WO2025004000A1 - Formulation for controling blowfly infestations - Google Patents

Abstract

The present invention relates to a formulation suitable for use in simultaneously reducing or ameliorating blowfly infestations, preventing blowfly strikes, and treating active blowfly strikes on animals, such as sheep. The present invention also relates to a process for producing the formulation, and uses of the formulation.

Description

FORMULATION FOR CONTROLING BLOWFLY INFESTATIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application is an International Patent Application which claims priority to Australia Patent Application No. AU2023902058 filed on 29 June 2023, the disclosure of which is incorporated herein in its entirety.

FIELD OF INVENTION

[0002] The present invention relates to a formulation suitable for use in simultaneously reducing or ameliorating blowfly infestations, preventing blowfly strikes, and treating active blowfly strikes on animals, such as sheep. The present invention also relates to a process for producing the formulation, and uses of the formulation.

BACKGROUND

[0003] While only a simple nuisance to humans, parasitic flies commonly referred to as blowflies (for example Lucilia cuprina) cause tissue damage (technically known as cutaneous myiasis) that can lead to meat production and reproduction losses, and poorer wool quality and quantity. Left uncontrolled, cutaneous myiasis can be serious enough to lead to the death of an infested animal. Because there are significant animal welfare and financial issues to be considered, farmers are highly interested in preventing blowfly infestations within their flocks of sheep. [0004] Massive cutaneous myiasis or blowfly larval (maggot) infestations (often referred to as blowfly strike or flystrike) on sheep are found particularly frequently in geographic areas that have a warm, humid climate. This is why numerous species of blowfly that cause flystrike occur throughout New Zealand and Australia as well as in North and South American countries, certain European countries, UK, and in Africa. There is also evidence that the blowfly (for example L. cuprina) will continue to extend its habitat into new areas. In New Zealand, for example, the relatively recent introduction of this aggressive blowfly has subsequently led to migration at a rapid speed southward through the country affecting most areas except perhaps the far south.

[0005] Myiasis can be extremely harmful, depending upon the species of fly and the circumstances surrounding the infestation. The larval or maggot stage of, for example, L. cuprina constitutes the real animal parasite. The life cycle of A. cuprina is described and demonstrates the horrific nature of the resulting disease and the speed with which fly populations can increase if the parasite is left uncontrolled.

SUMMARY OF THE INVENTION [0006] Controlling Blowfly Infestations

[0007] A key for controlling the problem is preventing infestations by interrupting the blowfly life cycle.

[0008] The life cycle of L. cuprina starts with each female laying about 200 eggs on the sheep. First instar maggots, about 1 mm long, will emerge within 12 hours and feed in damp fleece, in lumpy wool, fleece-rot lesions, in and around wounds, or in faecal or urine soiling. These first instar maggots have no rasping mouthparts and so are not capable of damaging the skin.

[0009] It is preferable therefore to control the life cycle at this point for blowfly strike prevention. Under favourable conditions the first instar will moult to the second instar about 18 hours after hatching. This moulting process allows the maggot to grow. After a second moult, about 36 hours after hatching, the third instar maggots will be very active and feeding voraciously. These maggots rasp the sheep’s skin with their mouthparts and produce enzymes that liquefy the skin and tissues of the affected animals. This process also attracts further strikes. During this feeding period the maggots grow very quickly, and they will be fully fed within 3-4 days of hatching. At full size the maggots are about 12 mm long, creamy white and very active. They drop from the sheep, usually at night, and burrow into the top few centimetres of soil. If the soil temperature is less than 15 °C, development may cease at this stage, otherwise pupation will occur. During pupation, chemical changes in the maggot’s skin transform it to a rigid barrel-shaped cocoon or pupa. Inside the cocoon, the maggot metamorphoses into a fly. Under ideal conditions a young fly will emerge from its pupa 12-14 days after the egg from which it was derived was laid. The young female fly will be very active in searching for food as she needs several protein feeds so her eggs can mature. After the feeding process she actively seeks sites suitable for egg-lay. She will mate only once, usually about three days after she has emerged from her cocoon. A female Lucilia sp. has an average life span of about 2-4 weeks in warmer months and considerably longer in cooler months. During her life, she may lay up to three batches of eggs.

[0010] It is also desirable to kill active maggots that are causing active blowfly strike to reduce the damage and illness incurred on sheep.

[0011] There are many products on the market for controlling insect parasites of sheep. However, most of them show certain disadvantages concerning, for example, the inability to knock down blowfly strike within 1 or 2 days, their spectrum of activity, the duration of the activity, their safety, or their ability to persist for an acceptable period of time in the wool. Importantly, blowflies tend to develop resistance to prior products over time. Many products are also disadvantaged if rainfall occurs, either just before treatment or soon after treatment. The commercially available insecticides vary in their effectiveness against particular insect species. Often the efficacy of these insecticides is not always satisfactory because of, for example, the development of resistance by the parasite to the therapeutic agent, as is the case, for example, with carbamates, organophosphorus compounds and pyrethroids.

[0012] An effective resistance management programme is clearly needed by the sheep farming industry, in particular. It would be desirous to include in this programme a product that combines the power of two effective therapeutic agents, which will help delay the onset of resistance by some insects to the agents. There is also a need in the market for a product that can be applied to flocks with some infestations and have an immediate knock down effect on the blowfly strikes. Such a product with immediate effect and also long-lasting durability has heretofore not been known. Thus, there is clearly a long felt need for a convenient, easy-to-use, safe, powerful, and long lasting product that can provide immediate amelioration of adverse impact blowfly strike and does not lead to the development of resistant insects, especially blowflies.

[0013] Moreover, there is a need in the art for an antiparasitic formulation which is easy to use on sheep, irrespective of the sheep’s size and the nature of the sheep’s wool and which does not need to be applied over the entire body of the animal to be effective.

[0014] Moreover, there is a real demand in the art for an effective easy-to-use product that provides efficient and long lasting simultaneous prevention of blowfly strike and treatment of active blowfly strike.

[0015] Likewise, there is a demand for an aid in control blowfly strike in long wool sheep, where some infestation has already been identified. The strategic use of therapeutic chemicals to prevent blowfly infestations should preferably occur. Ideally a product, such as the disclosure of the invention in this document, would be applied following wool harvest in the spring (or autumn in some geographic zones) such that when the first generation of flies emerges from the soil in the new fly season, their life cycle would be immediately broken when they come into contact with preventively treated sheep.

[0016] It has now surprisingly been found that one or more of the above-mentioned challenges can be addressed or even overcome by a combination of two known insecticides - dicyclanil and ivermectin. Careful observation has led to the conclusion that cross-resistance between these two compounds (ivermectin and dicyclanil) has not been observed in the field and so any emerging resistance to one or the other is believed to continue to result in effective blowfly control. [0017] However, merely combining those two actives into a ready to use, stable formulation is very challenging. Advantageously, the present inventors have identified that the above-mentioned challenges can best be addressed or even overcome if the combination of dicyclanil and ivermectin is formulated in a particular manner.

[0018] The Applicant has found that it is possible to obtain effective long-term simultaneous aid in control of existing blowfly strikes and prevention and treatment of blowfly strikes on sheep (in particular) using a specific formulation intended for topical application. Such treatment overcomes the limitations of many prior products which only slowly remedied the deleterious impacts of an ongoing blowfly strike infestation. In particular, the Applicant has found that the present formulation and methods of use result in immediate knock down of infestation within 1 or 2 days.

[0019] Without wishing to be bound by theory, the formulation of the present invention is believed to be particularly suitable for extensive pasture rearing of sheep. In such instances the effects of climate (especially rainfall) can have an adverse effect on the longevity of the chemical residues in the fleece. Some current products are particularly vulnerable to removal from the fleece by rainfall thus reducing the protection period against the target parasite. On the other hand, the formulation of the present invention is believed to be especially able to satisfactorily tolerate exposure to rainfall following application. For instance, in some embodiments the formulation of the present invention is able to prevent blowfly strike for a period after administration of at least 10 weeks, such as at least 15 weeks, such as at least 18 weeks.

[0020] In a first aspect the invention provides a formulation for controlling insect pests on a mammal comprising an amount of ivermectin and dicyclanil and a suitable carrier and/or diluent. [0021] As used herein the term “mammal” will typically refer to a domesticated farm animal, such as sheep, goats, cattle. Typically the mammal will be a sheep.

[0022] In a second aspect the invention provides a pour-on, or spray-on (preferably spray-on) formulation comprising an insecticidally effective amount of each of the two active ingredients ivermectin and dicyclanil and further comprising at least one of a surfactant, an emulsifier, a preservative, an “other additive” (such as EDTA), an antioxidant, an oily component, a solvent, a thickener, a neutralizer, and optionally a colouring agent, and optionally an antifoaming agent. [0023] While the formulation of the invention may be applied to a target animal such as a sheep by any mode, practically and advantageously the formulation is preferably applied as a spray-on. [0024] In a third aspect the invention provides the use of the formulation of the present invention for simultaneously controlling and preventing blowfly strikes on sheep. [0025] As used herein the term “controlling” (and “control” etc) in relation to controlling and preventing blowfly strikes on sheep may refer to “treating” (and “treatment”). Controlling may refer to limiting the number and/or spread of blowfly larvae on the target animal (such as sheep). Controlling may refer to reducing the rate of growth in the number of blowfly larvae, hindering the health of at least some of the blowfly larvae, and/or killing at least some of the blowfly lavae. [0026] As used herein the term “preventing” (and “prevent” etc) in relation to controlling and preventing blowfly strikes on sheep refers to reducing the incidence of blowfly strike on an animal compared with the same (or similar) animal to which the formulation has not been administered, for a period of time. For instance, an animal to which the formulation has not been administered will typically develop blowfly strike earlier and/or to a greater degree than an animal to which the formulation has been administered all else being equal. In some cases, prevention may be assessed by measuring when the cumulative number of flystrikes exceeds a strike rate figure set by the governing regulatory authority (e. g. 1 or 2% of the flock). The time taken to reach that point will be called the ‘protection period’ against flystrike will be determined. In some cases, “preventing” refers to the strike rate being less than 2% (such as less than 1%) of the flock for a period of at least 10 weeks, such as at least 15 weeks, such as at least 18 weeks.

[0027] In a fourth aspect the invention provides the use of a formulation of the present invention in the treatment of sheep against blowfly infestation. Treatment of sheep against blowfly infestations includes infestation knockdown. Complete infestation knockdown would include the elimination of live parasites on treated sheep after 1 or 2 days.

[0028] In a fifth aspect the invention provides a method for controlling blowfly infestation on sheep comprising administering the formulation of the present invention to one or more small areas of the wool or fibre of a sheep.

[0029] As used herein the term “small areas” may refer to a portion of the wool or fibre of a sheep that is exposed to spray on or pour on (preferably spray on) administration. Such areas may be along the backline and/or breech of the animal. “Small areas” is to be distinguished from the larger areas that are exposed to administration by dipping or jetting.

[0030] In a sixth aspect the invention provides a process for the preparation of the formulation of the present invention comprising the steps of:

(a) preparing a gel phase by mixing suitable solvent, preservative and a suitable emulsifier with water;

(b) preparing an oily phase by combining a suitable oily component with antioxidant preservative and a thickener and/or stabilizer; (c) transferring said gel phase and said oily phase to a mixing tank and homogenizing both phases;

(d) preparing an active phase by mixing an “other additive” (e.g. EDTA), solvent, surfactant and the active ingredients (dicyclanil and ivermectin) with water and milling the mixture until a lump free suspension is obtained;

(e) mixing the homogenized phase of step (c), the active phase of step (d) and a colouring agent to form a pre-formulation;

(f) optionally adjusting the pH of the pre-formulation; and

(g) optionally increasing the volume of the pre-formulation with water to provide the formulation.

[0031] It is an object of the invention to provide an effective formulation and/or method that may be used to reduce or ameliorate blowfly strikes on animals, such as sheep. One aspect of the invention is an effective formulation and/or method that both prevents blowfly strike from arising and knocking down active infestations rapidly.

[0032] Alternatively, it is an object of the invention to at least provide the public with a useful choice.

[0033] Further aspects of the invention, which should be considered in all its novel aspects, will become apparent to those skilled in the art upon reading of the following description which provides at least one example of a practical application of the invention.

DETAILED DESCRIPTION

[0034] Dicyclanil is 4,6-diamino-2-cyclopropylaminopyrimidine-5-carbonitrile which is described in US4,783,468 (the entire contents of which are incorporated by reference). It shows the following chemical structure:

[0035] As used herein, dicyclanil refers to all forms (including hydrate forms, solvate forms, salt forms, amorphous form(s), and crystalline polymorphs) of the active.

[0036] Dicyclanil is a pyrimidine derivative that is sold as a formulation under the trade names CLiK™, CLi KZiN ™ and CLiK Extra™. It is available in the form of a spray-on formulation applied to the backline and breech of sheep and is dosed according to bodyweight. While the exact mode of action for dicyclanil is not precisely known, it is understood that it interferes with how chitin is deposited into the cuticle of fly larvae. In Australia, CLiK provides 18-24 weeks protection against flystrike but has the extreme disadvantage that it does not kill larvae or treat an active existing blowfly strike infestation. Protection periods in other countries are shorter. Dicyclanil interferes with the moulting process of blowfly larvae, killing 1st stage larvae very readily. The effect on 2nd stage larvae and to a greater degree, 3rd stage larvae are less pronounced and the product may take more time to resolve an active flystrike, if at all.

[0037] Ivermectin is an orally bioavailable macrocyclic lactone derived from Streptomyces aver- mitilis, with antiparasitic activities. Fermentation of Streptomyces avermitilis yields eight closely related avermectin homologues, of which Bia and Bib (shown below as their corresponding 22,23 -dihydroavermectin derivatives) form the bulk of the products isolated. Subsequent hydrogenation of those compounds provides ivermectin, which is an approximately 80:20 mixture of the two 22,23 -dihydroavermectin Bia and B2a compounds shown below:

[0038] Traditionally ivermectin is administered to sheep either: orally (drenching); or for blowfly strike or lice by jetting in which a large total volume of formulation is forced under pressure to the skin’s surface to saturate and flow around the sheep’s body.

[0039] Upon administration, it is believed that ivermectin exerts its anthelmintic effect through binding and activating glutamate-gated chloride channels (GluCls) expressed on nematode neurons and pharyngeal muscle cells. This causes increased permeability of chloride ions, causing a state of hyperpolarization and results in the paralysis and death of the parasite. As used herein, ivermectin refers to all forms (including hydrate forms, solvate forms, amorphous form(s) and crystalline polymorphs) of the actives.

[0040] Ivermectin and dicyclanil have each, separately, been combined with other active components. However, while the biological profile of the insecticides is well known, and it is generally known in the art that it is sometimes possible to combine insecticides in order to broaden the insecticidal spectrum, it is not predictable, a priori, which combinations will be effective and/or safe for a particular animal or disease state. It cannot be foreseen whether the combination of two insecticides that exhibit totally different modes of action will influence each other in a favourable manner or even show antagonistic effects.

[0041] Insecticides are compounds that have to kill insects which are highly developed organisms. When applied to sheep (for example) it cannot be predicted with confidence that the insecticide will be safe or otherwise for the sheep. This unpredictability is amplified where a combination of active agents is used. There is always the risk that the combination may be too toxic or lead to complications in the target domesticated farm animal that cannot be tolerated. For these reasons, the results of various combinations are not always successful and there is a need in the art for more effective formulations that may be easily administered to the animal and which are well tolerated by the animal whilst killing the parasites for an extended period. In that regard, the pharmacokinetic behaviour of a combination can be totally different than the pharmacokinetic behaviour of the single products.

[0042] This unpredictability also extends to residues of the applied compounds, or combination, that may endure in the animal. It simply cannot be predicted how a combination might behave even in cases where the behaviour of the single components might be well known. One active could be accumulated in the wool of a target sheep and stay there for an unacceptable period of time, and the other active may stay in a specific tissue or organ. It may be the case that both actives may accumulate in specific tissues and cause health problems. [0043] More specifically - the effectiveness of a given formulation against blowflies in a specific host is difficult to predict because of the numerous and complex host-parasite-environment interactions and the complex biological and chemical conditions in the animal’s body and fleece. [0044] Advantageously the present invention provides a safe and well-tolerated formulation preferably in the form of a topical formulation that may take the form of pour-on, or preferably spray-on. In preferred embodiments, it is intended to simultaneously control, with extreme efficiency, blowfly on sheep and then protect the sheep from re-infestation by the parasite for a prolonged period. Especially preferred embodiments of the present invention include a combination of dicyclanil and ivermectin (together, the active ingredients), carriers suitable for spreading the active ingredients potentially over a portion of, such as a substantial portion of, such as all of the fleece and skin and, optionally, preservatives that help provide an effective and long shelflife. [0045] To date blowfly prevention and control have had to be effectively managed by different products and in cases, different application methods and times of treatment. Thus, a real advantage of the present inventive formulation is that a single dose (“one-shot”) administration leads to a long lasting action in preventing and acting against blowflies. Further, the inventive formulation provides rapid knock down of blowfly strike infestations within 1 or 2 days from application, while still providing long lasting prevention against blowflies. This reduces the workload, the costs, and improves the welfare of the animals. Further application may be “held back” in certain conditions with the fore-knowledge that an arising infestation can be quickly and effectively managed if it arises. These advantages could not have been expected in the industry, particularly by the claimed combination of actives in a ready to use topical formulation.

[0046] As used herein, the expression “topical formulation” is preferably understood to refer to a ready-to-use solution such as in the form of a pour-on, or (preferably) spray-on formulation, although other forms of formulation for administration are contemplated. Most preferably the formulation is a spray-on formulation. Ready-to-use formulations may be advantageous given their ease of application and that they typically avoid the need for extra water that might otherwise be needed such as for jetted products. This is an advantage where access to water is problematic. [0047] Spray-on formulations may be applied with or without power-assistance such as may be provided by an air compressor or a gas cylinder. In general delivery volumes are significantly smaller using pour on and spray on methods compared with jetting or dipping methods.

[0048] Ready-to-use formulations may also reduce exposure of the operator to the active ingredients because there is no need for manual dilution of a concentrate. [0049] Previous approaches to administering ivermectin to sheep have focused on applying the active in a formulation to clipped areas of sheep. Surprisingly the formulation of the present invention may be applied as a spray-on formulation to unclipped wool and yet still provide both fast knockdown of fly strike and provide resistance to reinfestation.

[0050] The topical formulation of the present invention may consist of a dispersion or suspoe- mulsion. The topical formulation is generally intended to be applied directly to a relatively small area of the animal (such as sheep), preferably on the animal’s back and breech or at several points along the line of the back and breech. The topical formulation is typically applied as a low volume of about 0.5 to 1 ml per kg (live weight of the animal), preferably about 0.5 ml per kg, with a total volume from 10 to 50 ml per animal, preferably limited to a maximum of about 40 ml.

[0051] The combination of dicyclanil and ivermectin has been shown to be extremely effective even when applied as a topical formulation, such as a spray on formulation. Therefore, it is not necessary to add further insecticides into the topical formulation according to the present disclosure. Thus, one objective of the present disclosure is providing a combination product for controlling insect pests on the subject animal (typically a mammal) comprising an insecticidally effective amount of ivermectin and dicyclanil and suitable carriers or diluents. Especially preferred are combinations in the form of a topical formulation for simultaneously controlling and preventing blowfly strikes on sheep comprising an insecticidally effective amount of each of the two active ingredients ivermectin and dicyclanil and suitable carriers or diluents.

[0052] The topical formulations according to the disclosure may advantageously be oil-in-water or water-in-oil suspoemulsions comprising both active ingredients, namely ivermectin and dicyclanil. Suitable carriers or diluents may be present.

[0053] As used herein, the term “suspoemulsion” refers to a mixture of one or more typically water insoluble active ingredients dispersed in a predominantly water-based solution. Typically the suspoemulsion will include an aqueous continuous phase, that includes a dispersed oil phase and at least one suspended solid phase.

[0054] More specifically, the topical formulation of the present disclosure is typically a pour-on, or spray-on (preferably spray-on) formulation in the form of an aqueous suspoemulsion incluing:

• an insecticidally effective amount of each of the two active ingredients ivermectin and dicyclanil; and • preferably further including at least one of: a surfactant; an emulsifier; a preservative; an “other additive” (e.g. EDTA); an antioxidant; an oily component; a solvent; a thickener; a neutralizer; and

• optionally further including one or more excipients selected from the group consisting of: a colouring agent; and an antifoaming agent.

[0055] The formulation (such as topical formulation) of the present invention may include ivermectin in the range of 0.05-2.5% (w/v), preferably 0.1-1.0% (w/v), ideally about 0.30% (w/v). [0056] The formulation (such as topical formulation) of the present invention may include di- cyclanil in the range of 0.50-7.5% (w/v), such as 1.0-7.0% (w/v), such as about: 1.25% (w/v); 5.00% (w/v); or 6.50% (w/v).

[0057] As used herein, the term “about” in relation to a numerical value (or range of numerical values) refers to a range of acceptable values in relation to that numerical value. The term “about” may be used to refer to +10% to -10% of the numerical value. For example, “about 5%” may be intended to refer to a range of 4.5-5.5%. The term “about” may be used to refer to +5% to -5% of the numerical value. For example, “about 5%” may be intended to refer to a range of 4.75-5.25%. The term “about” may be used to refer to +2% to -2% of the numerical value. For example, “about 5%” may be intended to refer to a range of 4.9-5. 1%.

[0058] Surfactant

[0059] The formulation of the present invention may include a surfactant in the range of 0. 10- 10.0% (w/v)or 0.15-10.0% (w/v), preferably 0.2-4.0% (w/v) or 0. 1-4.0% (w/v), more preferably 0.1-0.45% (w/v) or 0.2-0.45% (w/v), still more preferably 0.1-0.4% (w/v) or 0.2-0.4% (w/v), even more preferably 0.1-0.25% (w/v), ideally about 0.25% (w/v).

[0060] Examples of suitable surfactants include but are not limited to: anionic, cationic, nonionic, and amphoteric surfactants, as well as combinations thereof, and derivatives thereof.

[0061] Suitable anionic surfactants include: stearates, such as alkaline stearates (for example: sodium, potassium, or ammonium stearates; calcium stearate, triethanolamine stearate); sodium abietate; alkyl sulphates (for example: sodium lauryl sulphate and sodium cetyl sulphate); sodium dodecylbenzene sulphonate; sodium dioctylsulphosuccinate; fatty acids (such as those derived from coconut oil).

[0062] Suitable cationic surfactants include: (typically water-soluble) quaternary ammonium salts of formula N⁺RIR2R3R4Y" in which the radicals Ri to R4 are independently selected option- ally hydroxylated hydrocarbon radicals and Y is an anion of a strong acid such as the halide, sulphate and sulphonate anions - an example of which is cetyltrimethylammonium bromide; salts of amines of formula NR1R2R3 in which the radicals Ri to R3 are independently selected from H and optionally hydroxylated hydrocarbon radicals - an example of which amine salt is the hydrochloride salt of octadecylamine.

[0063] Suitable non-ionic surfactants include: sorbitan esters (which are optionally polyoxyeth- ylenated, in particular polysorbate 20, polysorbate 65, polysorbate 80); polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols (such as polyoxypropylene-styrol ether); polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide.

[0064] Suitable amphoteric surfactants include the substituted lauryl compounds of betaine. [0065] The most preferred surfactant is polysorbate 20. Polysorbates may be made by reacting ethylene oxide (a gas) with sorbitan esters (derivatives of sorbitol, another sugar alcohol similar in function to mannitol). Synonyms of polysorbate 20 are: polyoxyethylene sorbitan monolaurate E432; and polysorbate 20 NF (CAS No. : 9005- 64-5), and tween 20. This product is a non-ionic surfactant that is used to disperse and emulsify. Polysorbate 20 is used for oil-in-water emulsions, such as lotions, conditioners and cream rinses.

[0066] Emulsifier

[0067] The formulation of the present invention may include an emulsifier, which may be in the range of 0.01-0.30% (w/v), preferably 0.05-0.2% (w/v), ideally 0.08-0.2% (w/v), such as 0.09- 0.2% (w/v), such as about 0. 10% (w/v).

[0068] Without wishing to be bound by theory, it has been discovered that formulation stability (reduced prevalence of separation) may be improved by increasing the concentration of the emulsifier to greater than 0.08% (w/v), such as to 0.09% w/v, such as to 0.10% w/v, or greater. Stability is particularly improved at emulsifier (particularly pemulen) concentrations of at least 0.09% w/v when the composition is subject to elevated temperatures (such as at least 30 °C). This stability is particularly improved at emulsifier (particularly pemulen) concentrations of at least 0.10% w/v. Achieving this suspoemulsion stability while maintaining a suitable viscosity (to enable the formation of a spray-on formulation) was difficult to achieve and the result was unexpected. In particular, stability was achieved by preventing ‘creaming’ and subsequent sedimentation of actives, so as to provide good dose homogeneity. [0069] Examples of suitable emulsifiers for use in the present invention include: non-ionic surfactants (for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbi- tan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers); ampholytic surfactants (such as di-sodium JV-lauryl-beta-iminodipropionate or lecithin); anionic surfactants (such as sodium lauryl sulphate, fatty alcohol ether sulphates, the monoethanolamine salt of mono/dialkyl polyglycol ether orthophosphoric esters); cationic surfactants (such as cetyltrimethylammonium chloride), combinations thereof, and derivatives thereof. Especially preferred are polymeric emulsifiers, which include copolymers of acrylic acid, modified by long chain (C10-30) alkyl acrylates, and crosslinked with allylpentaerythritol. Within this group of polymeric emulsifiers the pemulens are most preferred. Pemulen polymeric emulsifiers are copolymers of acrylic acid, modified by long chain (C10-30) alkyl acrylates, and crosslinked with ally Ipentaerythritol. Pemulen polymeric emulsifiers are commercially available from different sources. For example, Pemulen™ TR-2 polymer is a polymeric emulsifier which is a high molecular weight, crosslinked copolymer of acrylic acid and a hydrophobic C 10-30 alkyl acrylate comonomer. It is a versatile, non-ethoxylated polymer designed to create stable and mild oil-in-wa- ter emulsions at low use levels.

[0070] Preservative

[0071] The formulation of the present invention may include one or more preservatives, which may (alone or together) be in the range of 0. 15-0.60% (w/v), 0.35-0.60% (w/v), preferably 0.40- 0.50% (w/v), ideally about 0.45% (w/v).

[0072] Examples of suitable preservatives are: benzoic acid (and salts thereof, such as sodium benzoate), benzyl alcohol, phenoxyethanol, pentylene glycol, alkyl hydroxybenzoates (such as propyl hydroxybenzoate and methyl hydroxybenzoate), propionic acid (and salts thereof, such as the sodium and calcium propionate salts, sorbic acid (and salts thereof, such as the potassium, and calcium sorbate salts), diethyl pyrocarbonate, and menadione sodium bisulfite, and combinations thereof. Most preferred are alkyl hydroxybenzoates, such as propyl hydroxybenzoate (propyl paraben) and methyl hydroxybenzoate (methyl paraben), and combinations thereof.

[0073] It may be beneficial to use a plurality of preservatives in particular where at least one preservative is provided in an aqueous phase and at least one preservative is provided in an oily phase.

[0074] Shelflife

[0075] Without wishing to be bound by theory, it is believed that the formulation of the present invention may provide a shelf life (against spoilage and/or separation) of 24 months or greater, such as at least 36 months. This is quite remarkable considering the different formulation preferences of the active ingredients - dicyclanil and ivermectin.

[0076] Other Additives

[0077] The formulation of the present invention may include an “other additive”, which may be in the range of 0.01-0.09% (w/v), preferably 0.03-0.07% (w/v), ideally about 0.05% (w/v).

[0078] An example of a suitable other additive is EDTA (ethylenediaminetetraacetic acid) and salts thereof. EDTA (ethylenediaminetetraacetic acid), and salts thereof, may function as a se- questrant and/or antioxidant. Accordingly, the “other additive” may be a sequestrant and/or antioxidant. The sequestrant can be calcium acetate. Salts of EDTA include disodium calcium EDTA, tetrasodium EDTA, and disodium dihydrogen EDTA (a.k.a. disodium EDTA). As a sequestrant, it may bind trace minerals such as copper, iron and nickel that may intentionally or unintentionally be included in the formulation. EDTA may also reduce the effect of, or prevent, oxygen causing colour changes and/or rancidity.

[0079] Antioxidant

[0080] The formulation of the present invention may comprise an antioxidant, which may be in the range of 0.01-0.09% (w/v), preferably 0.03-0.07% (w/v), ideally about 0.05% (w/v).

[0081] Examples of antioxidants that may be used include: BHT; alpha tocopherol; ascorbic acid; ascorbyl palmitate.

[0082] The preferred antioxidant is BHT, otherwise known as: Antioxidant CAO-3; butylated hydroxytoluene; 2,6-di-tert-butyl-p-cresol (DBPC) (CAS Number: 128-37-0).

[0083] Oily Component

[0084] The formulation of the present invention may include an oily component in the range of 5.0-20.0% (w/v), preferably 7.0-15.0% (w/v), ideally about 10% (w/v).

[0085] The oily component may include a triglyceride, such as a medium chain triglyceride (such as C6-12) such as glyceryl esters of capric acid and/or caprylic acid. Other oily components that may be used include C12-15 alkyl benzoate; isopropyl isostearate; isopropyl myristate.

[0086] The preferred oily component is a glyceryl ester of capric acid and/or caprylic acid, such as those that may be obtained from coconut (oil). An example of such an oily component is glyceryl tricaprylate. A commercial form of a preferred oily component is known as Miglyol 812. [0087] Solvent

[0088] The formulation of the present invention may include a solvent in the range of 5.0-30.0% (w/v), preferably 10.0-25.0% (w/v), ideally about 20% (w/v). [0089] Examples of suitable solvents include, but are not limited to, polyvinyl pyrrolidone and glycols (such as propylene glycol (PG), polyethylene glycol (PEG), butylene glycol (BG) and ethylene glycol (EG)), combinations thereof, and derivatives thereof.

[0090] Propylene glycol is the most preferred solvent.

[0091] Propylene glycol USP/EP is designed for foods, pharmaceuticals, cosmetics, and other applications involving possible ingestion or absorption through the skin. Propylene glycol USP/EP is tested for and meets the requirements of the Food Chemicals Codex (FCC), the United States Pharmacopoeia (USP), European Pharmacopoeia (EP), and Japanese Pharmacopoeia (JP). Propylene glycol USP/EP also complies with the Brazilian Pharmacopoeia (FB) monograph. Propylene glycol is odourless and colourless, has a wide range of solvency for organic materials, and is completely water soluble. It is a known antimicrobial and is effective as a food preservative.

[0092] Antifoaming Agent

[0093] The formulation may include an antifoaming agent, which may be in the range of 0.01- 0.05% (w/v), preferably 0.2-0.4% (w/v), ideally about 0.03% (w/v).

[0094] Thickener

[0095] The formulation may include a thickener in the range of 0.1-4.0% (w/v), preferably 1.0- 3.0% (w/v), ideally about 2.0% (w/v) to about 2.50% (w/v).

[0096] Examples of thickeners that may be used in the aqueous phase include: natural or chemically modified elastomers, agar-agar, agarose, agaropectin, alginic acid and its salts and derivatives, acacia gum, carboxymethylcellulose, carob gum, carrageenan, com syrup, deacetylated chitin, dextran, gellan gum, guar gums (natural or synthetic), gum arabic, gum ghatti, gum karaya, gum tragacanth, high and low methoxy pectins, hydroxyethylcellulose, konjac gum, locust bean gum, maltodextrin, pectin, polyvinyl alcohol, propylene glycol alginate, sodium carboxymethylcellulose, sodium alginate, tamarind gum, xanthan gum, combinations thereof, and derivatives thereof. Examples of thickeners that may be used in the oily phase include: inorganic thickeners such as bentonites, colloidal silica, aluminium monostearate; organic thickeners such as monoglycerides (for example Myverol® such as Myverol 18-92 or Myverol 18-99), cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates, methacrylates; and Aerosil® (Degussa, Technical Bulletin Pigments, No. 11 and No. 49).

[0097] Even though the term thickener is used herein, such thickeners of the present disclosure may also have other functions, such as a stabilizing and/or gelling function. [0098] The viscosity (such as dynamic viscosity) of the formulation of the present invention may be adjusted so as to remain below 400 cps. The viscosity (such as dynamic viscosity) of the formulation of the present invention may be adjusted so as to remain below 600 mPas, such as below 300 mPas.

[0099] Colouring Agent

[0100] The formulation may include a colouring agent, which may be in the range of 0.001- 0.05% (w/v), preferably 0.005-0.02% (w/v), ideally about 0.005-0.01% (w/v).

[0101] Suitable colouring agents include: ferric oxide, titanium oxide, prussian blue, alizarin dye, azo dye, and phthalocyanine dye. Most preferred are Brilliant Scarlet 4R Cl 16255, which is also known as Acid Red 41; Food Red 8; Scarlet 4R ; C. I. 16255; or E-124 and Brilliant Blue G- 250.

[0102] The inclusion of a colouring agent is largely, even exclusively, to indicate to the user where the formulation of the invention has been applied to the animal.

[0103] Neutralizer

[0104] The formulation may include a neutralizer, which may be in the range of 0.01-0.06% (w/v), preferably 0.01-0.05% (w/v), ideally about 0.03% (w/v).

[0105] The preferred neutralizer is an hydroxide salt, such as sodium hydroxide. Other neutralizers that may be considered include the following, which may be used at the Relative Base Strength Parts provided in square brackets [] with respect to emulsifier (such as pemulen): potassium hydroxide (such as may be provided as a 18% w/v solution in water) - [0.5 parts]; ammonium hydroxide (such as may be provided as a 28% w/v solution in water) - [0.3 parts]; triethanolamine (TEA) - [2.0 parts]; tromethamine (2 -amino-2 -hydroxymethyl- 1,3 -propanediol) - [2.0 parts]; aminomethyl propanol (AMP) - [1.5 parts]; tetrahydroxypropyl ethylene diamine - [2.0 parts] .

[0106] The neutralizer may be used in solid form, although liquid form (such as in solution, such as an aqueous solution of sodium hydroxide of known concentration) may be preferred. Where provided, the range in w/v of the neutralizer indicates the weight of the undiluted/dissolved neutralizer, rather than the weight of the solution of the neutralizer. The pH of the formulation of the present invention may be adjusted to from 5.5 to 7.5.

[0107] Carrier/Diluent

[0108] The formulation will typically include an aqueous carrier/diluent, such as (purified) water. Typically the amount of carrier/diluent is variable and will depend on the amount of other components in the formulation, since the carrier/diluent is used to adjust the final volume to the desired amount (i.e. quantum sufficit - q.s.).

[0109] The present disclosure will now be described in greater detail with the aid of non-limiting examples.

[0110] Table 1: Formulation Examples

[0111] It will be appreciated that not all of these ingredients in these formulation examples are required to provide a useful formulation according to the invention. For instance, colouring agent aids in visualising the formulation when applied, but of itself provides no meaningful efficacy against fly strike.

[0112] Table 2: Further Formulation Examples

[0113] It will be appreciated that not all of these ingredients in these formulation examples are required to provide a useful formulation according to the invention. For instance, colouring agent aids in visualising the formulation when applied, but of itself provides no meaningful efficacy against fly strike.

[0114] Table 3: Still Further Formulation Examples

[0115] It will be appreciated that not all of these ingredients in these formulation examples are required to provide a useful formulation according to the invention. For instance, colouring agent aids in visualising the formulation when applied, but of itself provides no meaningful efficacy against fly strike.

[0116] Generalised Preparation Method 1 - particularly (but not limited to) for low surfactant concentration

[0117] In a non-limiting example of the invention, the formulation of the present invention may be prepared in four stages. A gel phase is prepared by mixing solvent, preservative, and suitable emulsifier with water. This gel phase mixture is then transferred to the main mixing tank. An oily phase is prepared by combining a triglyceride oil (oily component) with antioxidant, preservative, and a thickener/stabilizer. After mixing, the oily phase is transferred to the main mixing tank where it is mixed with the gel phase.

[0118] The active phase is prepared by combining the “other additives” (e.g. EDTA), solvent, surfactant, and active ingredients with a portion of water. When a lump free suspension is obtained the active phase is milled and fed into the main tank with the combined gel and oil phases. [0119] The final stage is the addition of the colouring agent, adjustment of pH (using the neutralizer) and adjustment to final volume with water.

[0120] Generalised Preparation Method 2 - particularly (but not limited to) for high surfactant concentration

[0121] As an alternative to Preparation Example 1 (and advantageously if the surfactant concentration is high) the following method consisting of five stages may be adopted.

[0122] First, an ivermectin suspension concentrate may be prepared by combining ivermectin with a solvent, preservative, antifoaming agent, and surfactant(s).

[0123] Second, after mixing, the viscosity is adjusted with a suitable emulsifier and, if necessary, the pH adjusted with a neutralizer. This suspension concentrate is diluted further at a later stage.

[0124] Third, a dicyclanil intermediate mixture is prepared by charging dicyclanil into a pre-mix of triglyceride oil (oily component), antioxidant, preservative(s) and surfactant(s).

[0125] Fourth, the ivermectin suspension concentrate is then diluted to its final concentration in a mixture of water and “other additive” (e.g. EDTA).

[0126] Fifth, suspoemulsion blending then occurs as follows:

• solvent, preservative, water, and an emulsifier are combined and mixed.

• To this mixture the dicyclanil intermediate and the diluted ivermectin suspension concentrate are added.

• After mixing the colouring agent is added, the pH of the final product is adjusted with neutralizer, and the viscosity adjusted with an emulsifier.

[0127] Thus, the manufacturing of the formulation of the present invention may include:

(a) the preparation of a gel phase by mixing suitable solvent, preservative, and emulsifier with water;

(b) the preparation of an oily phase by combining a suitable triglyceride oil with antioxidant preservative and a thickener and/or stabilizer;

(c) and transferring said gel phase and said oily phase to a mixing tank and homogenizing both phases;

(d) the preparation of the active phase is prepared by mixing an “other additive” (e.g. EDTA), solvent, surfactant and the active ingredients with water and milling the mixture until a lump free suspension is obtained;

(e) the preparation of the final formulation by mixing the homogenized phase of step (c), the active phase of step (d) and the colouring agent; (f) adjustment of pH; and

(g) adjustment to final volume with water.

[0128] Manufacturing Example - Preparation of a 1000 litre batch

[0129] A 1000 litre batch of the inventive formulation can be prepared in the following manner. [0130] Phase 1: 160.00 kg of propylene glycol is added to a clean tank of suitable volume (e.g. 250-400 litre). Whilst the propylene glycol is stirred constantly, 1.50 kg of methyl hydroxybenzoate (methyl paraben) is added in small portions. The resulting mixture is stirred for another 20 minutes in order to complete the dissolution. Then, 30 litres of water is added and the mixture is stirred for another five minutes. The mixture is then transferred to a homogeniser (1400 rpm fixed speed). While mixing, 1.12 kg Pemulen TR-2 NF is added and the mixture is again stirred for about 10 minutes until a smooth dispersion is obtained. The resulting phase 1 is then transferred to a clean tank of suitable volume.

[0131] Phase 2: 100.00 kg of pre-warmed (40 °C) glycerol tricaprate/caprylate (a.k.a. glyceryl tricaprate/caprylate, a.k.a. Miglyol 812), 0.50 kg butylated hydroxytoluene antioxidant CAO-3 (BHT), and 3.00 kg propyl hydroxybenzoate (propyl paraben) are added to a clean tank of suitable volume and mixed for about 20 minutes. Afterwards 28.00 kg of pre-melted (40 °C) Myverol 18-92 is added in small portions and the resulting mixture is stirred for about 30 minutes. Then phase 2 is added to phase 1 and the mixture is stirred for another 10 minutes.

[0132] Phase 3: 200 litre of water is added to a clean tank of suitable volume. While stirring 0.50 kg disodium edetate dihydrate BP (disodium EDTA), 40.00 kg propylene glycol, 2.50 kg Polysorbate 20, 50.00 kg dicyclanil and 15.00 kg ivermectin are added in smaller portions to the water. The resulting composition is stirred until a lump free suspension is obtained. The phase is then milled through an appropriate mill with medium feed rate into the tank holding the combined phases 1 and 2 while stirring.

[0133] Final mixing and adjustment: To the combined phases 0.10 kg of Brilliant Blue dye is added and water is added to the 1000 Litre mark. The mixture is stirred for about 20 minutes and the pH value is measured and, if necessary, adjusted to the required range of 6.8-7.2 by adding aqueous 10% sodium hydroxide solution. In a last step water is added to the 1000 litre mark and the final mixture is stirred for about 30 minutes before packing off.

BIOLOGICAL EXAMPLES (EFFICACY) EXAMPLE 1

BLOWFLY PREVENTION EFFICACY TEST IN SHEEP [0134] Prophylactic Treatment to Prevent Flystrike and to treat active blowfly strikes. Large- scale field evaluations can be conducted to evaluate the efficacy against blowflies. In such cases large numbers of sheep in different geographic zones are treated with the formulation of the present invention (at the normal label dose rate) just prior to or during the blowfly season.

[0135] The sheep are then inspected at regular intervals to detect blowfly strikes when they occur.

[0136] When the cumulative number of flystrikes exceeds a strike rate figure set by the governing regulatory authority (e. g. 1 or 2% of the flock) the product is deemed to have ‘lost protection’. It is on this data that ‘protection periods’ against flystrike will be determined.

[0137] Animals found to be flystruck are treated with a registered fly dressing to resolve the strike. In a series of field trials in Australia, 8650 sheep (at 11 different sites) were treated with the formulation of the present invention or a currently registered product, used as a positive control. The formulation of the present invention was highly effective in preventing blowfly strike for a period of 18-24 weeks.

[0138] Moreover, resistance testing of the blowfly populations confirmed that the flies were representative of the more organophosphate (diazinon) resistant populations found in Australia, with some cross-resistance to ivermectin. Each of the populations tested was susceptible to the formulation of the present invention.

EXAMPLE 2

BLOWFLY CONTROL EFFICACY TEST IN SHEEP (FIELD TRIAL)

[0139] A field study was conducted to evaluate the efficacy of a combined formulation of di- cyclanil (5%) and ivermectin (0.3%) against active myiasis caused by the sheep blowfly (Lu- cilia cuprind) under Australian conditions.

[0140] A study site was selected based on the presence of suitably struck sheep. Twenty sheep with existing strikes were enrolled. The sheep were treated to the dose band of the individual body weight and the dicyclanil/ivermectin combination product was applied along the backline and on the breech.

[0141] Observations of active strike sites were made pre-treatment and at approximately 24 and 48 hours post-treatment. No active strikes remained on the sheep at the 48 hour observation.

[0142] The response to the treatment was graded:

AT = Larvae showing no effect from the chemical, fully active and feeding at skin level. Such a strike was to be terminated at the 24 hour inspection, or when its area exceeded 400 cm 2. Ai = Slight effect on larvae, mobility reduced but still feeding at skin level.

A2 = Obviously affected, larvae very slow, reduced in number, still at skin level but no feeding and dispersed from the infestation point.

A3 = Larvae severely affected, very slow, dispersed widely from infestation point - often out into the fleece.

D = All larvae dead.

A value was given to each strike end point assessment. These were: AT = 0, AI = 1, A2 = 5, A3 = 7, D = 10.

[0143] As used herein the term “controlling” refers to any outcome selected from Ai, A2, A3, and D. Preferably “controlling” will refer to any outcome selected from A2, A3, and D. Still more preferably “controlling” will refer to any outcome selected from A3, and D. Even more preferably “controlling” will refer to the outcome D.

[0144] The mean scores after treatment (arithmetic and geometric means), with minimum, maximum and median are below:

Table 4: Summary statistics of the assessment scores by time point

[0145] The differences between scores pre and post treatment and between 24 and 48 hours were highly significant (p<0.0001).

[0146] The percentage cure rate (%cr) was calculated based on the presence of severely affected larvae, dead larvae or combination:

Table 5: Cure rate (%) based on the proportion of animals with larvae classified as either A3, dead or both at 24 and 48 hours post-treatment

[0147] The efficacy of the treatment was high (24 hours) or complete (48 hours) after treatment. The combination of dicyclanil (50 g/L) and ivermectin (3 g/L) was highly effective with an overall cure rate against active myiasis of 95% at 24 hours and 100% at 48 hours post-treatment. EXAMPLE 3

BLOWFLY CONTROL EFFICACY TEST IN SHEEP (PEN TRIAL)

[0148] This randomized, controlled efficacy study aimed to determine the effectiveness of topically applied ivermectin, in combination with dicyclanil, to rapidly kill infestations of mixed stage L. cuprina larvae on sheep. In addition, blood, tissue and wool residues were collected for analysis of ivermectin and dicyclanil concentrations at various time points post-treatment.

[0149] Twelve sheep were selected from the Yarrandoo flock. The sheep were acclimatized to the Entomology Housing Facility pens for 5 days prior to treatment and underwent a veterinary inspection on day -2.

[0150] On day -1 the sheep were randomized, by live weight and gender, into two study groups (See table below).

[0151] T able 6 : T reatment groups

[0152] On day -1 and 0 the sheep were implanted with blowfly larvae L. cuprina. The implant sites were located within the treatment zone (site 1), immediately outside the treatment zone (within 2 cm) (site 2) and well outside the treatment zone (>10 cm) (site 3) so as to assess the movement of chemical in the fleece. All implants included first, second and third instar larvae. The sheep were treated at a dose of 0.5 mL/kg applied along the backline and on the breech. [0153] Observations of active implant sites were made pre-treatment (approximately 14 hours after implanting) and at approximately 8, 12 and 24 hours post-treatment. All active implants on the sheep in Group 1 were terminated after the 12 hour observation. Any active implants on the sheep in Group 2 were terminated after the 24 hour inspection.

[0154] The following tables present the results of the blowfly implants for each group at each of the three sites. The higher the value, the greater the efficacy of the treatment, with a maximum group value of 60 for each of the three sites.

Table 7: Blowfly implant assessment score - site 1 - within the treatment zone

Table 8: Blowfly implant assessment score - site 2 - just outside the treatment zone

Table 9: Blowfly implant assessment score - site 3 - well outside the treatment zone

[0155] Efficacy was demonstrated at all implant locations and there was no obvious reduction in the efficacy of the ivermectin when applied in the same formulation as the dicyclanil. This formulation was well tolerated by the sheep.

[0156] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to”.

[0157] The entire disclosures of all applications, patents and publications cited above and below, if any, are herein incorporated by reference.

[0158] Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that that prior art forms part of the common general knowledge in the field of endeavour in any country in the world.

[0159] The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features.

[0160] Where in the foregoing description reference has been made to integers or components having known equivalents thereof, those integers are herein incorporated as if individually set forth. [0161] It should be noted that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be included within the present invention.

Claims

Claims:

1. A formulation for controlling insect pests on a mammal comprising an amount of ivermectin and dicyclanil and a suitable carrier and/or diluent.

2. The formulation of claim 1, wherein controlling insect pests on the mammal comprises rapidly killing infestations of mixed stage L. cuprina larvae.

3. The formulation of claim 1 or claim 2 characterized in that it is in the form of a topical formulation for controlling and preventing blowfly strikes on sheep comprising about 1 to about 7% (w/v) dicyclanil and about 0.2 to about 0.4% (w/v) ivermectin.

4. The formulation according to any one of claims 1 to 3 characterized in that it is a spray-on formulation and has a dynamic viscosity of below about 400 cps.

5. The formulation according to any one of claims 1 to 4 characterized in that it is formulated to be effective against flies that are substantially resistant to organophosphorous and diflubenzuron-based insecticides.

6. The formulation according to any one of claims 1 to 5 characterized in that it is satisfactorily tolerant of rainfall.

7. A pour-on or spray-on formulation comprising an insecticidally effective amount of each of the two active ingredients ivermectin and dicyclanil and further comprising at least one of a surfactant, an emulsifier, a preservative, an other additive, optionally EDTA, an antioxidant, an oily component, a solvent, a thickener, a neutralizer, and optionally a colouring agent, and optionally an antifoaming agent.

8. The pour-on or spray-on formulation according to claim 7 comprising about 1 to about 7% (w/v) dicyclanil and about 0.2 to about 0.4% (w/v) ivermectin.

9. The pour-on or spray-on formulation according to claim 7 or claim 8 comprising a suitable surfactant in the range of 0.10-0.40% (w/v).

10. The pour-on or spray-on formulation according to any one of claims 7 to 9 comprising a suitable emulsifier in the range of 0.09-0.2% (w/v).

11. The pour-on or spray-on formulation according to any one of claims 7 to 10 comprising one or more suitable preservatives in the range of 0. 15-0.60% (w/v).

12. The pour-on or spray-on formulation according to any one of claims 7 to 11 comprising a suitable other additive (e.g. EDTA) in the range of 0.01-0.09% (w/v).

13. The pour-on or spray-on formulation according to any one of claims 7 to 12 comprising a suitable antioxidant in the range of 0.01-0.09% (w/v).

14. The pour-on or spray-on formulation according to any one of claims 7 to 13 comprising a suitable oily component in the range of 5.0-20.0% (w/v).

15. The pour-on or spray-on formulation according to any one of claims 7 to 14 comprising a suitable solvent in the range of 5.0-30.0% (w/v).

16. The pour-on or spray-on formulation according to any one of claims 7 to 15 comprising a suitable antifoaming agent in the range of 0.01-0.05% (w/v).

17. The pour-on or spray-on formulation according to any one of claims 7 to 16 comprising a suitable thickener in the range of 1.0-3.0% (w/v).

18. The pour-on or spray-on formulation according to any one of claims 7 to 17 comprising a suitable colouring agent in the range of 0.001-0.05% (w/v).

19. The pour-on or spray-on formulation according to any one of claims 7 to 18 comprising a suitable neutralizer in the range of 0.01-0.06% (w/v).

20. The formulation according to any one of claims 7 to 19 provided as a spray-on formulation.

21. The use of a formulation according to any one of claims 1 to 20 for simultaneously controlling and preventing blowfly strikes on sheep.

22. The use of a formulation according to any one of claims 1 to 20 in the treatment of sheep against blowfly infestation.

23. A method for controlling blowfly infestation on sheep comprising administering a formulation according to any one of claims 1 to 20 to one or more small areas of the wool or fibre of a sheep.

24. Process for the preparation of a formulation according to any one of claims 1 to 20 comprising the steps of:

(a) preparing a gel phase by mixing suitable solvent, preservative and a suitable emulsifier with water;

(b) preparing an oily phase by combining a suitable oily component with antioxidant preservative and a thickener and/or stabilizer;

(c) transferring said gel phase and said oily phase to a mixing tank and homogenizing both phases;

(d) preparing an active phase by mixing an “other additive” (such as EDTA), solvent, surfactant and the active ingredients (dicyclanil and ivermectin) with water and milling the mixture until a lump free suspension is obtained;

(e) mixing the homogenized phase of step (c), the active phase of step (d) and a colouring agent to form a pre-formulation; (f) optionally adjusting the pH of the pre-formulation; and

(g) optionally increasing the volume of the pre-formulation with water to provide the formulation.

25. The formulation of claim 2, wherein rapidly killing infestations of mixed stage L. cuprina larvae comprises no active strikes remaining at 2 days

26. The formulation of claim 2 wherein rapidly killing infestations of mixed stage L. cuprina larvae comprises no strike exceeding 400 cm² after 2 days.