemically within the animal.

To appreciate the inventiveness of this approach the following information is given by way of background. o The first major chemical group that included systemic pesticides used for control of ectoparasites on animals were the OPs. These systemically-active chemicals were absorbed by the animal and carried, via the bloodstream, to the parasite (Khan, 1964; Pitman & Rostas, 1981). During the 1960s there was a significant focus on development of systemic parasiticides for livestock with over 100 new compounds tested during this period (Khan, 1969). 5 The new, systemically-active compounds significantly influenced the evolution of ectoparasiticide products for livestock and three major trends were identified by Drummond (1985): 1) A reduction in the amount of material applied dermally (i.e. from spray or dip, to pour-on, to spot-on) :o 2) Increasing use of oral or percutaneously-absorbed chemicals to control various ectoparasites 3) The development of sustained-release devices to provide prolonged efficacy

During this period extensive research was conducted into the systemic OP chemicals for use in livestock species. There was a universal shift from high-volume to low-volume dermal 25 application methods (e.g. from dip to pour-on formulations) and the introduction of alternative routes of administration of systemic ectoparasiticides (i.e. oral or injectable). Despite these developments to products for other livestock and/or parasite species, no such advances occurred in the control of sheep lice. That is, until introduction of the (non-systemic) SP pour-ons in the early 1980s. 30 Therefore, for two decades (i.e. from 1958 until registration of the SPs), Australian sheep producers were reliant upon OP and arsenic-based dips for control of sheep lice (Levot, 2001). Numerous OPs were available for use on sheep, the most popular including: diazinon, chlorfenvinphos, coumaphos, fenthionethyl and carbophenothion (Levot 2001). These chemicals were usually applied by plunge or shower dipping - a mode of application intended 35 to bring the chemical into contact with the parasite rather than via systemic absorption (Pitman 5

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 & Rostas, 1981). Unfortunately, during this period, “the incidence of properties with lice was 25-30%” and “many treatments were ineffective” (Levot, 2001). In addition, there was regulatory pressure to quarantine those flocks affected (Levot, 2001).

Within this context there was certainly strong demand for new and effective sheep lousicide 5 products during the 1960s and 1970s in Australia. Unfortunately none of the developments in OP control of biting lice on other livestock species, e.g. cattle, were successful in sheep. For example, a fenthion-based product for sheep (Tiguvon® Sheep Dip) was available in Australia from the late 1960s. The efficacy of fenthion as a systemic insecticide for use in cattle was described in 1967 (Cox, Mullee & Allen, 1967). Despite the subsequent development of fenthion o into a highly-effective systemic spot-on for sucking and biting lice on cattle (Tiguvon® Spot-On Cattle Lice Insecticide), released in the early 1970s, a low-volume fenthion-based product was never successfully developed for control of sheep lice.

Coumaphos was another OP with established systemic activity in cattle (Cox, Mullee & Allen, 1967) that was used extensively for control of sheep lice in Australia from the 1960s. As for 5 fenthion, neither coumaphos nor any of the other OP chemicals with recognised systemic activity in other species and/or against blood-feeding parasites of sheep were developed into systemically-active products for sheep lice control.

The next major class of parasiticides to be developed with systemic activity were the MLs. These chemicals have been used extensively for control of internal and external parasites of !0 sheep and cattle since abamectin was introduced in Australia in 1985 (Holdsworth, 2005). The term ‘endectocide’ was coined to describe the MLs because they have been so successful for control of both internal (endo-) and external (ecto-) parasites. Abamectin, ivermectin, doramectin eprinomectin and moxidectin have all demonstrated activity against biting lice on cattle, i.e. Bovicola bovis (Titchener et al, 1994; Clymer et al, 1998; Colwell, 2002; Holste, 25 1 997; Lloyd et al, 2001; Lloyd et al, 1996). However, due to their skin-surface feeding habits, B. bovis are more susceptible to the topical formulations of MLs applied on or near the sites of infestation than those administered by injection (Logan et al, 1993; Cleale, 2004). Consistent with this observation is the fact that “sucking lice are typically more susceptible to injectable formulations of macrocyclic lactones than are chewing lice” (Cleale et al, 2004). 30 Although the purely systemic route of ML delivery to B. bovis is not ideal, injectable products based on doramectin and moxidectin carry claims to “aid in the control” of this parasite in Australia. Products based on all of the MLs (except eprinomectin) have been registered and used extensively since the 1980s for control of internal parasites of sheep in Australia. Topical formulations, i.e. an ivermectin jetting concentrate and an abamectin pour-on, have been used 35 for control of B. ovis on sheep. However, despite the experience with biting lice in cattle, none of the MLs delivered via the systemic route have been registered for control of biting lice on 6

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 sheep. Likewise, a search of the published literature does not yield evidence of any of the MLs providing control of these sheep lice when administered via the systemic route.

Doramectin has shown efficacy against biting lice when administered by injection to cattle. Based on published literature (Barber et al, 2003), this formulation was selected as a good 5 candidate to provide sufficient systemic levels to control sheep lice following injection. Doses up to 3-times that recommended for cattle were administered to sheep with natural infestations of B. ovis. No efficacy against the lice populations was observed (data not published).

The consensus in published literature is that, despite their activity against other ectoparasites of sheep, the MLs delivered via the systemic route do not provide effective control of the biting o louse, B. ovis (Coop et al, 2002; Bates, 2004). In reference to B. ovis, Bates (2012) states clearly: “No ML injection is effective against chewing lice”.

The reasons for the differences observed in ML activity following systemic administration for biting lice on cattle and sheep are unclear. Although related, B. bovis and B. ovis are distinct species of biting lice, which are known to be very host-specific. This means that each louse 5 species is highly adapted to its particular host animal species. In other words, B. bovis cannot infest sheep and B. ovis cannot infest cattle. Given that the lice are host-adapted, there may be differences in their biology (e.g. preferred skin substrates to feed on, frequency of feeding, proximity to skin surface, mobility) that make B. bovis on cattle more susceptible to MLs (and perhaps OPs) delivered via the systemic route. io Theoretically, chemicals present in the blood stream may be delivered to the skin surface by diffusion between cells of the skin (intercellular), diffusion through cells of the skin (intracellular), diffusion into the hair follicles, secretion in sweat, secretion in sebum or by accumulation inside epidermal cells which gradually move towards the skin surface (Patzelt et al 2008). It is not known precisely which of these mechanisms are responsible for the delivery 25 of ML and OP chemicals to the skin surface of cattle where they can exert an effect on B. bovis. However, marked differences in the skin layers and appendages (i.e. hair follicles, sebaceous glands and sweat glands) are known to occur between different species. For example, cattle skin may have around 890 follicles/cm2 whereas a Merino sheep can have up to 10,000 follicles/cm2 (Mills & Cross, 2006). The density of blood vessels, thickness of the skin, and the 30 rate and composition of the sebaceous secretions can also differ (Mills & Cross, 2006). It is evident that the significant structural and physiological differences between the skin of cattle and sheep could certainly influence the delivery of chemicals to biting lice feeding on the skin surface.

In preferred embodiments, thiacloprid is the neonicotinoid used. While neonicotinoids are 35 known as a class of insecticides, the inventors have determined that not all of these have 7

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 similar potency to thiacloprid when used against biting lice in sheep via the systemic route. For example, imidacloprid is one such related compound.

It is thought however that other members of the neonicotinoid insecticide class may also have the physicochemical properties, similar to thiacloprid, that are required to be effective via this 5 route.

It is believed by the inventor that contrary to expectations, a systemic introduction of a neonicotinoid causes the chemical to be present in vectors that biting lice feed on, for example skin, skin secretions and associated debris (e.g. dead cells) at concentrations sufficient to be lousicidal. o It should be appreciated that the present invention can be co-formulated with other active ingredients, for example anthelmintic treatments, vaccines, vitamins/mineral supplements and the like. Not only does this offer advantages by having two or more treatments being delivered in a single dose, but there may also be complementary effects resulting. For example, the inclusion of vitamins and minerals may assist the skin recovery of an animal once the biting lice 5 have disappeared as a result of the insecticide treatment.

As mentioned previously, the thiacloprid can be administered in a dosage of 40 milligrams per kilogram or less. It should be appreciated that considerable care is required when developing systemic treatments as a greater dose can lead to toxicity and harm to the animal, while too small a dose can lead to ineffectiveness. !0 As can be seen in the trial data discussed in the Best Modes portion of the specification, a single dose of 40 milligrams per kilogram of animal has been found to be very effective. However, for reasons of safety and cost effectiveness, smaller dosages are preferred.

Dosages of thiacloprid at 20 milligrams per kilogram in a single dose has been found to be effective by the inventors in clearing over 99% of lice (Bovicola ovis) after 69 days. 25 Likewise, split dosing of 15 milligrams per kilogram on day 0 and 15 milligrams per kilogram on day 1 were equally effective.

For optimum safety thresholds, a dosage of around 5 milligrams per kilogram would be desirable - yet a single dosage of 4 milligrams per kilogram was only partially effective in clearing lice. 30 Surprisingly, the inventors have found that a split dosage of 1 milligrams per kilogram on two consecutive days was significantly better than the 4 milligrams per kilogram on 1 day.

Therefore it appears that the present invention would be more effective if the neonicotinoid is administered over a period of time. This could include the administration of a number of 8

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013 discrete dosages over a few days, or alternate embodiments could involve the use of a slow release device.

Naturally, the composition being administered will vary dependent upon the administration route and whether a single dose will be used or the active is to be administered over time. Further, 5 as discussed previously, the present invention can be used with other actives as well.

Nevertheless, it is envisaged that preferred compositions will include neonicotinoid in the order of 2% to 80% w/v. As can be seen in the examples given, a formulation having the neonicotinoid in the order of 40% is particularly stable.

In preferred formulations, in addition to the active there may be provided dispersing agents, o preservatives, anti-foaming agents and humectants. Thiacloprid is water soluble and therefore it is envisaged that water would be a carrier in preferred embodiments of the present invention.

It can be seen that the present invention has a number of advantages over the prior art.

Firstly, there is provided an alternate treatment for biting lice which does not have the intensive labour requirement, capital overheads and potential human health risks of topical treatments. 5 Further, by determining a systemic administration route, and an appropriate dosage level then equal delivery of a sufficiently high dosage to all of the parasites can be ensured - providing reliable efficacy and avoiding factors that accelerate the development of insecticide resistance.

Further, minimization of insecticide residues in the fleece will reduce the risks to the environment secondary to wool processing. !0

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present invention will become apparent from the ensuing description which is given by way of example only and with reference to the accompanying drawings in which: 25 Figure 1 Illustrates mean plasma thiacloprid concentrations in accordance with treatment regimes in accordance with the present invention. 9

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013

BEST MODES FOR CARRYING OUT THE INVENTION

Below are shown formulations which have worked in accordance with one embodiment of the present invention. T1844 %w/v Thiacloprid (Micronised) ** 5.00 Xanthan gum 0.2 Polysorbate 80 2.5 Methyl paraben 0.2 Propyl paraben 0.04 Plasdone K25 3 wacker silica 1 citric acid 1.75 Sodium hydroxide 0.95 Defoamer RD 0.1 Deionised water qs T1836 %w/v Thiacloprid (Micronised) ** 7.875 Cremophor EL 2.0 N-Methyl - 2 -Pyrroidone (NMP) 40.0 Glycerine formal stabilised qs. T1837 %w/v Thiacloprid (Micronised) ** 10.5 Benzyl alcohol 1.0 Span 80 (sorbitan monooleate) 0.10 Phospholipon H90 (Phosphatidylcholine , hydrogenated) 0.10 Cotton seed oil qs. ** 5% overages added.

It should be appreciated that these figures are given by way of example only, and that other 10 formulations can be used in accordance with the present invention. 10

James & Wells ref: 133719AU/3 2013204134 12 Apr 2013

Below are results of a trial which utilised the above formulations and provides support for the present invention

Table 1 Sheep Lice Count Reductions (%)

Formulation Route of Admin. Dose (mg/kg) Days after treatment 7 14 28 T1844 Oral 5 93.6% 86.6% 51.1% T1836 Subcutaneous injection 5 80.4% 84.9% 20.6% T1837 Subcutaneous injection 5 96.4% 76.9% 5.8%

Below are results of trials which utilised an earlier formulation and provides further support for 5 the present invention.

Table 2 Sheep Lice Count Reductions (%)

Route of Admin. Dose (mg/kg) Weeks after Treatment 2 3 4 6 10 15 Oral 50 100 100 100 Oral 48 100 98.3 93.0 Oral 40 99.7 99.7 100 Oral 30 99.7 100 99.7 Oral 15+15* 100 100 100 Oral 20 100 99.0 99.4 Oral 4 63.1 50.9 31.9 Oral 1+1* 84.4 70.3 71.4 Oral 0.5 46.5 5.6 0 * Doses split over 24 hours (e.g. 15 mg/kg on Day 0 then 15 mg/kg on Day 1)

Additional formulations to be delivered orally and/or via injection are given below. In particular it should be noted that castor oil has been chosen for this purpose, as it is known to provide a prolonged release of lipophilic actives. 11 2013204134 12 Apr 2013

James & Wells ref: 133719AU/3

Thiacloprid Oral 5% T1919 T1920 T1921 Ingredients %w/v %w/v %w/v Thiacloprid 5.0* 5.0** 5.0** Xanthan gum 0.2 0.2 0.2 Polysorbate 80 2.5 12 20 Methyl paraben 0.2 0.2 0.2 Propyl paraben 0.04 0.04 0.04 Plasdone K25 3 3 3 Wacker silica 1 1 1 Citric acid 1.75 1.75 1.75 Sodium hydroxide 0.95 0.95 0.95 Castor oil 0 3 5 Defaomer RD 0.1 0.1 0.1 Deionised water qs qs qs *Non micronized active **Micronized active Thiacloprid Injection 10%

T1909 T1910 T1911 Ingredients %w/w %w/w %w/w Thiacloprid 10.0* 10.0** 10.0*** Benzyl alcohol 1.00 1.00 1.00 Span 80 (Sorbiton Monooleate) 0.10 0.10 0.10 Phospholipon H90 (Phosphatidylcholine , hydrogenated 0.1 0.1 0.1 Castor oil 0 5 10 Cotton Seed oil QS QS QS 5 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. 12

Claims (16)

1. WHAT WE CLAIM IS:

   1. A method of treating a sheep infested with Bovicola ovis characterised by the step of administering internally to the animal a pharmaceutically effective amount of neonicotinoid such that the neonicotinoid is present systemically within the animal.
2. 2. A method as claimed in claim 1 wherein the administration route is oral.
3. 3. A method as claimed in claim 1 wherein the administration route is via injection.
4. 4. A method as claimed in any one of claims 1 to 3 wherein the neonicotinoid is thiacloprid.
5. 5. A method as claimed in any one of claims 1 to 4 wherein the thiacloprid is administered in a dosage of 40 milligrams per kilogram or less of the animal.
6. 6. A method as claimed in any one of claims 1 to 5 wherein the neonicotinoid is administered over a period of time.
7. 7. A method as claimed in claim 6 wherein the neonicotinoid is administered in multiple doses.
8. 8. A method as claimed in claim 6 wherein the neonicotinoid is administered in slow release form.
9. 9. A dosage regime to treat Bovicola ovis on a sheep characterised by the step of administering a neonicotinoid systemically with a dosage in the order of 40 milligrams per kilogram or less of the animal.
10. 10. A dosage regime as claimed in claim 9 wherein the administration is over a period of time.
11. 11. A dosage regime as claimed in claim 9 wherein the neonicotinoid is administered in multiple doses.
12. 12. A dosage regime as claimed in claim 10 wherein the neonicotinoid is administered by a slow release route.
13. 13. A dosage regime as claimed in the previous claim wherein the neonicotinoid is administered to the animal in the order of two or more 1 milligram per kilogram dosages spaced apart by a day or more.
14. 14. A method as claimed in claim 1 substantially as herein described in the Best Modes Section with reference to and as illustrated by the accompanying formulations T1844, T1863, T1837, Thiacloprid Oral 5% and Thiacloprid Injection10%.
15. 15. A composition for use in the treatment of Bovicola ovis on a sheep substantially as herein described in the Best Modes Section with reference to and as illustrated by the accompanying formulations T1844, T1863, T1837, Thiacloprid Oral 5% and Thiacloprid Injection10%.
16. 16. A dosage regime as claimed in claim 10 for sheep substantially as herein described in the Best Modes Section with reference to and as illustrated by the accompanying formulations T1844, T1863, T1837, Thiacloprid Oral 5% and Thiacloprid Injection 10%.