AU2023200609A1

AU2023200609A1 - Topical compositions comprising a neonicotinoid and a macrocyclic lactone, methods and uses thereof

Info

Publication number: AU2023200609A1
Application number: AU2023200609A
Authority: AU
Inventors: Amit Kumar Jain; Alan Leslie JOHNSON
Original assignee: Boehringer Ingelheim Vetmedica GmbH
Current assignee: Boehringer Ingelheim Vetmedica GmbH
Priority date: 2019-01-16
Filing date: 2023-02-06
Publication date: 2023-03-09
Also published as: AU2020208145B2; WO2020150032A1; AU2020208145A1; NZ776819A

Abstract

This invention relates to topical compositions for combating ectoparasites and endoparasites in animals, comprising a combination of a macrocyclic lactone active agent and a neonicotinoid active agent in combination with a pharmaceutically acceptable carrier comprising a pyrrolidone solvent and a glycol ether solvent, and optionally an antioxidant. This invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the compositions of the invention to the animal in need thereof.

Description

TITLE OF THE INVENTION TOPICAL COMPOSITIONS COMPRISING A NEONICOTINOID AND A MACROCYCLIC LACTONE, METHODS AND USES THEREOF.

FIELD OF THE INVENTION The present invention provides topical veterinary compositions comprising at least one neonicotinoid active agent and at least one macrocyclic lactone active agent for controlling ectoparasites and endoparasites in and on animals. The invention also provides for the use of these compositions against ectoparasites and/or endoparasites, and methods for preventing or treating parasitic infections and infestations in animals using the compositions.

CROSS REFERENCE TO RELATED APPLICATIONS The application is a divisional application of Australia Patent Application No. 2020208145, which is the Australian National Phase Application of PCT/US2020/012450, which claims the benefit of priority to U.S. Provisional Application No. 62/793,301, filed January 16, 2019, all of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION Animals such as mammals and birds are often susceptible to parasite infestations/infections. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Domesticated animals, such as cats and dogs, are often infested with one or more of the following ectoparasites: - fleas (e.g. Ctenocephalidesspp., such as Ctenocephalidesfelisand the like), - ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentorspp., Amblyomma spp., and the like), - mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., and the like), - lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp. and the like), - mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the like) and - flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp. and the like). Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals and humans, such as dog tapeworm (Dipylidiumcaninum).

Similarly, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are the vector of pathogenic agents in both humans and animals. Major diseases which are caused by ticks include borreliosis (Lvme disease caused by Borrelia burgdoferi), babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host. Likewise, farm animals are also susceptible to parasite infestations. For example, cattle and sheep are affected by a large number of parasites. Parasites that are particularly harmful against sheep include body lice (Bovicola ovis) and gastrointestinal nematodes including, but not limited to, Haemonchus contortus, Telorsagia circuncinta and Trichostrongvlus colubrifornis. Sheep body lice are ubiquitous parasites of sheep and are estimated to cost Australiansheep producers $120 million per year in costs of control, loss of production and fleece derangement. Sheep lice may also become a significant welfare problem due to the discomfort caused to sheep while fleece derangement snakes them more susceptible to other serious conditions such as flystrike. Sheep roundworms are a ubiquitous parasite of sheep resulting in increased costs of control and loss of production. Roundworms are also a significant welfare problem due to potential mortality and scouring causing predisposition to flystrike. A parasite which is very prevalent among farm animals is the tick genus Rhipicephalus, especially those of the species microplus (cattle tick), decoloratus and annulatus. Ticks, such as Boophilus Inicroplus, are particularly difficult to control because they live in the pasture where farm animals graze. Animals and humans also suffer from endoparasitic infections including, for example, helminthiasis which is most frequently caused by a group of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flukes). These parasites adversely affect the nutrition of the animal and cause severe economic losses in pigs, sheep, horses, and cattle as well as affecting domestic animals and poultry. Other parasites which occur in the gastrointestinal tract of animals and humans includeAncylostoma, Necator, Ascaris Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strongyloides,Toxocara and Trichinella Milbemycin or avermectin compounds are natural or semi-synthetic compounds that contain a 16-membered macrocyclic ring. The avermectin and milbemycin series of compounds are potent anthelmintic and antiparasitic agents against a wide range ofinternl and external parasites. The natural product avermectins are disclosed in U.S. Patent 4,310,519 to Albers-Schonberg, et a]., and the 22. 23-dihydro-avermectin compounds are disclosed in Chabala, et al., U.S. Patent 4,199,569. For a general discussion of avermetins, which include a discussion of their uses in humans and animals, see "Ivermetin and Abamectin," W.C Campbell, ed., Springer-Verlag, New York (1989). Naturally occurring milbemycins are described in Aoki et al., U.S. Patent No. 3,950,360. Abamectin is a naturally-occurring compound of the avermectin family and consists of a mixture of isomeric compounds, isomer Bia and isomer Bib, which differ by a. single methylene group. The Bia and Bib isomers have the following structures: R

HO H

~OH~

R= CH OH ON Abamectin has been approved for use in animal medicine and is the starting material for the semi-synthetic avermectin. ivermectin. Abamectin differs from ivermectin only in the presence of a double bond at C-22/C-23. Abamectin exhibits superb potency against most species of gastrointestinal nematodes via subcutaneous injection. Abamectin, like other avermectins, binds selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells.This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. The neonicotinoids are a class of ectoparasiticides that bind and inhibit insect specific nicotinic acetylcholine receptors. In one embodiment, the topical formulation of the invention will comprise at least one neonicotinoid insecticidal agent combined with at least one macrocyclic lactone active agent. Imidacloprid is a well-known neonicotinoid active agent and is the key active ingredient in the topical parasiticide products Advantage© Advantage* II, K9 Advantix©, and K9 Advantix I11 sold by Bayer Animal Health. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or in EP 0 892 060, (incorporated by reference) among others. Another well-known neonicotinoid is nitenpyram. Nitenpyram is the active ingredient in the oral product CAPSTART Tablets sold by Novartis Animal Health. Nitenpyram has a very fast onset of actionagainst fleas. For example, CAPSTARTM Tablets begin to act against fleas in as early as 30 minutes after administration and is indicated for use as often as once a day. Imidacloprid is also used as a lousicide for sheep sold as the product AVENGETM by Bayer Australia Ltd. However, since imidacloprid is not active against internal nematodes, products containing imidacloprid only are not effective against internal parasites. AVENGET contains 3.5% (w/v) imidacloprid in a carrier comprising 30% (w/v) N-methylpyrrolidone and > 60% (w/v) dipropylene glycol monomethyl ether. Notwithstanding the compositions comprising a milbemycin or avermectin active agent alone or incombinationwithotheractiveagents described in the documents above, thereia need for veterinary compositions and methods with improved efficacy and spectrum of coverage and increased shelf life to protect animals against both endoparasites and ectoparasites. INCORPORATION BY REFERENCE Any foregoingapplications, and all documents cited therein or during their prosecution ("application cited documents") and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. SUMMARY OF THE INVENTION The present invention provides topical compositions comprising at least one macrocyclic lactone compound in combination with at least one neonicotinoid compound; uses thereof for the treatment or prophylaxis of parasitic infections and infestations of animals (either wild or domesticated), including livestock and companion animals such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeysand cattle, Inan embodiment, thetopical veterinary composition of the invention are advantageously inthe form of a spot-on or a pour-on formulation for application to localized areas on the animal to be treated. In one embodiment, the topical compositions of the invention comprise a macrocyclic lactone active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin and selamectin; and milbemycins such as milbemectin, milbemycin D, ilbemycin oxime, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins. In one embodiment, the neonicotinoid active agent is acetaiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a mixture thereof. In a preferred embodiment, the neonicotinoid active agent is imidacloprid. The invention also provides methods for the treatment or prevention of parasitic infections and infestations in animals, comprising administering an effective amount of a composition described herein to the animal. The present invention provides also provides uses of the compositions described for the treatment or prevention of a parasitic infestation or infection in an animal. It is an object of the invention to not encompass within the invention any previously knonr product, process of making the product, or method of using the product such that the Applicants reserve the right and hereby disclose a disclaimer of any previously known product, process, or method. It is further noted that the invention does not intend to encompass within the scope of the invention any product, process, or making of the product ormethod of using the product, which does not meet the written description and enablement requirements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83oftheEPC),suchthat Applicants reserve the right and hereby disclose a disclaimer of any previously described product, process of making the product, or method of using the product. These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.

DETAILED DESCRIPTION The present invention provides surprisingly stable and efficacious compositions comprising at least one macrocyclic lactone compound in combination with at least one neonicotinoid compound together with a pharmaceutically acceptable carrier or diluent, and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise an effective amount of at least one macrocyclic lactone active agent in combination with an effective amount of at least one neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof; together with a pharmaceutically acceptable carrier that comprises a combination of a pyrrolidone solvent and a glycol ether solvent, and optionally an antioxidant. In vet another embodiment, the invention provides topical compositions that comprise at an effective amount of an avermectin or milbemycin active agent in combination with an effective amount of at least one neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof; together with a pharmaceutically acceptable carrier that comprises a combination of a pyrrolidone solvent and a glycol ether solvent, and optionally an antioxidant. In some embodiments of the invention, the compositions are in a form that is suitable for topical administration. In one embodiment, the composition is a spot-on formulation that is applied to a localized area on an animal. In another embodiment, the compositions of the invention are in the form of pour-on formulations. Pour-on formulations typically differ from spot-on formulations in that they are higher volume formulations that are applied as a stripe down the back side of the animal, e.g. a stripe from head to tail of the animal. Pour-on formulations are typically used with livestock animals such as sheep and cattle while spot-on formulations are typically used with companion animals such as cats and dogs. These formulations provide surprisingly effective protection of the animals against ectoparasites and endoparasites for an extended period of time. In one embodiment, the compositions of the invention comprise at least one avermectin or milbemcin compound. In another embodiment, the at least one avermectin or milbemycin compound is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemy cin oxime, moxidectin or nemadectin. In vet another embodiment, the compositions of the invention comprise abamectin. In one embodiment, the compositions of the invention comprise acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a mixture thereof In a preferred embodiment of the invention, the neonicotinoid active agent in the topical compositions is imidacloprid. Also provided are methods and uses for the treatment and/or prophylaxis of parasitic infections and infestations of animals, comprising administering an effective amount of a formulation of the invention described herein to the animal. In this disclosure and in the claims, terms such as "comprises" "comprising,"

"containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean "includes," "including," and the like; "consisting essentially of" or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments: and "consist of" likewise has the meaning ascribed in U.S. Patent law and excludes any element, step, or ingredient not specified in the claim. It is also noted that in this disclosure and in the claims and/or paragraphs, the compounds of the invention are intended to include all stereoisomers and crystalline forms (which includes hydrated forms, polymorphic forms and amorphous forms with up to 15% by weight crystalline structure) thereof. Definitions Terms used herein will have their customary meaning in the art unless specified otherwise. The organic moieties mentioned in the definitions of the variables of formula (I) or (IA) are - like the term halogen - collective terms for individual listings of the individual group members. 'The prefix C-Cs indicates in each case the possible number of carbon atoms in the group. The term "animal" is used herein to include all mammals, birds and fish andalso include all vertebrate animals, including humans. Animals include, but are not limited to, humans, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also includes an individual animal in all stages of development, including embryonic and fetal stages. By "effective amount" is intended a sufficient amount of a composition of the invention to eradicate or reduce the number of parasites infesting the animal. In some embodiments, an effective amount of the active agent achieves at least 70% efficacy against the target parasite. In other embodiments, an effective amount of the active agent achieves at least80%, or at least 90% efficacy against the target pests. Preferably, an effective amount of the active agent will achieve at least 95%, at least 98% or 100% efficacy againstthe target parasites. Stereoisomers and polymorphic forms It will be appreciated by those of skill in the art that certain compounds within the compositions of the invention may exist and be isolated as optically active and racemic forms. Compounds having one or more chiral centers, including at a sulfur atom, may be present as single enantiomers or diastereomers or as mixtures of enantiomers and/or diastereomers. For example, it is well known in the art that sulfoxide compounds may be optically active and may exist as single enantiomers or racemic mixtures. In addition, compounds within the compositions of the invention may include one or more chiral centers, which results in a theoretical number of optically active isomers. Where compounds within the compositions of the invention include n chiral centers, the compounds may comprise up to 2" optical isomers. The present invention encompasses the specific enantiomers or diastereomers of each compound as well as mixtures of different enantiomers and/or diastereomers of the compounds of the invention that possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic forms by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution. The compounds within the compositions of present invention may also be present in different solid forms such as different crystalline forms or in the form of an amorphous solid. The present invention encompasses different crystalline forms as well as amorphous forms of the inventive compounds. In addition, the compounds within the compositions of the invention may exist as hydrates or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in the crystalline form. The compositions of the invention may include hydrates and solvates of the active agents. Salts Also contemplated within the scope of the invention are acid or base salts, where applicable, of the compounds of the invention provided for herein. The term "acid" contemplates all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hy drohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid. Organic acids include all pharmaceutical acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment of the acids, the acids are straight chain or branched, saturated or unsaturated CC2o aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C6 2 aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid,valeric acid, a-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glucoheptonic acid and lactobionic acid. The term "base" contemplates all pharmaceutically acceptable inorganic or organic bases, including hydroxides, carbonates or bicarbonates of alkali metal or alkaline earth metals. Salts formed with such bases include, for example, the alkali metal and alkaline earth metal salts, including, but not limited to, as the lithium, sodium, potassium, magnesium or calcium salts. Salts formed with organic bases include the common hydrocarbon and heterocyclic amine salts, which include, for example, ammonium salts (NH4+), alkyl- and dialkylammonium salts, and salts of cyclic amines such as themorpholine and piperidine salts, Compositions In one embodiment, the invention provides compositions that comprise at least one macrocyclic lactone active agent in combination with at least one neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier or diluent that comprises a pyrrolidone solvent and a glycol ether solvent, and optionally an antioxidant. The macrocyclic lactone compounds are also well known in the art and can be obtained commercially or through known synthesis techniques. For avermectins, ivermectin and abamectin, reference may be made, for example, to the publication "Ivermectin and Abamectin", 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag., "Macrocyclic Lactones in Antiparasitic Therapy", 2002, by J Vercruysse and RS Rew published by CAB Publishing or Albers-Schonberg et al. (1981) "Avermetins Structure Determination", J Am. Chem. Soc., 103, 4216-4221. For doramectin, "Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15 may be consulted. For milbemycins, reference may be made, inter alia, to Davies H.G, et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermetins, Terahedron Lett., 24, 5333-5336, U.S. Patent No. 4,134,973 and EP 0677 054, all of which are incorporated herein by reference. Macrocyclic lactones are either natural products or are semi-synthetic derivatives thereof. The structures of the avermectins andnilbemycins are closely related, e.g., by sharing a complex 16-membered macrocyclic lactone ring; milbemycins lack the glycosidic moiety of the avermectins. The natural products avermectins are disclosed in U.S.

Patent No. 4,310,519 to Albers-Schonberg et al., and the22.,23-dihvdro avermectin compounds are disclosed inChabala et al., U.S. Patent No. 4,199,569. Mention is also made of Kitano, U. S. Patent No. 4,468,390, Beuvry et al., U.S. Patent No. 5,824,653, EP 0 007 812 Al U.K. Patent Specification 1 390 336, EP 0 002 916., and Ancare New Zealand Patent No. 237 086, inter ala. Naturally occurring milbemycins are described in Aoki et al., U.S. Patent No. 3,950,360 as well as in the various references cited in'"The Merck Index" 12* ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in the "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug InJrmation, vol. 17, no. 4, pp. 263- 286, (2003). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Patent No. 5,077,308, U.S. Patent No. 4,859,657, U.S. Patent No. 4,963,582, U.S. Patent No. 4,855317, U.S.Patent No. 4,871,719, U.S. Patent No. 4,874,749, U.S. Patent No. 4,427,663, U.S. Patent No. 4,310,519, U.S. Patent No. 4,199,569, U.S. Patent No. 5,055,596, U.S. Patent No. 4,973,711, U.S. Patent No. 4,978,677, U.S. Patent No. 4,920,148 and EP 0 667 054, all incorporated herein by reference. As noted above, the neonicotinoids are a class of ectoparasiticides that bind and inhibit insect specific nicotinic acetylcholine receptors. Inidacloprid is a well-known neonicotinoid active agent and is the key active ingredient in the topical parasiticide products Advantage, Advantage 0 II, K9 Advantix, and K9 Advantix* 11 sold by Bayer Animal Health. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or in EP 0 892 060, (incorporated by reference) among others. Veterinary compositions comprising neonicotinoid active agents are described in U.S. Patent Nos. 6,444,690; 6,232,328; 6,372,765; 6,001,858; 6,218,407; 6,369,054; 6,372,765; 7,728,011; 8,691,256and 8,849,259, all incorporated herein by reference in their entirety. Another well-known neonicotinoid isntenpyram. Nitenpyram is the active ingredient in the oral product CAPSTARM Tablets sold by Novartis Animal Health. The avermectin and nilbemycin active agents include, but are notlimited to, abaiectin, dimadectin, doramectin., emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, nibemycin D, nibemycin oxime, moxidectin or nemadectin, or mixtures of these active agents. Neonicotinoid active agents that may be included in the compositions of the invention include, but are not limited to, acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, and combinations thereof. Neonicotinoid active agents that may be included in the compositions of the invention also include newer neonicotinoids such as guadipyrand hunanyaglin (see, e.g., N. Simon-Delso et al., (2015) Systemic insecticides (neonicotinoids and fipronil): trends, uses, mode of action and metabolites. Environ Sci Pollut Res 22:5-34; and Shao X, Swenson TL, Casida JE; (2013) Cycloxaprid insecticide: nicotinic acetylcholine receptor binding site and metabolism. J Agric Food Chem 61:7883-7888) and also include neonicotinoid-like insecticides such as cis neonicotinoids (e.g. cycloxaprid and paichongding, see Shao X, Liu Z, Xu X, LiZ. Qan X (2013) Overall status of neonicotinoid insecticides in China: production, application and innovation. J Pest Sci 38:1---9; and ), nitroguanidine thiazole neonicotinoids (e.g. imidaclothiz, see Wu M, Cai J, Yao J, Dai B, Lu Y (2010) Study of imidaclothiz residues in cabbage and soil by HPLC with UVdetection. Bull Environ Contai Toxicol 84:289-293 ), and sulfoxaflor (see Watson GB, LosoMR, Babcock JM, Hasler JM, Letherer TJ, Young CD, Zhu Y. Casida JE, Sparks TC (2011) Novel nicotinic action of the sulfoximine insecticide sulfoxaflor. Insect Biochem Mol Biol 41:432---439). Pvrrolidone solvents that may be used in the compositions of the invention include, but are not limited to, 2-pyrrolidone, 1-(C1-20-alkvl)-2-pyrrolidone, in particular 1 methylpyrrolidone (also known as N-methylpyrrolidone), 1-ethylpyrrolidone, 1-n propylpyrrolidone, 1-octylpyrrolidone, I-dodecylpyrrolidone, I-isopropylpyrrolidone, 1-(s- or t- orn-butyl)pyrroldonde, -hexylpyrrohdone, 1I-(C2-20-alkenyl)-2-pyrroidone such as 1-vinyl 2-pyrrolidone, 1-(C3-scycloalkyl)-2-pyrrolidone such as 1-cyclohexylpyrrolidone, I-(C1-6 hydroxyalkyl)-2-pyrroidone, I-(Cw-6-alkoxy-C1-6-alkyl)-2-pyrrolidone such as 1-(2 hydroxyethyl)-pyrrolidone, 1-(3-hydroxypropyl)pyrroidone, 1-(2-methoxyethy1) pyrrolidone, 1-(3-methoxypropyl)pyrrolidone and 1-benzypyrrolidone, and the like. Glycol ether solvents that may be used in the compositions of the invention include, but are not limited to, diethylene glycol monoethyl ether (Transcutol©), butyl diglycol, propylene glvcol monomethv ether, propylene giyco imonoethyl ether, dipropyeneglycol n-buty7ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and dipropylene glycol monomethyl ether, or a combination thereof The pyrrolidone solvent will typically be present in the compositions of the invention in a concentration of about 10% (w/v) to about 50% (w/v). In one embodiment, thepyrroidone solvent will be present in a concentration of about 20% to about 50% (w/v). In yet other embodiments, the pyrrolidone solvent will be present in a concentration of about 20% to about 40% (w/v) or about 25% to about 35% (w/v). In a particular embodiment, the compositions of the invention will comprise about 30% (w/v) of a pyrrolidone solvent. The glycol ether solvent will typically be present in a sufficient quantity to complete the formulation (quantumsufficit or q.s.).

In an embodiment, the invention provides surprisingly stable topical compositions(e.g., spot-on, pour-on) comprising a combination of macrocyclic lactone active agent in combination with at least one neonicotinoid active agent having an extended shelf-life for the treatment or prevention of a parasitic infection or infestation in an animal, wherein the composition has a shelf-life of at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or at least 48 months. In another embodiment, the invention provides topical compositions that comprise an effective amount of at least one avermectin or milbemycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D. milbemycin oxime, moxidectin and nemadectin, or a mixture thereof. in combination with an effective amount of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin. dinotofuran, inidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof together with a pharmaceutically acceptable carrier that comprises a combination of a pyrrolidone solvent and a glycol ether solvent, and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of an effective amount of abamectin and an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises a combination of a pyrrolidone solvent and a glycol ether solvent, and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise a combination of an effective amount of abamectin and an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises a combination of a pyrroidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpVrrolidone, I-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec-butylpyrrolidone, 1- butylpyrrolidone, 1-n-butylpyrrolidone, 1-hexylpyrrolidone, I-vinvi-2-pyrrolidone, 1 cyclohexylpyrrolidone, I-(2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolIdone, 1 (2-methoxvethyl)-pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent, and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise a combination of an effective amount of abamectin and an effective amount ofimidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmiaceutically acceptable carrier that comprises a combination of a pyrrolidone solvent selected from the group consisting of 2-pyrroidone, N-inethylpyrrolidone, I-ethylpyrrolidone, I-octylpyrrolidone, I-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-sec-butylpyrrolidone, I-t butylpyrrolidone. 1-n-butylpyrrolidone. I-hexylpyrrolidone. 1-vinyl-2-pyrrolidone, 1 cyclohexylpyrrolidone, 1-(2-hydroxyethyl)-pyrrolidone, I-3-hydroxypropyl)pyrroidone, 1 (2-methoxyethyl)-pyrroidone, 1-(3-methoxvpropyl)-pyrroidone and 1-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof, and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of an effective amount of abamectin and an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises a combination of N-methylpyrrolidone and dipropylene glycol monomethyl ether, and optionally an antioxidant. In yet another embodiment, the invention provides topical compositions that comprise a combination of an effective amount of abamectin and an effective amount ofiidaloprid, or pharmaceutical acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises a combination of N-methylpyrrolidone and dipropylene glycol monomethyl ether, and butylated hydroxytoluene or butylated hydroxyanisole. In another embodiment, the invention provides topical compositions consisting essentially of an effective amount of a macrocyclic lactone active agent, an effective amount of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent and an antioxidant. In yet another embodiment, the invention provides topical compositions consisting essentially of an effective amount of an avermectin or nilbemycin active agent, an effective amount of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent, adanantioxidant. In another embodiment, the invention provides topical compositions consisting essentially of an effective amount of an avermectin ormilbemycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidetin and nemadectin, an effective amount of a neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent, and an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of an effective amount of abamectin, an effective amount of imidacloprid. or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent, and an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of an effective amount of abamectin and an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone. 1-ethylpyrrolidone, I octylpyrrolidone, I-dodecylpyrrolidone, 1-isopropylpyrrolidone, I-sec-butylpyrrolidone, I-t butylpyrrolidone, 1-n-butylpyrrolidone, 1-hexylpyrrolidone, I-viny1-2-pyrrolidone, 1 cyclohexylpyrrolidone, 1-(2-hvdroxvethyl)-pyrrolidone, 1-3-lydroxypropyl)pyrrolidone, 1 (2-methoxvethvl)-pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and I-benzylpyrrolidone; a glycol ether solvent and an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of an effective amount of abamectin, an effective amount of imidaclopid, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent selected from the group consisting of2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrroidone, I octylpyrrolidone, I-dodecylpyrrolidone, 1-isopropylpyrrolidone, i-sec-butylpyrrolidone, 1- butylpyrrolidone, 1-n-butvlpyrroidone, 1-hexylpyrrolidone. 1-vinyl-2-pyrrolidone, 1 cyclohexylpyrrolidone, 1-(2-hydroxyethyl)-pyrrolidone., 1-3-hydroxypropyl)pyrrolidone., 1 (2-methoxyethyl)-pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrroidone; a glycol ether solvent selected from the group consisting of propylene glycolmonornethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethvl ether; and an antioxidant that is butylated hydroxytoluene or butylated hydroxy anisole. In another embodiment, the invention provides topical compositions consisting essentially of an effective amount of abamectin, an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, N-methylpyrrolidone, dipropylene glycol monomethyl ether, and butylated hydroxytoluene. In yet another embodiment, the invention provides topical compositions consisting of an effective amount of an avermectin or milbemycin active agent, an effective amount of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent, an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of an effective amount of an avermectin ormilbemycin active agent selected from the group consisting of abanectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemvcin D, milbemycin oxime, moxidectin and nemadectin, an effective amount of a neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid. thiamethoxam, or a combination thereof, or pharmaceutical acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent, an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of an effective amount of abamectin, an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent, a glycol ether solvent, an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of an effective amount ofabamectin andan effective amount ofimidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1 dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec-butylpyrrolidone, 1-t-butylpyrrolidone,1 n-butylpyrrolidone, I-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone,1 (2-hydroxvethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrroidone., I-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone; a glycol ether solvent, an antioxidant andadye. In still another embodiment, the invention provides topical compositions consisting of in effective amount of abamectin, an effective amount of imidacloprid, or pharmaceutical acceptable salts, hydrates or solvates thereof; a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methiylprroidone, 1-ethylpyrrolidone, 1-octyipyrroidone, I dodecylpyrrolidone, I-isopropylpyrrolidonel 1-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1 n-butylpyrrolidone, I-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrroidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and I-benzylpyrrolidone; a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethvl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether in antioxidant that Is butylated hydroxytoluene or butylated hydroxyanisole, and a dye. In another embodiment, the invention provides topical compositions consisting of an effective amount of abamectin, an effective amount of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, N-methyIpyrrolidone, dipropylene glycol monomethyl ether, butylated hydroxytoluene and a dye. Typically the compositions of the invention will comprise between about 0.1 to about 20% (w/v) of the neonicotinoid active agent. In other embodiments, the compositions may comprise about 0.1% to about 10% (w/v), about 0.1% to about 5% (v/v) orabout 1% toabout 5% (w/v) of the neonicotinoid active agent. In another embodiment, the compositions of the inventionmayvcomprise about 2% to about 4% of the neonicotinoid active agent. In a particular composition of the invention, the composition will include about 3.5% (w/v) of the neonicotinoid active agent. The compositions of the invention will typically comprise about 0.01% to about 5% of the macrocyclic lactone active agent. In other embodiment., the compositions iill comprise about 0.1% to about 5% (w/v) or about 0. I to about 2% (/v) of the macrocyclic lactone active agent. In another embodiment, the compositions of the invention will comprise about 0.1% to about 1% (w/v) or about 0.4% (w/v) of the macrocyclic lactone active agent. In yet another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 5% (w/v) of an avermectin or milbemycin active agent in combination with about 1% (w/v) to about 10% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 10%(w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 5% (w/v) of at est one avermetin ormilbemycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 1%(w/v)to about 10% (w/v) of atleast one neonicotinoidactive agentselected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier thatcomprises about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a lyvcol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of about 0.1%(w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 10% (w/v) to about 50% (w/v) of a pyrroidone solvent and a glycol ether solvent (q.s.) and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 5% (xv/v) of abamectin and about 1% (v/v)toabout10%(w/v)of inidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof together with a pharmaceutically acceptable carrier that comprises about 10% (w/v) to about 50% (w'v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, I-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec butylpyrrolidone, 1-t-butylpyrrolidone, 1-n-butylpyrrolidone, 1-hexvlpyrrolidone, 1-vinyl-2 pyrrolidone, 1-cyclohexylpyrrolidone, 1-(2-hydroxyethyl)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, I-(2-methoxyethyl)-pyrrolidone, 1-(3-methoxypropyl) pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 5% (v/v) of abamectin and about 1% (v/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 10%(w/v) to about 50% (w/v) of a pyrrolidone solventselected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, I-ethylpyrrolidonel-octylpyrrolidone,I-dodecylpyrrolidone,-isopropylpyrrolidone,I-see butylpyrrolidone,1-t-butylpyrrolidone,I-n-butyVpyrrolidone,1-hexylpyrrolidoneI-vinyl-2 pyrrolidone, I-cyclohexvlpyrrolidone, 1-(2-hvdroxyethyl)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-2-methoxyethyi)-pyrrolidone, 1-(3-methoxypropyl) pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 10% (w/v) to about 50% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a. combination of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) ofimidacloprid, or pharmaceutical acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 10% (w/v) to about 50% (w/v) ofN-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 2% (w/v) of butiated hydroxytoluene or butylated hydroxyanisole. In yet another embodiment, the invention provides topical compositions that comprise combination of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) ofimidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 10% (w/v) to about 50% (w/v) N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.) and about0.01% (w/v)toibout 2% (w/v)ofbutylatedhydroxytouene. In yet another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 2% (w/v) of an avermetin or milbemycin active agent in combination with about 1% (w/v) to about 5% (w/v) of a. neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 2% (w/v) of at least one avermetin or milbenycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 1% (w/v) to about 5% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of about 0.1% (w/v) to about 2% (w/v) of abamectinand about 1% (w/v) to about 5% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 2% (w/v) ofabamectin and about 1% (w/v) to about 5% (w/v) of unidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20%(w/v) to about 40% (w/v)ofa pyrrolidone solvent selected from the group consisting of 2-pyrroidone, N-methylpyrrolidone, 1-ethylpvrrolidone, 1-octylpyrroidone, 1-dodecylpyrrolidone, 1-isopropylpvrrolidone, l-sec butylpyrrolidone. 1-t-butylpyrrolidone, 1-n-butylpyrrolidone, I-hexylpyrrolidone, 1-vinyl-2 pyrrolidone., I-cyclohexylpyrroidone, 1-(2-hydroxyethyl)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-(2-methoxyeIthl)-pyrrolidone, I-(3-methoxypropyl) pyrrolidone and 1-benzylpyrroidone together with a glycol ether solvent (q.s.). and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methiylpyrroidone, I-ethvipyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, i-sec butylpyrrolidone, 1-t-butylpyrrolidone, I-n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2 pyrrolidone, I-cvclohexylpyrrolidone, 1-(2-hydroxyethyli)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-(2-iethoxyethyl)-pyrrolidone, 1-(3-methoxypropyl) pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene givcol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s,), and optionally an antioxidant.

In another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 2% (w/v) abamectin and about 1% (w/) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) of N-methlpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) ofN-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 1% (w/v) of butylated hy droxytoluene or butylated hydroxyanisole. In vet another embodiment, the invention provides topical compositions that comprise a combination of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutical acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 20% (w/v) to about 40% (w/v) N-methVlpyrroiidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 1% (w/v) of butylated hydroxytoluene. In vet another embodiment, the invention provides topical compositions that comprise about0.1% (w/v) to about 1% (w/v) of an avermectin or milbemycin active agent in combination with about 2% (w/v) to about 4% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.) and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 1% (w/v) of at least one avermectin ormilbemycin activeagent selected from the group consisting of abametin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, inlbemectin, milbemvcin D, milbemycin oxime. moxidetin and nemadectin, or a mixture thereof, in combination with about 2% (w/v) to about 4% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (wv) to about 35% (wv) of a pyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a. combination of about 0. 1% (w/v) to about 1% (w/v) of abanectin and about 2% (w/v) to about 4% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s., quantum sufficit), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2%(w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (w/v) to about35% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrroidone, I-ethylpyrroidone,1-octylpyrrolidone,1-dodecylpyrrolidone,1-isopropylpyrrolidone,I-sec butylpyrrolidone,1-butylpyrrolidone,1-n-butylpyrrolidone,1-hexylpyrrolidone,1-vinyl-2 pyrrolidone, 1-cyclohexylpyrrolidone, 1-(2-hvdroxyethl)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-(2-methoxyethiyl)-pyrrolidone, I-(3-methoxypropyl) pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about I% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof together with a pharmaceutical acceptable carrier that comprises about 25% (w/v)to about 35% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, I-ethylpyrroidone, I-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, i-sec butylpyrrolidone, 1-t-butylpyrrolidone, 1-n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2 pyrrolidone, I-cyclohexylpyrrolidone, 1-(2-liydroxvethyl)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl)-pyrrolidone, 1-(3-methoxypropyI) pyrrolidone and 1-benzyipyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylerie glycol monomethyl ether, ethylene glycol monoethvl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (qs.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 1% (w/v) abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (w/v) to about 35%(w/v) of N-methylpyrroiidone and dipropylene glycol monomethyl ether (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of about 0.1% (w/v) to about I%(w)of abamectin andabout 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (w/v) to about 35% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 0.5% (w/v) of butylated hydroxytoluene or butylatedhydroxyanisole.

In yet another embodiment, the invention provides topical compositions that comprise a combination of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 25% (w/v) to about 35% (w/v) N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.) and about 0.0 1% (w/v) to about 0.5% (w/v) of butylated hydroxytoluene. In another embodiment, the invention provides topical compositions that comprise a combination of about 0.4% (w/v) of abamectin and about 3.5% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 30% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s., quantum sufficit), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.4% (w/v) of abamectin and about 3.5% (wv) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 30% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, 1-octylpyrrolidone, 1 dodecylpyrrolidone, I-isopropylpyrrolidone, 1-sec-butylpyrrolidone, I-t-butylpyrrolidone, I n-butylpyrrolidone, I-hexylpyrrolidone, I-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions that comprise about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 30% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, I-ethylpyrrolidone, 1-octylpyrrolidone, 1 dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1 n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrroidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and I-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise about 0.4% (w/v) abamectin and about 3.5%(wv) ofimidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 30% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.). and optionally an antioxidant. In another embodiment, the invention provides topical compositions that comprise a combination of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises about 30% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyi ether (q.s.), and about 0.1% (wv) of butylated hydroxytoluene. In yet another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 5% (w/v) of an avermectin ormilbemycin active agent in combination with about 1% (w/v) to about 10% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially ofabout 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s., quantum sufficit) and optionally 'in antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 5% (w/v) of at least one avermectin or milbemycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemnycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 1% (w/v) to about 10% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutical acceptable salts, hydrates or solvates thereof. together with a pharmaceutically acceptable carrier that consists essentially of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a glvcol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 10% (w/v) to about 50% (wv) of a pyrroldone solvent selected from the group consisting of 2 pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone., -octylpyrrolidone, 1 dodecylpyrrolidone,I-isopropylpyrrolidone,I-sec-butylpyrrolidone,1-t-butylpyrrolidone,1 ni-butylpyrrolidone, I-hexylpyrrolidone, I-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of iidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with apharmaceutically acceptable carrierthat consists essentially of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent selected from the group consisting of 2 pyrrolidone, N-methylpyrrolidone, I-ethylpyrrolidone, i-octylpyrrolidone, 1 dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1 n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxvethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolidone., 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidonetogether with aglycol ether solvent selected from the group consisting of propylene glycol monomethylether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 10% (w/v) to about 50% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (wv) to about 5% (w/v)of abametin and about 1% (w/v) to about 10% (v/v) ofimidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 10% (w/v) to about 50% (w/v) of N-nethylpyrroidone and dipropylene glycol monomethylether(q.s.), and about 0.01% (w/v)toabout 2% (w/v)ofbutylatedhydroxytoluene or butylated hydroxyanisole. In yet another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1%(w/v)toabout 10% (w/v) of imidaloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrierthat consists essentially of about10(/v)toabout 50% (w/v) N-methylpyrrolidone and dipropylene glycol monomethyl ether (qs.), about0.01% (w/v) to about 2% (w/v) of buitylated hydroxytoluene. In yet another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 2% (w/v) of an avermectin ormilbemycin active agent in combination with about 1% (w/v) to about 5% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of apvrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 2% (w/v) of at least one avermectin or milbemycm active agent selected from the group consisting of abamectin, dimadectindoraectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 1% (w/v) to about 5% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutical acceptable salts, hydrates or solvates thereof. together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about 2% (wAv) of abamectin and about 1% (w/v) to about 5% (w/v) imidaloprid, or pharmaceutical acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycolether solvent (q.s., quantum sufficit), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 2% (w/v) of abamectin and about I% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent selected from the group consisting of 2 pyrrolidone, N-methylpyrrolidone, I-ethylpyrrolidone., -octylpyrrolidone, 1 dodecylpyrrolidone,I-isopropylpyrrolidone,I-sec-butylpyrrolidone,1-t-butylpyrrolidone,1 n-butylpyrrolidone, I-hexylpyrrolidone, I-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolidone, 1-(2-methoxvethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, togetherwith apharmaceutically acceptable carrierthat consists essentially of about 20% (w/v) to about 40% (w/v) f a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1 isopropylpyrrolidone, I-sec-butylpyrrolidone, I-t-butylpyrroiidone, I-n-butylpyrrolidone, 1 hexylpyrrolidone, 1-vinyl-2-pyrroidone, I-cyclohexylpyrrolidone, 1-(2-hydroxyethyl) pyrrolidone, I-3-hydroxypropyl)pyrrolidone., -(2-methoxyethyi)-pyrrolidone, 1-(3 methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 2% (w/v) abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 1% (w/v) of butylatedhy droxytoluene or butylated hydroxyanisole. In yet another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvatesthereof, togetherwith apharmaceuticallyacceptable carrierthat consists essentially of about20% (w/v) to about 40% (w/v)N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.01% (w/v) to about1% (w/v) of butylatedhy droxytoluene. In yet another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about1% (w/v) of an avermectin ormilbenycin active agent in combination with about 2% (w/v) to about 4% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially ofabout 25%(w/v) to about 35% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s., quantum sufficit), and optionally 'in antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 1% (w/v) of at least one avermectin or milbemycin active agent selected from the group consisting of abamectin,dimadectidoramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemcin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 2% (w/v) to about 4% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutical acceptable salts, hydrates or solvates thereof. together with a pharmaceutically acceptable carrierthat consists essentially of about 25% (w/v) to about 35% (w/v) of apyrrolidone solvent and a glycol ether solvent (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consistin essentially of a combination of about 0.1% (w/v) to about 1% (wAv) of abamectin and about 2%(w/v) to about 4% (w/v) imidaloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent and a lvcol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid. or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (wv) of a pyrrolidone solvent selected from the group consisting of 2 pyrrolidone, N-methylpyrrolidone, I-ethylpyrrolidone., -octylpyrrolidone, 1 dodecylpyrrolidone,I-isopropylpyrrolidone,I-sec-butylpyrrolidone,1-t-butylpyrrolidone,1 n-buitylpyrrolidone, I-hexylpyrrolidone, I-vinyl-2-pyrrolidone, I-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxvpropyl)pyrrolidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent selected from the group consisting of 2 pyrrolidone, N-methylpyrrolidone, I-ethylpyrrolidone, i-octylpyrrolidone, 1 dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1 n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-idroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolidone., -(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzylpyrrolidonetogether with aglycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (w/v) to about 1% (w/v) abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof together with apharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about1% (w/v)of abametin and about 2% (w/v) to about4% (w/v) ofimidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about25%(wv)toabout 35% ofN-methylpyrroidone and dipropylene glycol (wv) monomethyl ether (q.s.). and about 0.01% (w/v) to about 0.5% (w/v) of butylated hydroxytoluene or butylated hydroxyanisole. In yet another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.1% (w/v) to about1% (w/v)of abametin and about 2% (w/v) to about 4% (w/v) of imidacloprid. or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v)N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.01% (w/v) to about 0.05% (w/v)of butylated hydroxytoluene. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.4% (w/v) of abamectin and about 3.5% (w/v) inidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with pharmaceutically acceptable carrier that consists essentially of about 30% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s., quantum sufficit), and optionally an atioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 30% (w/v) of a pyrrolidone solventselected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone,

I-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, I-sec butylpyrrolidone. 1-t-butylpyrrolidone, I-n-butylpyrrolidone, I-hexylpyrrolidone, I-vinyl-2

pyrrolidone, I-cyclohexylpyrroidone, 1-(2-hydroxyethyl)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-(2-methoxyeIthl)-pyrrolidone, I-(3-methoxypropy) pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.). and optionally an antioxidant. In still another embodiment, the invention provides topical compositions consisting essentially of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid. or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 30% (w/v) of a pyrrolidone solvent selected fromthe group consisting of2-pyrrolidone, N-methiylpyrrolidone, I-ethvipyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, i-sec butylpyrrolidone, I-t-butylpyrrolidone,I -n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2 pyrrolidone, I-cvclohexylpyrrolidone, 1-(2-hydroxyethyi)-pyrrolidone, 1-3 hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl)-pyrrolidone, 1-(3-methoxypropyl) pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (qs.), and optionally anantioxidant. In another embodiment, the invention provides topical compositions consisting essentially of about 0.4% (w/v) abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a

pharmaceutically acceptable carrier that consists essentially of about 30% (w/v) of N methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and optionally an antioxidant. In another embodiment, the invention provides topical compositions consisting essentially of a combination of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 30%(w/v) of N methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.1% (w/v) of butylated y droxytoluene. In yet another embodiment, the invention provides topical compositions consisting of about0.1% (w/v) to about 5% (w/v) of an avermetin or milbemycin active agent in

30( combination with about 1% (w/v) to about 10% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 10%(w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of about 01% (w/v) to about 5% (w/v) of at least one avermectin ormilbemycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, Iatidectin, lepimectin, selamectin milbemetin, milbemycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 1% (w/v) to about 10% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutical acceptable carrier that consists of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of a combination of about 0. 1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s), an antioxidant and a dye, In still another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with apharmaceutically acceptable carrier that consists essentially of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N methylpyrrolidone, 1-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1 isopropylpyrrolidone, 1-sec-butylpyrroidone, 1--butylpyrrolidone, 1-n-butylpyrrolidone, I hexylpyrrolidone, I-vinyl-2-pyrrolidone. I-cyclohexylpyrrolidone, 1-(2-hvdroxyethyl) pyrrolidone, 1-3-hydroxypropyl)pyrrolidone, 1-(2-inethoxyethyl)-pyrrolidone, 1-(3 methoxypropyl)-pyrrolidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutical acceptable carrier that consists essentially of about 10% (wv)to about 50% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N methylpyrroidone, I-ethylpyrrolidone. 1-octylpyrrolidone, 1-dodecylpyrrolidone, I isopropylpyrrolidone, I-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1-n-butylpyrrolidone, 1 hexylpyrrolidone, I-vinyl-2-pyrrolidone, I-cyclohexylpyrrolidone, 1-(2-hvdroxyethyl) pyrroiidone, 1-3-hydroxypropyl)pyrroiidone, 1-(2-methoxyethyl)-pvrrolidone, 1-(3 methoxypropyl)-pyrrolidone and I-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol inonomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), butylated hdroxy toluene or butylated hydroxy anilsole and a dye. In another embodiment, the invention provides topical compositions consisting ofabout 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (W/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists ofabout 10% (w/v) to about 50% (w/v)of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), butylated hydroxy toluene and a dye. In another embodiment, the invention provides topical compositions consisting of a combinationofabout 0.1%(w/v)to about% (w/v)ofabamnectinand about 1% (w/v)toabout 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 10% (w/v) to about 50% (wv) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.). about 0.01% (wv) to about 2%(wv) of butylated hydroxytoluene or butylated hydroxyanisole and a dye. In yet another embodiment, the invention provides topical compositions consisting of a combination of about 0.1% (w/v) to about 5% (w/v) of abamectin and about 1% (w/v) to about 10% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 10% (w/v) to about 50% (w/v) N-mnethylpyrrolidone and dipropylene glycol monomnethyl ether (q.s,), about 0.01% (w/v) to about 2% (w/v)of butylated hydroxytoluene and a dye. In yet another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 2% (w/v) of an avermectin or milbemycin active agent in combination with about( v)toabout 5% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.). an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of about 0.1% (w/V) to about 2% (w/v) of at least one avermectin or milbemycin active agent selected from the group consisting of abamectin, dimadetin, doramectin, emarnectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof, in combination with about 1% (w/v) toabout5% (w/v) ofat least one neonicotinoid active agentselectedfromthegroupconsisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 20% (w/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), an antioxidant and a dye. In another embodiment, the inventionprovides topical compositions consisting of a combination of about 0 1% (w/v)to about 2%(wv)ofabamectinand about 1%(w/v) toabout 5% (w/v) inidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 20% (W/v) to about 40% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with pharmaceutically acceptable carrierthat consists essentially of about20% (w/v) to about 40% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N methylpyrrolidone, I-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1 isopropylpyrrolidone, I-sec-butylpyrrolidone, 1--butylpyrrolidone, 1-n-butylpyrrolidone, 1 hexylpyrrolidone, I-vinyl-2-pyrrolidone, I-cyclohexylpyrrolidone, 1-(2-hydroxyethyl) pyrrolidone, 1-3-hydroxypropyl)pyrroidone, 1-(2-methoxyethyi)-pyrrolidone, 1-(3 methoxypropyl)-pyrroidone and 1-benzylpyrrolidone together with a glycol ether solvent (q.s.), an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with apharmaceutically acceptable carrier that consists essentially of about20% (w/v) to about 40%

(wv) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N methylpyrrolidone, I-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1 isopropylpyrrolidone, I-sec-butylpyrrolidone, 1-t-butylpyrrolidone, I-n-butylpyrrolidone,1 hexylpyrroidone, I-vinyl-2-pyrrolidone, I-cyclohexylpyrrolidone, I-(2-hydroxyethyl) pyrrolidone. 1-3-hydroxypropyl)pyrroiidone, 1-(2-methoxyethyl)-pyrrolidone, 1-(3 methoxypropyl)-pyrrolidone and -benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glvcol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethvl ether, or a combination thereof (q.s.),butylated hydroxytoluene or butylated hydroxyanisole and a dye. In another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 2% (v/v) abamectin and about 1% (w/v)to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 20% (w/v) to about 40% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q~s.). butylated hydroxy toluene and a dye. In another embodiment, the invention provides topical compositions consisting of a combination of about 0.1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 20% (w/v) to about 40% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about % (w/v) of butylated hydroxy tolueneand adye. In yet another embodiment, the invention provides topical compositions consisting of a combination of about 0 1% (w/v) to about 2% (w/v) of abamectin and about 1% (w/v) to about 5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceuticals acceptable carrier that consists of about 20% (w/v) to about 40% (w/v) N-methylpyrrolidone and dipropylene glvcol monomethyl ether (q.s.), about 0.01% (w/v) to about 1% (w/v) of butylated hydroxytoluene and a dye. In yet another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v)to about 1% (w/v) of an avermectin ormilbemycin active agent in combination with about 2% (w/v) to about 4% (w/v) of a neonicotinoid active agent, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about I% (w/v) of at least one avermectin or milbemycin active agent selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D. milbemycin oxime,moxidectin and nemadectin, or a mixture thereof, in combination with about 2% (w/v) to about 4% (w/v) of at least one neonicotinoid active agent selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a combination thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent and a lyvcol ether solvent (q.s.), an antioxidant and a dye. In another embodiment, the invention provides topical compositions consisting of a combination of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w.v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 25% (w/v) to about 35% (w/v) ofa pyrrolidone solvent and a glycol ether solvent (q.s.), an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid,or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent selected from the group consisting of2pyrrolidone,N methylpyrrolidone, I-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1 isopropylpyrrolidone, I-sec-butpyrrolidone, 1-t-butylpyrrolidone, I-n-butylpyrrolidone,1 2 hexylpyrroidone, I-vinyl- -pyrrolidone, I-cyclohexylpyrrolidone, I-(2-hydroxyethy) pyrrolidone. I-3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl)-pyrrolidone, 1-(3 methoxypropyl)-pyrrolidone and i-benzylpyrrolidone together with a. glycol ether solvent (q.s.). an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 25% (w/v) to about 35% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N methylpyrrolidone, I-ethylpyrrolidone, -octylpyrrolidone, I-dodecylpyrrolidone, 1 isopropylpyrrolidone, 1-sec-butylpyrrolidone, I-t-butylpyrrolidone, 1-n-butylpyrrolidone, 1 hexylpyrrolidone, 1-vinyl-2-pyrrolidone, I-cyclohexylpyrrolidone, 1-(2-hydroxyethyl) pyrrolidone, 1-3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyi)-pyrroidone, 1-(3 methoxypropyl)-pyrrolidone and I-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glvcol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), butylated hydroxy toluene or butylated hydroxyanisole and a dye. In another embodiment, the invention provides topical compositions consisting of about 0.1% (w/v) to about 1% (w/v) abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 25% (w/v) to about 35% (w/v) of N-methylpyrrolidone and dipropylene glvcol monomethyl ether (q.s.), butylated hydroxy toluene or butvlated hydroxyanisole and a dye. In another embodiment, the invention provides topical compositions consisting of a combination of about 0. 1% (w/v) to about 1% (w/v) of abamectin and about2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 25% (w/v) to about 35% (w/v) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 0.5% (w/v) of butylated hydroxytoluene or butylated hydroxyanisole and a dye. In yet another embodiment, the invention provides topical compositions consisting of a combination of about 0.1% (w/v) to about 1% (w/v) of abamectin and about 2% (w/v) to about 4% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists essentially of about 25% (w/v) to about 35% (w/v) N-methylpyrrolidone an d dipropylene glcol monomethyl ether (q.s.). about 0.01% (w/v) to about 0.05%(w/v) of butylatedhydroxytoluene and a dye. In another embodiment, the invention provides topical compositions consisting of a combination of about 0.4% (w/v) of abamectin and about 3.5% (w/v) imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 30% (w./v) of a pyrrolidone solvent and a glycol ether solvent (q.s.), 0.1% (w/v) butylated hydroxy toluene and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidaloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 30% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, I-octylpyrrolidone, 1 dodecylpyrrolidone, 1-isopropylpyrrolidone, I-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1 n-butylpyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1 (2-hydroxyethyl)-pyrrolidone, 1-3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and 1-benzvlpyrrolidone together with a glycol ether solvent (q.s), an antioxidant and a dye. In still another embodiment, the invention provides topical compositions consisting of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 30% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methipyrrolidone, I-ethylpyrrolidone, l-octyipyrrolidone, 1 dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-sec-butylpyrrolidone, I-t-butylpyrrolidone, 1 n-butylpyrrolidone, I-hexylpyrroidone, 1-vinyl-2-pyrrolidone, I-cyclohexylpyrrolidone, 1 (2-hydroxVethVl)-pyrroidone. 1-3-hydroxypropyl)pyrroidone, 1-(2-methoxyethyl) pyrrolidone, 1-(3-methoxypropyl)-pyrrolidone and I-benzylpyrrolidone together with a glycol ether solvent selected from the group consisting of propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether, or a combination thereof (q.s.), butylated hydroxy toluene or butylated hydroxyanisole and a dye. In another embodiment, the invention provides topical compositions consisting of about 0.4% (w/v) abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 30% (w/v) of N-methylpyrrolidoneand dipropylene glycol monomethyl ether (q.s.), 0.1% (w/v)of butylated hydroxy toluene or butylated hydroxyanisole and a dye. In another embodiment, the invention provides topical compositions consisting of a combination of about 0.4% (w/v) of abamectin and about 3.5% (w/v) of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that consists of about 30% (w/v) ofN-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.1% (w/v) of butylatedhydroxytoluene and a dye.

The compositions of the invention, which include two different active agents in a carrier system that is compatible with each active agent, have been surprisingly discovered to be stable, to have an extended shelf-life, and to be effective against a broad spectrum of ectoparasites and/or endoparasites. It will be well apparent to one of skill in the art that combination of two active agents in a single composition withoutaffecting the stability of the active agents during storage or the efficacy of each active upon administration is extremely difficult and unpredictable. The two classes of active agents included in the inventive compositions have substantially different structures and consequently have different solubility and stability requirements. This presents a significant problem when including the multiple active agents in a single formulation, particularly in formulations that require the two active agents to be in solution, such as in spot-on or pour-on formulations. The solubility, logP, molecular weight and other physical characteristics of each active agent in the carrier system affects the ability to deliver the drug into the coat of the animal or to permeate the skin as required. The identification of a suitable carrier system that will solubilize each active agent in a stable solution while being able to deliver the active agents to the targeted location on the animal at the required concentration is a very difficult task and is not predictable or obvious. Furthermore, the identification of a suitable carrier system to produce a stable, extended shelf-life composition comprising two different classes of active agents is challenging and unobvious. It is well known in theart that it is very difficult to formulate macrocyclic lactone active agents together with certain other actives due to different carrier requirements and the susceptibility of macrocyclic lactones to degrade in certain solvents. Avermectins and milbemycins are poorly soluble in water and not compatible with acidic conditions, while some anthelmintic agents such as levamisole are more water soluble and require acidic pH for optimum stability (see US 2006/0128641 Al). For example, WO 00/74489 describes liquid compositions comprising a macrocyclic lactone and another anthelmintic (levamisole) where the composition contains separate phases which contain the different active agents in order to meet the different solubility and stability requirements of each active. U.S. Patent No. 6,489,303 to Jancys et al. describes that mixtures of a macrocyclic lactone and another insoluble anthehnintic agent resulted in an increased rate of degradation of the macrocyclic lactone active agent, requiring the addition of excess antioxidant to stabilize the mixture. Therefore, the combination of two active agents, including a macrocvclic lactone, in a single liquid composition that is both stable for an extended period of time and efficacious against a broad spectrum of ectoparasites and endoparasites represents a significant achievement in the field of veterinary medicine that is not predictable or obvious. The compositions of the present invention combine active agents that are efficacious against internal and/or external parasites. The compositions of the invention, which in some embodiments are in the form of topical solutions in a homogeneous carrier, are unique in that they achieve excellent efficacy against external parasites, such as lice and fly, and effectively controlling internal parasites such as gastrointestinal nematodes and other parasitic worms. The compositions of the invention surprisingly achieve the required distribution of an effective amount each different active to the site of the animal required to achieve the superb efficacy against harmful internal and/or external parasites. In particular, the superb efficacy achieved against sheep body lice (Bovicola ovis) while at the same time exhibiting efficacy against the gastrointestinal nematodes Haemonchus contorts, Telodorsagia circuncintaand Trichostrongylus colubriformis noteworthy and unique. It is well know that macrocyclic lactone active agents are required to be absorbed into the blood stream to be efficacious against internal parasites. As such, some formulations directed to the treatment and control of endoparasites may contain strong solvents and/or penetration enhancing agents that can disrupt the barrier function of the stratum corneum to allow passage of the actives into the blood stream. Penetration enhancers include compounds with a polar head group and long alkyl chains such as non-ionic surfactants, oleic acid, propylene glycol, decyl methyl sulfoxide and Azone*, among others. In an embodiment of the inventive compositions, the composition will be in the form of a liquid solution or suspension. The pharmaceutically acceptable carrier may be any suitable carrier or diluent commonly used in the formulation art including aqueous or organic solvents or mixtures of solvents. These organic solvents may be found, for example, in Remington Pharmaceutical Sciences, 1 6 th Edition (1986). Organic solvents that can be used in the invention include the pyrrolidone and glycol ether solvents described above. Other suitable solvents include but are not limited to: acetyltributyl citrate, oleic acid, faty acid esters such as the dimethyl ester; dialkylesters of dicarboxylic acids including, butnotlimited to, diisobutyI adipate, diisopropyl adipate (also known as CERAPHYL 230), dieth sebacate, diisopropyl sebacate, dibutyl sebacate, and the like; ketones including acetone, methylisobutyl ketone (MIK) and methyl ethyl ketone and the like, acetonitrile, benzyl alcohol, methanol, ethyl alcohol, isopropanol, butanol, aromatic ethers such as anisole, amides including dimethylacetamide and dimethylformamide, diiethyl sulfoxide, ethylene glycol, propylene glycol, glycol carbonates, monomethylacetamide, liquid polyoxyethylene glycols (PEG) of different average molecular weight ranges, glycerol formal, dimethyl isosorbide, triacetin, Ci

Cio esters of carboxvlic acids such as butyl or octyv acetate, benzyl acetate, ary Iestersincluding benzyl benzoate, ethyl benzoate and the like, propylene carbonate, butylene carbonate, and diethyl phthalate, or a mixture of at least two of these solvents. These solvents can be supplemented by various excipients according to the nature of the desired phases, such as C8-Ci caprylic/capric triglyceride (ESTASAN or MIGLYOL 812), oleic acid or propylene glycol. In one embodiment of the invention, the pharmaceutically acceptable carrier of the formulation comprises C-Cio alcohols or esters thereof (including acetates, such as ethyl acetate and the like), Cio-Cis saturated fatty acids or esters thereof, Ci-Cis monounsaturated fatty acids or esters thereof, monoesters or diesters of aliphatic diacids, or mixtures thereof In some embodiments, the carrier or diluent includes a derivative of glycerol including, but not limited to, glycerol monoesters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides), glycerol triesters (e.g. triglycerides such as triacetin), or glycerol formal, or mixtures thereof Glycerol formal is a mixture of 5-hydroxy-1,3-dioxane and 4 hvdroxymethyl-1,3- dioxolane (approximately 60:40), which are cyclic ether compounds derived from glycerol and having 2 oxygen atoms in the ring structure and substituted by alcohol group. Glycerol Formal is a low odor and low toxic solvent for a wide variety of applications in pharmaceutical and cosmetics industry including anti-parasite veterinary formulations. In one embodiment, the carrier may include C1-C10 esters of carboxylic acids such as butyl or octyl acetate. In some embodiments of the invention, the carrier nay comprise dimethyl isosorbide. Dimethyl Isosorbide (DMI) is a high purity solvent and carrier which offers a safe, effective delivery enhancement mechanism for active ingredients in personal care products and pharmaceutical formulations. In addition dimethyl isosorbide is sometimes used as an epidermal penetration enha-ncer to provide enhanced penetration of active agents to the epidermis. It may also provide delivery of active agents into the skin while avoiding crystallization of the active agent, which will severely limit the effectiveness of the formulation. Dimethyl Isosorbide is soluble in a variety of ingredients including water, cottonseed oil, isopropanol, isopropyl imyristate, propylene glycol, polysorbate 20, and polysorbate 80. It is insoluble in hydrogenated castor oil, lanolin, mineral oils or silicone oil (dimethicone). In other embodiments, the carrier or diluent may include dimethyl sulfoxide (DMSO), glycol derivatives such as, for example, propylene glycol, polyethylene glycols or glycerol, As vehicle or diluent, mention may also be made of plant oils such as, but notlimited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but notlimited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C8 to Cu) triglycerides, or mixtures thereof In one embodiment of the invention, compositions suitable for topical administration to an animal are provided. Topical, dermal and subdermal formulations can include emulsions,. creams, ointments, gels, pastes, powders, shampoos, spot-on and pour-on solutions, emulsions and suspension formulations and ready-to-use formulations. In an embodiment, the compositions of the invention are in the form of a spot-on formulation that is applied to a localized area on an animal, rather than the entire coat of the animal or a large portion of the animal's coat. In one embodiment of a localized region, the location is between the shoulders. The spot-on formulation according to the present invention provide long-lasting and broad-spectrum efficacy against ectoparasites and/or endoparasites when the solution is applied to the mammal or bird. The spot-on formulations provide for topical administration of a concentrated solution, suspension, microemuilsion or emulsion for intermittent application to a spot on the animal, generally between the two shoulders (solution of spot-on type). Spot-on formulations are well known techniques for topically delivering an antiparasitic agent to a limited area of the host. For example, US. Patent Nos. 5,045,536 6,426,333; 6,482,425; 6.962,713; and 6,998,131, all incorporated herein by reference, describe spot-on formulations. WO 01/957715, also incorporated herein by reference, describes a method for controlling ectoparasites in small rodents as well as interrupting or preventing the diseases caused by arthropods in small rodents, which comprise applying topical formulations, such as spot-on compositions, to the skin, or hair of the rodents. For spot-on formulations, the pharmaceutical acceptable carrier may be a liquid carrier vehicle as described herein, and other carriers described in the art, for example inU.S Patent No. 6,426,333, which is incorporated herein by reference. In some embodiments, the liquid carrier vehicle can optionally contain a crystallization inhibitor such as the crystallization inhibitors to inhibit the formation of crystals or precipitate of the active components. Spot-on formulations, described for example in U.S. Patent No. 7,262,214 (incorporated herein by reference), may be prepared by dissolving the active ingredients into the pharmaceutically or veterinary acceptable vehicle. Alternatively, the spot-on formulation can be prepared by encapsulation of the active ingredients to leave a residue of the therapeutic agent on the surface of the animal. These formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host. Pour-on formulations are described, for example, in U.S. Patent No. 6,010,710, which is incorporated herein by reference. Pour-on formulations generally comprise a diluent or vehicle which may include a solvent (e.g. an organic solvent) described herein to dissolve the active agent. Some pour-on formulations may include oily carriers while other pour-on formulations may be in hydrophilic carriers. Pour-on formulation may be administered to livestock animals such as cattle and sheep. Typically, pour-on formulations are administered to the animal as a stripe to an external surface of the animal, eg. a stripe from head to tail of the animal. In one embodiment, the process comprises applying the solution to livestock animals before they arrive in the Feed Lot, it being possible for this application to be the final one before the animals are slaughtered. The veterinarily acceptable carrier for the topical compositions of the invention will generally comprise a diluent or vehicle in which the active agents resoluble. Theformulations may include organic solvents such as those described herein for the macrocyclic lactone active agent and the neonicotinoid. Preferred solvents include pyrrolidone solvents and glycol ether solvents and combinations thereof. It will be apparent to those of skill in the art that the carrier or diluent of the topical compositions must be able to deliver the active agents to the targeted locationwithouttheactiveagentsprecipitating from solution or forming crystals. In some embodiments, the carrier or diluent of the compositions will be suitable to avoid precipitation or crystallization of the active agents. In other embodiments, the compositions may include a crystallization inhibitor in addition to the carrier or diluent. In some embodiments of the invention, an emollient and/or spreading and/or film forcing agent may be added to the topical compositions of the invention. In some embodiments the emollient and/or spreading and/or film-forming agents include: (a) polyvinylpyrrolidone polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example those containing silanol functionalities, or a45V2 oil, (b) anionic surfactants such as alkaline stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (e.g. sodium lauryl sulfate andsodiumcetylsulfate);sodium dodecyl benzenesulfonate, sodium dioctylsulphosuccinate. fatty acids (e.g. those derived from coconut oil), (c) cationic surfactants such as water-soluble qualernary ammonium salts of formula N*R'R"R'R""Y-, in which the R radicals are optionally hydroxylated hydrocarbon radicals and Y- is an anion of a strong acid such as the halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used, (d) amine salts of formula N+ R'R"R' in which the R radicals are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, (e) nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (e.g. 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, (f) amphoteric surfactants such as the substituted lauryl compounds of betaine, and (g) a mixture of at least two of these agents. In one embodiment, the emollient is used in a proportion of from about 0.1 to about 10%, or about 0.25 to about 5% (v/v).

The volume of the topical composition applied is not restricted as long as the amount of substance administered is shown to be safe and efficacious. Typically, the volume applied depends on the sizeand weight of the animal as well as the concentration of active, the extent of infestation by parasites and the type of administration. For spot-on compositions, the volume applied is typically of the order of about 0.1 to about I ml, or about 0.1 ml to about 5 ml, or about 0.1 ml to about 10 ml. In other embodiments, the volume may be about 4 ml to about 7 ml. For larger animals, the volume may be higher including, but not limited to, up to 10 ml, upto20 mlorupto 30 ml, orhigher. In one embodiment of the volume., the volume is onthe order of about 0.5 ml to about I ml or about 0.5 ml to about 2 ml for cats, and on the order of about0.3 to about 3 ml or 4ml for dogs, depending on the weight of the animal. In another embodiment, the volume of the spot-on composition for administration to cats is about 0.3 ml. In another embodiment, the volume is about 0.9 ml. For the pour-on form of the composition, typically, volume application rate of about 0.5 nil to about 2 ml of the composition per kg of the animal is administered. In one embodiment, a volume of about I ml to about 1.5 ml of the pour-on composition per kg body weight is administered. Typically, the volume applied can be of the order of about 10 to about 100 mL. In other embodiments, volume applied of the pour-on formulations may be about 20 ml to about 90 ml, about 30 ml to about 80 ml or about 40 ml to about 70 ml. In still other embodiments, the volume may be about 45 ml to about 65m1. In certain embodiments, the volume is about 40 ml or about 60 ml. Methods of Treatment In another aspect of the invention, a method for preventing or treating a parasite infestation/infection in an animal is provided, comprising administering a composition described herein, for example, a composition comprising an effective amount of at least one macrocy clic lactone active agent in combination with at least one neonicotinoid agent, together with a pharmaceuticaly -acceptable carrier, and optionally an antioxidant and/or a penetration enhancer. The compositions or formulations of the invention have an extended shelf-life and a long-lasting efficacy against endoparasites and/or ectoparasites (e.g. lice and fly) that harm animals. The compositions or formulations of the invention are also rainfast, and provide persistency/prevention of reinfection against ectoparasites such as lice for up to 5 weeks following treatment. In one embodiment of the invention, methods for the treatment or prevention of a parasitic infestation or infection in a an animal are provided, which comprise administering a composition comprising an effective amount of at least one macrocyclic lactone active agent and at least one neonicotinoid active agent to the animal. Ectoparasites against which the methods and compositions of the invention are effective include, but are not limited to, lice, fleas, mites, mosquitoes and flies. The compositions and methods of the invention are also effective against endoparasites including, but not limited to, cestodes, nematodes, hookworms and roundworms of the digestive tract of animals and humans and filarial worms such as Diro//laria iinwis (heartworm). In a particular embodiment, the methods of the invention exhibit excellent efficacy against sheep body lice (Boicolaovis) while at the same time exhibiting superior efficacy against the gastrointestinal nematodes Haenonchus contorts, Telodorsagia circumcintaandTrichosrongyluscolubriformis. In one embodiment, the invention provides methods for the treatment and prevention of parasitic infections and infestations of animals (either wild or domesticated), including livestock and companion animals such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle, with the aim of ridding these hosts of parasites commonly encountered by such animals. By "treating"or"treat" or "treatment" is intended the application or administration of a composition of the invention to anannimal that has a parasitic infestation for the eradication of the parasite or the reduction of the number of the parasitesinfesting the animal undergoing treatment. It is noted that the compositions of the invention may be used to prevent such a parasitic infestation. It will be appreciated by those of skill in the art that the methods of the invention encompass administering the macrocyclic lactone active agent(s) and the neonicotinoid active agent(s) together in the same carrier or diluent or separately where each active agent or mixtures of the active agents are present in their own carriers or diluents. For example when the active agents are administered topically, the macrocyclic lactone active agent(s) may be administered at the same location on the animal at the same time as the neonicotinod active agent(s), or the macrocyclic lactone active agents) may be administered at a different location on the animal than the neonicotinoid active agent(s). Each active agent may be administered simultaneously or sequentially in separate carriers, which may be the same or different. Furthermore, each of the active compound(s) may be administered by the same mode of administration (e.g. topical, oral, parenteral, etc.), or the different active agents may be administered by different modes of administration. In an embodiment, the macrocyclic lactone active agent is abamectin and the neonicotinoid active agent is imidacloprid. In another embodiment of the invention, the method comprises administering each of the macrocyclic lactone(s) and the neonicotinoid(s) simultaneously. In this embodiment, the macrocvcic lactone active agent is abamectin and the neonicotinoid active agent is imidacloprid. In yet another embodiment of the invention, the method comprises administering each of the macrocyclic lactone(s) and the neonicotinoid(s) simultaneously in the same carrier or diluent. In this embodiment, the macrocyclic lactone active agent is abamectin and the neonicotinoid active agent is imidacloprid. In still another embodiment, the method comprises administering macrocyclic lactone active agent(s) and the neonicotinoid active agent(s) separately in a separate carrier, which may be the same or different for the two active agents. In this embodiment, the macrocyclic lactone active agent is abamectin and the anthelmintic active agent is imidacloprid. In another aspect of the invention, a kit for the treatment or prevention of a parasitic infestation in an animal is provided, which comprises at least one macrocyclic lactone(s) and at least one neonicotinoid(s) together with apharmaceutically acceptable carrier that comprises a combination of a pyrrolidione solvent and a glycol ether solvent and a dispensing device for topical application of the composition. The dispensing device may be a pipette., syringes, roll on, droppers, capsules, foil packages, vials, twist tip containers and other single dose and multi dose containers, which includes an effective dose of each active agent in the pharmaceutically acceptable carrier or diluent. In one embodiment, the macrocyclic lactone active agent is abamectin and the anthelmintic active agent is imidacloprid. The compositions of the invention may be administered to the animal at different intervals depending on the dose administered. In one embodiment, the compositions of the invention may be administered to the animal monthly. In other embodiments, the compositions may be administered twice a month or even weekly. Additional Active Ag4ents Additional veterinary/pharmaceutical active ingredients may be used with the compositions of the invention. In some embodiments, the additional active agents may include, butare not limited to, acaricides, anthelmintics, anti-parasitics and insecticides. Anti-parasitic agents can include both ectoparasiticidal and endoparasiticidal agents. Veterinar pharmaceutical agents that may be included in the compositions of the invention are well-known in the art (see e.g. Plumb' VeterinaryDrug Handbook, 5" Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) orThe Merck Veterinary Manual, 9th Edition, (January 2005)) and include but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcvsteine, acitretin, acyclovir, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentanuide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitriptyline, amilodipine besylate, ammonium chloride, ammonium molvbdenate, amoxicillin, clavulanate potassium, amphotericin B desoxycholate, amphotericin B lipid-based, ampicillin, anprolium, antacids (oral), antivenin, apomorphione, apramycin sulfate, ascorbic acid, asparaginase, aspiring, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbituates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, camitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxine sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts., clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazinine, clomipramine, claonazepam. clonidine, cloprostenol sodium, clorazepate dipotassium, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate, detornidine. dexamethasone, dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenyihydramine, disopyramide phosphate., dobutamine., docusate/DSS, dolasetron mesylate, domperidone, dopamine, doramectin. doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium.calcium EDTA, edrophonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin,eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionae, ethacrynic acid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole. flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide., glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine, glyburide, glycerine (oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN@), heparin, hetastarch, hy aluronate sodium, bydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate, impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium), ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levetiracetam, levothyroxine sodium, lidocaine, lincomycin. Iiothyronine sodium, lisinopril, lomustine (CCNU), lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine. meclofenamic acid, medetomidine, medium chain triglycerides, medroxvprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate/hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone, midazolam mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decaioate, naproxen, narcotic (opiate) agonist nalgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine. novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, oneprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine, pencillamine, general information penicillins, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine. pheylbutazone, phenylephrine, phenypropanolamine, phenytoin sodium, pheromones, parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glvcosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosm, prednisolone/prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, propionibacterium acnes injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin, selegiline/l-deprenyl, sertraine, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinycholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim, sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine, tepoxaline, terbinafline, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyrotropin. tiamulin, ticarcilin disodium, tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tocainide, tolazoline, telfenamic acid, topiramate, tramadol, trimeinolone acetonide, trientine, trilostane,trimepraxine tartrate v/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide., verapamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zonisamide and mixtures thereof

In yet another embodiment of the invention, additional aduticide insecticides and acaricides can also be added to the composition of the invention. These include pyrethrins (which includecinerin I, cinerin IIjasmolin I.jasmolin II, pyrethrinI. pyrethrinII and mixtures thereof) and pyrethroids, and carbamates (which include but are not limited to benomyl, carbanolate, carbaryl, carbofuran, meththiocarb, metolcarb, promacyl. propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxime and thiofanox). Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naftalofos and dichliorvos, heptenophos, inevinphos, monocrotophos, TEPP, tetrachlorvinphos, and arylpyrazoles, e.g., fipronil. In another embodiment of the invention, nodulisporic acid and its derivatives (a class of known acaricidal, anthelmintic, anti-parasitic and insecticidal agents) may be included in the compositions of the invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Patent No. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are hereby incorporated by reference in their entirety. The compositions may include one or more of the known nodulisporic acid derivatives in the rt,including all stereoisomers, such as those described in the literature cited above. In yet other embodiments, the compositions of the invention may include other active agents that are effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stirofos, allethrin, cyhalothrin, cyperminethrin thin, fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato acetate, monosulfiram, pirenonylbutoxide, rotenone, triphenvitin acetate, triphenyltin hydroxide, deet, dimiethyl phthalate, and the compounds 1,5a,6,9,9a,9b-hexabvdro-4a(4i) dibenzofurancarboxaldehde(MGK-1),2-(2-ethylhexyl)-3a,4,7,7a-tetrahdro-4,7-methano 1-sondoe-32)(MGK-264)diopropyl-2,5-pyridinedicarboxylate(G K-326)and 2-(octylthio)ethanol (MGK-874). Inanother embodiment, the compositions of the invention may advantageously include one or more compounds of the isoxazoline class of compounds. These active agents are described in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 andUS 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541 WO

2005/085216 US 8466115, US 8853186, US 8383659 and US 2007/0066617 and WO 2008/122375, all of which are incorporated herein by reference in their entirety. In certain embodiments, an insecticidal agent that can be combined with the compositions of the invention is a semicarbazone, such as metaflumizone. In certain embodiments of the invention, the compositions may include a spinosyn active agent produced by the soil actinomyceteSaccharopolysporaspinosa (see, for example Salgado V.L. and Sparks T.C. ."The Spinosyns: Chemistry, Biochemistry.Mode ofjAction. and Resistance," in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi synthetic spinosoid active agent. The spinosyns are typically referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, 0, P, Q, R, S,T, U, V, W, or Y. and any of these components, or a combination thereof, may be used in the compositions of the invention. The spinosyn compound may be a 5,6,5-tricylic ring system, fused to a 12-membered macro cyclic lactone, a neutral sugar (rhamnose), and an amino sugar (forosamine). These and other natural spinosvn compounds, including 21-butenyl spinosyn produced by Saccharopolyspora pagona, which may be used in the compositions of the invention, may be produced via fermentation by conventional techniques known in the art. Other spinosyn compounds that may be used in the compositions of the invention are disclosed in U.S. Patent Nos. 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,76T253; 5,840,861; 5,670,486; 5,631,155 and 6,001,981, all incorporated by reference herein in their entirety. The spinosyn compounds may include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or combinations thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spinetoram is a combination of 3'-ethoxy-5,6-dihydro spinosyn J and 3'-ethoxy spinosyn L. In general, the additional active agent is included in the composition in an amount of between about 0.1 pg and about 1000mg. More typically, the additional active agent may be included in a dose of about 10tg/kg to about 500 mg/g body weight ("bwt"), about 1 mg/kg to about 300 mg/kg bwt, about 10 mg/kg to about 200 mg/kg or about 10 mg/kg to about 100 mg/kg bwt. In one embodiment of the invention, the additional active agent is included in a dose of between about 1 g/kg and about 10 mg/kg bwt. In other embodiments of the invention, the additional active agent may be included in a dose of about 5 pg/kg to about 50 mg/kg per weiht of the animal. In other embodiments, the additional active agent may be present in a dose of about 0.01 mg/kg to about 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg, or about 0.1 mg/kg to about 10 mg/kg ofweight of animal. In other embodiments, the additional active agent may be present in a dose of about 5 pg/kg toabout 200 Ig/kg or about 0.1 mg/kg to about

1 mg/kgof weight of animal. In still another embodiment of the invention, the additional active agent is included in a dose between about 0.5 mg/kg to about 50 mg/kg. Optionally, a fragrance may be added to any of the compositions of the invention. Fragrances which are useful for the invention include but are not limited to: (i) carboxylic acid esters such as octyl acetate, isoamyl acetate, isopropyl acetate and isobutyl acetate: (ii) fragrant oils such as lavender oil. The compositions of the invention are made by mixing the appropriate amount of the active agents, pharmaceutically acceptable carrier or diluent and optionally a crystallization inhibitor, antioxidant, preservative, film former, etc., to form a composition of the invention. Various forms (e.g. tablets, pastes, pour-on, spot-on, collars, etc.) of the composition can be obtained byfollowing the method of making these forms described above by the description of making these forms found in general formulation text known to those in the art, e.g. Remington The Science and Practice of Pharmacy (25" Edition) (2005), Goodman & Gilman's The PharmacologicalBasis of Therapeutics (ithEdition) (2005) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8' Edition), edited by Allen et a., Lippincott Williams & Wilkins, (2005). The inventive formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the formulation art. Antioxidant such as an alpha tocopherol, ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol and the like, may be added to the present formulation. The antioxidants are generally added to the formulation in amounts of from about 0.01 to about 2.0% (w/v), with about 0.05 to about 1.0% (w/v) being especially preferred, and about 0.10% (w/v) being most preferred. In some embodiments, the formulations contain an antioxidant. In one embodiment, the antioxidant is BHT. In another embodiment, the antioxidant is BHA. Preservatives, such as the parabens (methylparaben and/or propylparaben), are suitably used in the formulation in amounts ranging from about 0.01 to about 2.0%, with about 0.05 to about 1.0% being especially preferred. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben., imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenyimercuric borate, pheniymercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Preferredranges for these compounds includefrom about0.01 to about 5%. Compounds which stabilize the pH of the formulation are also contemplated. Again, such compounds are well known to a practitioner in the art as well as how to use these compounds. Buffering systems include, for example, systems selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tataric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutanic acid/glutamates and sodium carbonate. The compositions of the inventionare administered in parasiticidally effective amounts which are determined by the route of administration, e.g. oral, parenteral, topical, etc. In each aspect of the invention, the compounds and compositions of the invention can be applied against a single pest or combinations thereof The compositions of the invention may be administered continuously, for treatment or prevention of parasitic infections or infestations. In this manner, the compositions of the invention deliver an effective amount of the active compounds to the animalin need thereof to control the target parasites. By "effective amount" is intended a sufficient amount of a composition of the invention to eradicate or reduce the number of parasites infesting the animal. In some embodiments, an effective amount of the active agent achieves at least 70% efficacy against the target parasite. In other embodiments, an effective amount of the active agent achieves at least 80%, or at least 90%efficacy against the target pests. Preferably, an effective amount of the active agent will achieve at least 95%, at least 98% or 100% efficacy against the target parasites. Generally, a dosage of the neonicotinoid active agent(s) of about 20 mg/kg to about 60 mg/kg of bodyweight is administered. In some embodiments, a dosage of about 30 mg/kg to about 50 mg/kg or about 40 mg/kg to about 50 mg/kg of the neonicotinoid is administered. In one embodiment, the maximum dosage of the neonicotinoid is about 42 mg/kg to about 51 mg/kg of bodyweight. In a preferred embodiment, the maximum dosage of the neonicotinoid administered is about 46.5 mg/kg of bodvweight. It is well within the routine skill of the practitioner to determine a particular dosing regimen for aspecific host and parasite. For the macrocyclic lactone active agent(s), a dosage of about 1 mg/kg to about 10 mg/kg of bodvweight is administered. In some embodiments, a dosage of about 2 mg/kg to about 8 mn/kg or about 3 mg/kg to about 7mg/kg of the macrocy clic lactone(s) is administered. In one embodiment, the maximum dosage of the macrocyclic lactone(s) is about 4 mg/kg to about 6 mg/kg of bodyweight. In a preferred embodiment, the maximum dosage of the macrocyclic lactone(s) administered is about 5.3 mg/kg of bodyweight. It is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific host and parasite. The solutions according to the invention may be applied using any means known per se, e.g. using an applicator gun or a metering flask, pipette. syringes, roll on, droppers, capsules, foil packages, vials, twist tip containers and other single dose and multi-dose containers, EXAMPLES

The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. Example 1: Exemplified formulations A composition of the present invention was formulated as a topical formulation with the specifics shown below in Table IA. Table IA. Topical formulation Ingredient Concentration

Imidacloprid .

Abamectin 0.4 BHT' 0.1 Patent Blue V dye 0.01 NMP 2 30 DPM (DPGME)3 qs 'Butylated hydroxytoluene; 2N-methylpyrrolidone: 3Dipropylene monomethyl ether

Patent Blue V is a dye present as a scourable marker to assist in stock treatment identification on the farm. Material used in topical formulation 1A was supplied by Vidhi Dyestuffs Mfg Ltd. It contains a minium of 85% pure dye; no correction was made for dye potency. N-methylpyrrolidone was used as a solvent to dissolve the API's (imidacloprid and abamectin) before dilution to volume with the dipropylene monomethyl ether vehicle. The manufacturing process for the topical formulation is shown inTable 1B.

Table 1B. Manufacturing Process fori midacloprid Abamectin Pour On StepNuminber Step Descriptioni 1. Load NMP 2. Add and dissolve BHT 3. Add and dissolve abamectin with mixing

4. Add and dissolve imidacloprid with mixing 5. Add and dissolve Patent Blue V with mixing 6. Make to volume with DPM'

Mix unti homogeneous (minimum 10 minutes)

8. Filter 50 micron during filling N-methylpyrrolidone;2 Butylatedhvdroxytoliuene ;3Dipropylene monomethliether

Additional compositions according to the invention are shown inTable IC. The results of a

stress study on Composition IC-a as shown in Table ID indicated no significant loss of API after 4 weeks storage at at 55C.

Table IC. Topical formulations Concentration (% w/v) Ingredient Composition Composition IC- Composition IC-a b IC-c Imidacloprid 3.5 3.5 3.5 Abamectin 0.2 0.1 0.05 BHT- 0.1 0.1 0.1 NMP2 30 30 30 DPM (DPGME) 3 qs qs qs 2 'Btitylated hydroxytoluene; N-.methylpyrrolidone; Dipropylene monomethyl ether

Table 1D._Stress study on Composition IC-a 1 @ % Loss API,--'oLs--A T'ime ---------- ----------. 55°C 1-------- Imidacloprid_ Abamectin ------ 4 Wk nil ------------- --- -------------- . 0,1% 'API- Active Pharmaceutical Ingredient. 'Stability performed in 500mL HDPE fluorinated container with cone-seal lid.

Example 2: Efficacy against lice The Example 2 study was done to confirm the efficacy (via reductions in total lice counts) of a single dose of 35mg/mLimidacloprid + 4mg/mL abamectin pour-on formulation (according to Table 1) against sheep body lice (Bovicola ovis) when applied at the recommended therapeutic dose level to naturally infected sheep within 24 hours of shearing or 7 days post-shearing. Treatment efficacy was determined by whole body lice counts post treatment and comparison of treated and untreated group mean lice counts. The experimental and observational unit for the study was the individual sheep (female merino breed, 32.0-59.0 kg at treatment, 3-7 years at treatment). The animals were naturally infested with the sheep body louse (Bovicola ovis). Animals that had been treated with persistent lice control products in the previous 6 months, or that were debilitated, suffering from disease or injury, fractious or otherwise unsuitable were excluded from the study. No animals were removed from the study. Individual animal lice counts were performed on all available trial sheep on Day -9. The sixty sheep with the highest lice counts were selected, ranked by lice counts from highest to lowest, sequentially blocked into blocks of 3 animals and randomly allocated from each block to 3 treatment groups via the "draw from the hat method". Allocation was such that each group had similar group arithmetic mean lice counts and range of lice counts within the group. Group mean lice counts at allocation were analysed for significant differences between groups using One-Way Analysis of Variance and a commercially available software package (Statistix 10.0, 2013). The investigational veterinary product ("IVP") was a 35 mg/mL imidacloprid + 4 mg/mL abamectin pour-on formulation as shown in Table 1A, and the maximum dose level was 46.51 ing imidacloprid/kg body weight and 5.32 mg abamectin/kg body weight. Study animals were dosed according to the treatment regime detailed inTable 2 shown below. Table 2.Treatnente im-e Treatment Schedule and Number Group Treatment Actives Application Method Dose level of Animals 1 Untreated Nil N/A* N/A* 0 control In'daeloprid 35 g/L Shorn Day -1 Treated Day MaximumDose 2 IVP Abamectin 4 g/L per 0: over 30 kg bwt, two strips Level: 46.51mg20 Table 1A either side of dorsal midline mnidacloprid per from mid-neck to base of kg body weight; tail. 5.32 mg Imidacloprid 35 g/L Shorn Day -7; Treated Day abamectin per IVP Abamectin 4 g/L per 0: over 30 kg bwt, two strips kg body weight 20 Table 1A either side of dorsal midline from mid neck to base of tail. Not Applicable

Group 2 animals were treated within 24 hours of shearing. Group 3 animals were treated

7 days post shearing. The IVP was applied along the back line using the supplied commercial pour on "T-bar" applicator. Because all trial animals were >30kg, the dose of IVP was divided into 2 equal measures and applied as two strips (one each side of the dorsal midline) extending from the mid neck to the tail base. The applicator was verified prior to use and treatment time, calculated dose and applied dose was recorded. Study animals were observed at 2 and 24 hours post-treatment, no clinical abnormalities were observed. Total live lice counts were performed in the groups in the order of Group 2, Group 3 thence Group I (untreated animals). Individual lice counts were performed with sheep manually restrained on a ground sheet in the central yard between the group paddocks during counting, with treatment groups being counted separately (with the exception of Day 7, when the animals were brought to the main sheep yards). All sheep in a group were counted before the group was returned to its group paddock and the next group brought into the central yard for counting. The number of live adult and nymph sheep body lice on each individual sheep was counted in a total of 40 wool partings, each parting being approximately 10 cm inlength. 20 partings were carried out on the left side of each sheep followed by 20 partings on theright

side. Four wool partings were made at each of the following five regions on each side of each sheep; neck, shoulder, mid-side, flank and rump to give the 20 wool partings. 80 partings per sheep (40 partings per side) were carried out on all sheep on Day 140 A representative sample of lice was removed from the untreated control group after the conclusion of the trial for the purpose of determining the lice populations' resistance to synthetic pyrethroids ("SP's"). This was done by exposing a known number of lice to different concentrations of cypermethrin (on calico cloth) for approximately 30 minutes in conditions conducive to their survival (approximately 34oC and greater than 65% humidity). Four concentrations were used (5 20, 100 and 500 ppm), as well as a control group. Two tests were conducted. After 30 minutes had elapsed the lice were examined under a microscope and assessed as:

Alive (walking normally) or Dead (includes alive but immobile and not walking away when probed) The results ofthe tests were then scored according to the following criteria: If the control mortality exceeds 10% the test must be rejected and repeated. If no lice are alive at 5 ppm then the population is highly susceptible to SP's. If no lice are alive at 20 ppm then the population is susceptible to SP's. If any lice are alive at 100 ppm then the population is resistant to SP's. If any lice are alive at 500 ppm then the population is highly resistant to SP's.

The presence of living lice at 500 ppm indicated that the lice population was highly resistant to synthetic pyrethroids. Group arithmetic means, geometric means and treatment efficacies, for each day lice counts occurred are listed in Tables 3 and 4 below. The arithmetic and geometric efficacy of the IVP, applied to lice infested sheep within 24 hours off shears and 7 days off shears, was 100% at 7 days post treatment in both treatment groups and remained at thatlevel throughout the 140 day study period. Table 3. Group Mean Lice Counts Arithmetic Means

Lice Count

Day or Day- Day Day Day Day Day Day Day Day Day Day Day Groups Treatment Shearing 9 7 13 27 41 56 69 83 98 112 126 140

Untreated 1 -1 94.88 15.6' 1381 5.81 31' 49 6.9' 8_4' 11.8' 124' 17.7a 40la Control

Imidacloprid 2 3 5g/L +

Abamectin [ 94,.6 0.02 0.02 0.0 0 0.02 0.02 0.02 ()(2 0.02 (.0h 0 0. b 4g/L

Indacloprid 35g/L- +

Abamectin 94.63 0.02 ()(2 0.02 0. 00.22002 0.02 0 2 0.02 0.02 0. 0(b 00b 4g/L

Geometric Means

Day of Day- Day Day Day Day Day Day Day Day Day Day Day Shearing 9 7 13 27 41 56 69 83 98 112 126 140 Groups Treatment

-1 9L5 1. 1 11.0' 3.11 1.7' 3.31 481 3.91 56 1 7.5' 7.01 19.4' 1 Nil

Imidacloprid 35g/L±+ -1 91.7 0.02 )0 0.02 0.02 ()() 0.02 (),02 0.02 0.02 0.02 0.02 2 Abamectin 4g/L

Iindacloprid

3 35g/L ~ ~ 0.02 0.02 0.02 0.02 0.01 0.02 0.02 0.02 0.02 0.02 0.02 +

91.5E' Abamecti0 4g/L

Means in the same sub-column with the same superscript ()are not significantly different at p<0.05 using One Way Analysis of Variance.[ means in the same sub-column with the same superscript (I) are not significantly different at p<0_05 sing the Kruskal Wallis Non Parametricanalysis of variance

Table 4. Treatment Efficacies

DaI of DAY Group Shearing 7 13 27 41 56 69 83 98 112 126 140

2 -1 100 100 100 100 100 100 100 100 100 100 100

100 1001 100 100 to00 1001 1001 100lo 10 100 100

Day of DAY Group Shearig 13 12 41 56 69 83 98 112 126 140

2 100 I0 I0 100 100 100 100 100 100 [100 [100

107 1)0 100 100lO 100 100 [00 10100 100 100

Example Efficacy a ns nworngsidaemnong hu co20tprtu lelo2drMa circumicincta and Trichostrongylus colubriformis) The Example 3 study was done to confirm the efficacy of a single dose of 35g/inL imidacloprid + 4mg/mL abamectin pour-on formulation (Investigational Veterinary Product "IVP" see Table IA) against adult and immature stages of macrocyclic-lactone susceptible strains of laenonchus contortus, Telodorsagiacircurncinctaand Trichostrongylus coiubri/brmis in sheep when treated within 24 hours of shearing or up to 7 days post-shearing at the recommended dose level. Treatment efficacy was determined by comparison of treated and untreated group mean Faecal Egg Counts (FECs) and total worm counts. The study was a blinded positive/negative controlled, dose confirmation study using a randomized block design where blocks were based on pre-treatment body weights (Cohort A) or faecal egg counts (Cohort B). The experimental unit was the individual animal, which was Merino male castrate sheep 6-7 months of age (20.5kg to 23.0 kg, at induction) due to theirsusceptibility to gastrointstinal strongyles at a young age. The treatment regime for Cohorts A and B is shown in Table 5. Treatment data for Cohorts A & B are summarized in Tables 6 and 7, respectively.

This study confirmed the efficacy of a single dose of 35mg/mL imidacloprid

+ 4mg/mL abamectin pour-on formulation against adult and inmature stages ofmacrocyclic lactone susceptible strains of Haenonchus contorts, Telodorsagiacircumcincta and Trichostrongvuscoibrjormis in sheep when treated within 24 hours of shearing or up to 7 days post-shearing at the recommended dose level. Treatment efficacy was determined by comparison of treated and untreated group total worm counts as reflected in Tables Sa and 9a), and mean faecal egg counts (FECs), in Tables 8b and 9b.

Table 5. Treatment regime

Cohort A ApphecationNo ITramn Group Treatment Sequence/Purpose method and No treatment dose level Day Laailchallenge Days 0 Dose level - Up to and 1, shorn Day 0, 46.51 mg treated Day 7, imidacloprid per sacrificed Day 41 kg bwt (1I,3l3 mil, per kg bwt) lp to p 5.3mgabamectin 7Day Larval challenge Days0 ay a per kg bwt (1.33 anL per kg bwt) treated Day7 see Table7. sacrificedDay 41 Dose method - Up to 30 kg bwt, single strip from poll to base of tail Positive Larval challenge Days 0 Dose level Control (PC) and 1. shorn Day 7, ImL/4kg treated Day 7. Dose method sacrificedDay41 Oral

Cohort B Application No. Treatment Group Treatment Sequence/Purpose method and doselevel Larvalchallenge Days 0 Dose level - Up to 4 I VP and 1 shornDa24, 46.51 mg Day 31 treated Day 31, imiidacloprid per sacrificed Day 41 kg bwt (1.33 ml per kg bwt). Up to i IVP iVP Lanal challenge Days 0 5.32 mg pyr g babamectin tin 7Da3 and 1, shorn Day 3 L perkg bwt( -1.33 treated Day 31, see bl seTable'8.e 8 sacrificed Day 41 Dose method - Up to 30 kg bwt, single strip from poll to base of tail

Postive Larval challenge Days 0 Dose level Control (PC) and I, shorn Day 31, 1mL/4kg 6 r 1 Day 31 treated Day 31, Dose method sacrificed Day 41 Oral Larvalchallenge Days 0 Untreated and 1. shorn Day 31, N/A* 7 Untreated control_ _ sacrificed Day 41 *N/A = Not Applicable Table 6. Summary treatment data Cohort A Group1 12 Treatment I ___ -PC Day of Shearing IDay 0 IDay 7 |)ay 7 Mean Bodyweight (kg) 19.9 19.7 20.2 Mean Calculated Dose (nL) 21.4 2 | Mean Administered Dose (mL) 21.4 22.1 5.1 Mean Imidacloprid Dose Level (mg/kg) 37/ 393 |0 Mean Abamectin Dose Level (mg/kg) 4 .311 4.488 ;0.204 Processing Time (AEST) 14:07 14:15 13:36 Investigational Product imidacloprid 35g/L + Abamectin 4g/L per Table [A 2 Postive Control Product VIRBAMEC ORAL Broad Spectmm Oral Anthehnitic for Sheep, 0.8 gabamectin /L; 0.2mg /kg dose. I niL/4 kg bodyweight

Table 7. Summary treatment data Cohort B Group 4 5 6 7 Treatment IVP IVPI PC2 Control Day of Shearing Day 24 Day 31 Day 31 Day 31 Mean Bodyweight (kg) zO. 1 20.4 20.4 N/A Mean Calculated Dose (mL) 21 236 5.1 N/A Mean Administered Dose ) 2211 23J6 5.1 /A 'lean imidacioprid Dose Level (nig/g) 18.6 40.3 0 N/A Mean Abamectin Dose Level (mgkg) 4.406 4.610 0.201 AA Processing Time (AEST) 10:49 10:58 10:30 N/=A Investigational Product Imidacloprid 35g/L Abamectin 4g/L perTable IA 2 Postive Control Product VIRBAMEC ORAL Broad Spectnun Oml Anthelniintic for Sheep, 0.8 g abamectin /L 0.2mg /kg dose, InL/4 kg bodyweight 3 N/A = not applicable. Control sheep were untreated

Table 8a. Group mean total worm counts (larval stages at treatment) Dayof Group Treatment Infection/Shearing/ H.c. T. c.2 Tri c. 3 Treatment

Arithmetic Means Infected Day 0/1

194 Shorn Day 0 60.0 2.9 2.9 Treatment Day 7 60.0 2.9 2.9

VJRBAMEC Infected Day 0/1 J ~ .

. 1 2____9_ 0____0_ 3 ORAl?, Shorn Dav 7 65___7_ _________I 1 ~~Tre ited-Da-v7 ___________________

Untreated Infected Day 0/1 control hornDay 3 1 18. 443 21.

InetdDy0144.1 1.4 0.5 Iip Shorn Day 0 TreatnrnDa,_7 ______

2 Infected Dav 0/1 43.4 0.5 0.5 VIRBAMEC Shorn Day 7530. oralL, Treated Day,7 53.9____ 0_______ 0.0____

7Untreated Infected Day 0/1 1305.7 2342.3 23275.3 ____ _ control Shorn Day 31__________________ 1 4 Raemonchus contortns.2 Teadrsaiacircumonla: DTrichosixongvhus c 1 bjni Visetgto Product hnidacloprid 35gtL-Abanecti 4gL perable IX:PositiveControl Product VIR3ANIEC ORAL Broad SpectrumiOral Antlihninticfor Sheep,(0.8 Iabamnectiii/L;0.2mng/kg dose,1ImiL/4 kg bodyweigt

5 Table 8b.Efficacy (total wormicount reduction) laral stages at teatment )7s _______

Day of Group Treatment hinfection/Shearing! ~ . .c r.C Group I Tcatmcnt ~ Treatment ~ fX

Arithmetic Means InfectedIDay 01 IVP4Shorn Day 0 Treatmenit Dav 71 96.2%N 99.80/ 199.9%X 2 VIRBAMEC ORAL I1nfected Day 0/] Shorn Day7 Treated Day_' 758 96.2%

19% 90.0 99.9% 1I/____ 99.9%

Geometric Means

Infected Day 0/1 I IVp4 Shorn Dav0 960/ 99.9% 100. W% TreatnrnDa,_71 2 _________ Infected Day 0/1 96.7%/ 100,00 100,0% VIRBAMEC Shorn Day 7 3 ORAL_5 Treated DLay7 959 100.0% 100.0% 11i-feonclsconiors;2eadraiafdunh rkhiostrongyluscolubryfbr~ws. 4 ;Vp:Ivesigational Product Infidaciopfid 35g/l± ,Abaniectin 4 'v/L perTable IA> poSiivControl Prodct VIRBAM\fEC:ORAL Broad Spectrum(IOaiAnhelminic for Shep 0.8 gabamnectin/,; 0.2rng/ikg dose, 1mL/4kgovw I,

Table 9a.

Group I Treatment I group mean total worm counts adultt stages at treatment) ay of Trfetioimeant J I1 ______________

T.x 2 1'. Ti. c. 3

Arithmetic Means 11 ected Dav0/1 4 Vp4 hr Day 24 1 400O 0.0 48.6 _______ ___________ TreatnmentDLy_31 ____ ___________

5 Infected Day 0/1 45.7 8.6 62.9 VIRBAMEC Shorn Day 31 6 ORAL5 Treated Day3122.9 5.7_ 0.0

Untreated Infected Day 0/1 Shorn Day 31 1582.9 2454.3 2417.1 control Geometric Means Infected Day 0/1 23.0 0.0 13.3 4 Iyp4 Shorn Day 24. Treatment Day 31 5 Infected Day 0/1 42.5 2.7 10.7 VIRBAMEC Shorn Day 31 6 ORAL 5 r D 31 10.7 0. 0.0 _______ _______________ TreatedDay_31 _____________ ______

Untreated Infected Day /15 2342.3 1235.3 I_____ control Shorn Day _1_305._7_ 2342.3_2_ 3 -___5._3 Haemonchus contortus;2 Teladorsagiacircumcincta; 3 Trichostrongyluscolubrifmi;s. IV P: Investigational Product Imidacloprid 35g/L + Abamectin4g/L per Table 1A; 5Positive Control Product VIRBAMEC ORAL Broad Spectnun Oral Anthelmintic for Sheep, 0.8 g abanictinL 0.2 mg/kg dose, I nL/4 kg bodyweight

Table 9b. Eficacy (total worm count reduction) vs adult stages at treatment Day of Group Treatment Infection/Shearing/ .C. Tc Tri. c. Treatment

Arithmetic Means Infected Day 0/1 4 1yp4 Shorn Day 24 97.5% 100.0% 98.0% Treatment Day 31 5 Infected Day 0/1 971% 99.7% 97.4% VIRBAMEC Shorn Day 31 6 ORALT 98.6% 99.8% 100.0% Treated Day 31

Geometric Means Infected Day 0/1 98.2% 100.0% 99.4% 4 Iyp4 Shorn Day 24, TreatmentjDay31 5 Infected Day 0/1 96.7% 99.9% 99.6% VIRBAMEC Shorn Day31 99.2% 100.0% ORAL' Treated Day 31 Haemonchuscontorus;-2Teadorsagia circumcincta; Trichosrngvuscolubrifornis.'IVP: hivestigational Product Imidacloprid 35g/ + Abamectin 4gjL perTable IA;5 Positive Control Product VIRBAMEC ORAL Broad Spectrum Oral Anthelintic for Sheep, 0,8;g abamecin /L; 0.2 ing /kg dose, InL/4 kg bodyweight

Example 4:Efficacyagmngtroudvorm (aemonchus_(ont(rtuATelpdo

circumcincta and Trichostrongylusrugatus and enatodirus s pp) The Example 4 study was done to confirm the efficacy of a single dose of 35mg/ml imidacloprid + 4mg/ml abanectin pour-on formulation against adult and immature stages of muacrocyclic-lactone susceptible strains of Haemonchus contortus, Teiodorsagia circumcincta, Trichostrongygus rugatus and Nenatodirus spp in sheep when treated within 24 hours of shearing or up to 7 days post-shearing at the recommended dose level. Treatment efficacy was determined by comparison of treated and untreated group mean Faecal Egg Counts (FECs) and total worm counts. This study is a second roundworm dose confirmation study utilizing a different suite of macrocyclic lactone susceptible larve to the first roundworm dose confirmation study (Example 3 herein). The nematode strains used in the study were: I.conlortus TBZ: isolated from the field by CSIRO in 1976; susceptible to all commercial anthelmintics except thiabendazole.

Teladorsagia circumcincta 3061 and Trichostrongylus rugatus 3061: obtained by Veterinary Health Research ("VHR") in 2016 from the Southern'Tablelands of NSW as a mixed infection; susceptible to abamectin, resistant to levamisole and albendazole. In this study, none of the T rugatus larvae established in the control animals, as opposed to T vitrinus which did establish.

Nematodirus spathiger SA: isolated by VHR in 2015 from South Australia; susceptible to abamectin.

The study was a partially blinded', positive/negative controlled, dose confirmation study using a randomized block design where blocks were based on pre-treatment body weights (Cohort A) or faecal egg counts (Cohort B). The experimental unit was the individual animal, which was Merino male castrated sheep, 6-7 months of age (21.0 kg to

25.0 kg, at induction). The treatment regime for Cohorts Aand B is shown in Table 10. Treatment data for Cohorts A and B are summarized in Tables 11 and 12, respectively. Removal of pre-existing worm burdens was confirmed by FEC on Day -7 (all egg counts zero). Sheep were artificially infected on Day -2 and Day I with the following number of L3 larvae of the target parasites:

3,113 3rd stage (L3) Telodorsagia circuncincta(3061strain) - Day 1

3,913 3srd tage (L3) Trichosirongylus rugatus (3061 strain) - Day 1

3,603 3 rd stage (L3) Haemnonchus contortus (TBZ strain) - Day 1

6,000 3 rd stage (L3) Nematodirusspathiger("NEM") (SA strain) - Day -2

I Personnel involved in perfonming artificial infection, post treatment FECs, cultures (CUL) or total worn counts (TWC) were blinded to treatments administered. Those involved in group allotaction and treatment administration were not blinded as to treatment. Treatment assignments were not reveal until completion of the laboratory phase.

Some species other than the strains identified above may be present in the cultured larvae due to the challenge associated with maintaining pure larval cultures. Minor larval contaminants of other species such as T.axei had no impact on this study. The culture containing the Trichostrongylus and Telodorsagia larvae also contained Oesophagostomurm. Infection statistics indicated that all infection levels were adequate for the assessment of efficacy.

Table 10. Treatmentregime Cohort A Application method No. Treatment Group Tareatment Sequence/Purpose addose level Sheep Day Larval challenge on Day -2 for S iyp Nemnatodirs and Day 1 for Dose level - Up to 46.51 7 Day 7 HTaemonchus, Teladorsagiaand ig imidacloprid per kg Trichostrongylus, shorn Day 0, bwt (1,33 iL per kg treated Day 7, sacrificed bwt). Up to 5.32nmg Day 41 or 42 abamectin per kgb Larval challenge onDay -2 for (1. 33 mL per kg bwt) 2 IVP Nemalodirus and Day 1 for 7 Day 7 Haem;onchus, Teladorsagiaand Dose method - Up to Trichostrongylus, shorn Day7 30 kg bwt, single strip treated Day 7, sacrificed fronpoll to base of Day 41 or 42 tail Larval challenge on Day -2 for PC Nematodirus and Day I for Dose level - inL/10kg Day7 Haemonchus, Teladorsagiaand Dose method - Oral Trichostrongylus, shorn Day 7 treated Day 7, sacrificed Day 41 or42

Cohort B Application method No. Treatment Group Treatment Sequence/Purpose adds ee and dose level he Sheep) a Day Larval challenge on Day -2 for 4 IV Nemaodirus and Day I for Dose level - Up to 46.51 7 Day 31 Haiemonchus, Teladorsagiaand mg imidacloprid perkg Trichostrongylus, shorn Day 24, bt (1.33 mL per kg treated Day 31, sacrificed bwt). Up to 5.32 mg Day 41 or 42 abanectin per kg bwt Larval challenge on Day -2 for (1.33 mL per kg bwt) 5 IVP Nemalodirus and Day 1 for 7 Day31 Haemnonchus, Teladorsagiaand Dose method -_Up to Trichostrongyls, shorn Day 31 30 kg bwt, single strip treated Day 31, sacrificed from poll to base Day 41 or 42 of tail Larval challenge on Day -2 for 6 PC Nematodirnus and Day 1 for Dose level Haemonchus, eIadorsagiaand ImL/I0kg Dose Trichostrongyls, shorn Day 31, method - Oral treated Day 31. sacrificed ------------------- Day 4 1 or 4 2

Larval challenge on Day -2 for 7 Untreated Aematodrus and Day 1 for N/A* 7 Not Untrod Hoemonchus, Teladorsagiaand treated control 2'richostrongus,shorn Day 31, sacrificed Day 41 or 42 *N/A = Not Applicable

TableI Smninar treatment data means CohortA Applied Applied Ap2ple ABA Dose Group Treatment Dose Level (kg) (ml) g/) IVP' Shorn Day 0 Treated Day 7 21.2 23.6 4.44

2 IVP' Shorn Day 7Treated Day 7 21,8 24.3 4.46

3 VIRBAMEC Shorn Day 7 Treated Day 7 22.5 2.3 0.202 'IVP investigationalveterinary product according to Table IA; 2ABA- abamectin

Table 12. Slnmary treatment data means Cohort B Applied Applied ABA 2 Doe Group Treatment Dose Level

4 IVP Shorn Day 24 Treated Day31 23.1 25.7 4.46

5 IVP Shorn Day 31 Treated Day 31 24.3 26.4 4.35

6 VIRBAMEC Shorn Day 31 Treated Day 31 23.3 2.4 0.203 'IVP - investigational veterinary product according to Table 1A; 2ABA- abamectin

This study confirmed the efficacy of a single dose of 35mg/nl imidaloprid- 4mg/nml abamectin pour-on formulation against adult and immature stages ofmacrocyclic-lactone susceptible strains ofTelodorsagiacircumcincta, Trichostrongylus axei. Iichosrongvs vitrinus andNematodirusspathiger in sheep when treated within 24 hours of shearing or at 7 days post-shearing at the recommended dose level. Treatment efficacy was determined by comparison of treated and untreated group mean faecal egg counts (Tables 13A and 13B) and total worm counts (Tables 15A, 15B, 16A, and 16B). The positive control ("PC") failed to demonstrate 95% efficacy against larval stages of Teladorsagiacirumcincta by total worm count reduction (TWCR). The larval differential results are shown in Table 14. In thisstudy, it appears thatfaemonchus contortus strain (TBZ) was mildly resistant to macrocyclic-lactone as both the investigational veterinary product ("IVP") and positive control both failed to achieve efficacy above 95%. As this isolate of . conortus was isolated in 1976, prior to the introduction ofmacrocyclic- lactones, itappears that the strain has been contaminated prior to Veterinary Health Reseaarch ("VHR") obtaining the strain in 2014. As the IVP and PC efficacies were both similar it indicates that the IVP is likely to control rnacrocyclic-lactone susceptible II. contortus in a field situation. Control of adult Niematodirus spathiger was achieved by the IVP as assessed by TWCR and faecal egg count reduction ("FECR"), as was control of immature stages following treatment with IVP within 24 hours of shearing. Control of theimnature stage by the IVP when applied 7 days off shears was demonstrated as assessed by TWCR using geometric means, but not via FECR. This is likely due to the sporadic nature by whichVN spathiger lay eggs; only one control animal had a positive Nematodirus FEC on Day 41-42 even though all of the controls were infected as assessed by total worm count.

Table 1-3-A,.Grioujpit)-eaiFECDa 4 1 -42 Group Treatment Cohort FEC(epg) Strongyle NEM Arithmetic Means I IVP Shon Day 0 A 11 114

IVP Shorn Day 7 A 1125.7 00 Treated Day 7 (Larval Stages) VIRBAME ShornDay 7 A 0.0 Treated Day 7 (Larval Stages) 4 IVP Shorn Day4 0.0 Treated Day31 (Adult Stages) 5 IVP Shorn Day31 B 820 Treated Day 31 (Adult Stages) 6 VIRBAMEC Shorn Day 31 B 0.0 Treated Day 31 (Adult Stages)

Treated Day 7 Stages) 2 IVP Shorn Day 7 A (Larval 1019.1 0.0 _________ Treated Day 7 Stages) __________ S VIRBAMECShornDay7 A(Larval 57.0 0.0 _________ Treated Day 7 ~Stages) __________________

4 IVP Shorn Day 24 B (Adult 422,2 0.0 Treated Dav 31 Stages) 5 IVP Shorn Day31 B (Adult 697.6 1.0 Treated Day 31 Siages) 6 VIRBAM EC Shorn Day 3 B(Adult 60.8 0.0 'Treated Day 31 Stages) UntreatedControl A&B 6908.0 12 Shorn Day 31

Table 13B. Efficacy Day 41-42 (by faecal egg count reduction) Treatment Efficacy Group Treatment Cohort F NEM EEC Arithmetic Means

A I VP Shorn Day A Stages) (Larval 89.6% 100.0%

Treated Day 7 _________________________ Stages) IVP Shorn Day24 B Treated Day31 (AdultStages) IVP Shorn Day 31 B 9.%100 Treated Day 31 (Adult Stages) VIRBAMEC Shorn Day31 B Treated Day31 (AdultStages) 7Untreated Control A&B- IVP Shorn Day 1

[(Larval 86.1% -089% Treated Day3 Stages)

2 IVP Shorn Day7 Treated Day(u Larval Saes) 852% 100.0%

VIRBAMEC ShornDy (Larval 934% [00.0% Treated Day~ 7tgs IVP Shorn Day24 B 4hr 931% 100.0% Treated Day 31 (Adult Stages)

6 VIRBAMEC ShornDay 3t B- 0 Treated!ay ls __ (Adult Stages) 7 Untreated Control A&B ShornoDan 1

Table14. Larval Differential Results (Day 41-42) Total #

a ayof Larvae Group Treatment Trreatmient Hlaem) Trich Ost. Counted 1IVP Day 7 99 1 010 2 IVP Day 7 98 88. 0 74 .992100 0 10.0 11. 3PC Day 7 96 0 4 100 4 IVP Day 31 100 0 0 100 5 IVP Day 31 100 0 0 100 6 PC D)ay 99 0 9 100 7 treated Dap A67 'Haem = Haemnonchus contorts, Trich. =Trichostrongy/usspp, 3 0st = Telodors.agia spp

TableI15A. Group mean total worm counts larval stagespresent at treatment Group Treatment Cohort 1 Haern? 1 Ost? 1Trich ITrich. NEM 6 Arithmetic Means VP Shorn Day0 A 1 TreatedDay Larval Stagest3 0. 1 IVP1 Shorn Day 7 A 2 TR Larvaltaoes 157.1 60.0 0.0 0.0 2.9 Untreated ayt7 ola

VIRBAMEC Shiom Day 7 A 102.9 145.7 0.0 0,0 2.9 Treated Day 7 Larval Stages Untreated Control A&B 7 1231,4 1645.7 354.3 160,0 945.7 Shorn Day 3 1 Geometric Means IVP1 Shlorn Day 0 A 185.9 13.8 0.0 0.0 7.5 Treated Dav 7 LarvalStags 2VP Shorn Day 7 A 2dr t 129.0 10.1 0.0 0.0 0.5 Treated D___LarvalStage VIRBAM\/EC Shiom Day 7 A 5 1. 133.1 0.0 0.0 0.5 Treated Dav 7 LarvalStags Untreated Control 7 A&B 712,8 1545.1 314.3 139,3 585.6 Shorn Day 31 'Investigational Veterinary Product; 2!aemoc s conors'Idadrsagia Trihostrongylusaxei; Nematodirusspy)

Table 15B. Group mean total worm counts (adult stages at time of treatment) Rich, rich. Group Treatment Cohort Haem. 2 Ost NEM6 Arithmetic Means INVi Shorn Day 0 A 1xS% Adl151.4 37 1 0.0 0.0 5 Treated Day 7 Adult Stages iVP Shorn Day 7 A 2. ..1 14 1. 0.0 0,0 0.0 Treated Day 7 Adult Stages VIRBAMEC Shorn Day 7 A 3 145.7 371. 1 0.0 0.0 0.0 Treated Day7 Adult Stages UnTrtreated Control 7dA&B 1231.4 1654.7 34 160.0 945.7 Shorn Day 31 Geometric Means SIP' Shorn Day 0 A Ia A 137.7 5.5 00 0.0 0.7 Treated Day 7 Adult Stages 2 IVP Shorn Day 7 A 0.2 33 0.0 00 0.0 Treated Day7 Adult Stages VIRBAMEC Shorn Day 7 A 3 Treated Day 7 ~135. Adult Stages 9,0 00 0 0.0(M UnTrtreated Control 7dA&B 712.8 1545.1 3143 139.3 585.6 Shorn Day 31 Investigational Veterinary Product according to Table 1;2 Haemonchus contortus; Teldadorsagia 5 spp.;4Trichostronylusaxei; Nematodirus spp.

Table 16A. Efficacy (total worm count reduction) vs larval stages at treatment Trich. Trich NEM 6 Group Cohort Haein Ost3 eTreatment Arithmetic Means TVP' Shorn Day 0 A Shorn A 84.7% 95.5% 100.0% 100.0% 86.1% L_ ___Treae a7 yaa Sta IViShorn Day 7 A 2 87.2% 96.4% 100.0% 100.0% 99.7% Treated Day 7 Larval Stages VIRBANEC Shorn Day 7 A 91.6% 91.1% 100.0% 100.0% 99.7% 1 ______ .,97.9%' ____________________ Geometric Means 99.1% ____ 100.% 100 87 IVP' Shorn Day 0 A Treated Day 7 Larval Stages 278.9% VP1 lShorn Day7 A 99.3% 100.0% 100.0%/ 99.9%11

Treated Day 7 Larval Stages VIRBIAMEC Shorn Day 7 A 1 92.8% 91 4%N 100.0% 100.0%N 99.9%11/ Treated Day 7 Larval Stages

'Investigational Veterinary Product; 2aemonchus contortus; 3 Teldadorsagiaspp.ir;ichostrongilus oxei; 'Nematodirusspp.

Table 16B. Efficacy (total worm count reduction) vs adult stages at treatment Trich. Trich. Group Treatment Cohort T Iaem? Ost.3 i4 axei spp , NEM

, Arithmetic Means 877 977 1000% I 00.0% 99.4%N IYP' Shorn Treated Day314 Day 31 Adult BStages 2__ Treated Day 31 B 91.0% 99.1% 100.0% 100.0% 100 0% Treated Day 31 Adult Stages

Geometric Means 80.7% 99.6% 100.0% 100.0% 99.9%

2 ISTreated Day 31 Adult85% 998% 100.0% 1000% 100.0% VIRBAMEC ShornDay 31 B 8

I[nvestigationaliVeterinary Product according to Table IA;2aemonchuscontorus;3Tedaorsgia spp;[ricostrongsaxei ; NemAtodiuls sp.

Example 5. Persistence against sheep body lice TheExample5study wasdone toconfirmthe periodofpersistency(viareductionsin

total lice counts) of a single dose of 35mg/mL imidacloprid + 4mg/mL abamectin pour-on formulation against sheep body lice (Bovicola ovis) when applied at the proposed therapeutic dose level to naturally infected sheep immediately off-shears subsequently challenged 21 or 28 days post-treatment. Treatment efficacies were determined by comparison of treated and untreated group mean lice counts post-treatment. This study was a non-blinded negative controlled, single site, period of persistency study using a randomized block design where blocks were based on pre-treatment sheep bodyweights - Cohort A or live lice counts - Cohort B. One hundred and ten Merino sheep (Cohort A, n=110) with a minimum of 6 months wool growth were selected from a commercial flock on the basis of known freedom from the sheep louse (Bovicoa ovis) as determined by zero live lice counts at selection. Sheep were allowed to acclimatise for a minimumof 2 weeks prior to IVP treatment on Day 0. Individual bodyweights were determined on Day -8 and the heaviest 100 sheep selected and allocated to 5 groups, each of 20 sheep. Sheep in Group I were shorn on Day -7 and sheep in Groups 2, 3, 4 and 5 were shorn on Day 0. Sheep in Groups 1, 2 and 3 wereweighed and treated according to individual bodyweight on Day 0. Sheep in Groups 4 and 5 were retained untreated as negative control groups for Group 2 (Group 4) and Groups I and 3 (Group 5). A second cohort of fifty (50) Merino sheep (Cohort B) were selected from commercial flocks on the basis of known infection (minimum 40 lice per animal) with the sheep louse (Bovicola ovis) and allowed to acclimatise for a minimum of 2 weeks prior to IVP treatment day (Day 0). These fifty (50) 'challenge' sheep were retained in full wool. On Day 21 the 50 'challenge' sheep were allocated to 5 groups (Groups 6, 7, 8, 9 and 10), each of 10 sheep. Sheep in Group 6 were introduced as challenge animals to Group I (between Days 28 and 35), sheep in Group 7 were introduced as challenge animals to Group 2 (between Days 21 and 28), sheep in Group 8 were introduced as challenge animals to Group 3 (between Days 28 and 35), sheep in Group 9 were introduced as challenge animals to Group 4 (between Days 21 and 28) and sheep in Group 10 were introduced as challenge animals to Group 5 (between Days 28 and 35). Individual lice counts were conducted on all animals in Groups 1, 2, 3, 4 and 5 on Days 49, 56, 70, 84, 98, 112, 126, 140, 154 and 173. Group mean lice counts were compared and treatment efficacies calculated to determine the period of persistent activity. Cohort A: Individual animal bodyweights were determined on Day -8 with sheep ranked by bodyweight from highest to lowest and the 10 animals with the lowest bodyweight removed. The remaining 100 sheep were then sequentially blocked in order of bodyweight (into blocks of 5 animals) and randomly allocated to the 5 treatment groups via the "draw from a hat" method. Allocation was such that each group had a similar group mean bodweight and range of bodyweights. Group mean bodyweights were compared between groups using One-Way Analysis of Variance within a commercially available software package (Statistix 10.0, Analytical Software 2013) confirming no differences exist at p<0.05. Cohort B: Individual animal total lice counts were determined on Day20. The fifty (50) sheep were ranked by lice count (from highest to lowest) then sequentially blocked (into blocks of 5 animals) and randomly allocated to the 5 treatment groups via the "draw from a hat" method. Allocation was such that each group had a similar group mean lice count and range of lice counts within the group. Group mean lice counts were compared between groups using One-Way Analysis of Variance and a commercially available software package (Statistix 10.0, Analytical Software 2013) to confirmno differences exist at p<O.05. The Investigational Veterinary Product ("IVP") for this study was the imidacloprid/abametin pour-on according to Table IA having a composition of 35 g/L imidaclopridand 4,g/L abamectin. The maximum dose level was 46.51 mg imidacloprid per kg body weight, and 5.32 mg abamectin per kg body weight. Study animals were dosed according to the treatment regime in Tables 17A and 17B

Table I7A. Cohort A Application No.' Treat. Group Treatment Sequence/Purpose nito No iat ______ _______________ ___________________ ethod Sheep Day-___

Shorn Day -7, treated Day 0 I IVPT up to 310 ko 20 Day 0 challenged Day 28 - 35 bwt, single Shorn Day 0. treated Day 0 ti IVP challenged Day 21 - 28 stripfrom 20 Day 0 poll to base 3 WP Shorn Day 0, treated Day0, ofrail 20 Day0 challenged Day 28 - 35 Negative Untreated Shorn Day0: 20 N/A controls (for Group 2) challenged Day 21- 28 N !A Negative Untreated Shorn Day' 0; (Untreated) 5 controls 20 N/A challenged Day 28 - 35 (for Grops I and 3) 'No.= number; 2Treat, Day =Treatment Day; 3N/A =Not Applicable

Table 17B. Cohort B Application No!1 Group ITreatment Sequence/Purpose Chall. days 6 Untreated challenge Unshorn,Challenge to 10 28-35 sheep Group 1 Unrtreated challenge Unshom,Challenge to t() 2t-28

Untreated challenge Unshorn, Challenge to N/A 3 10 28-35 sheep Group3 (Untreated) sheep. Untreated .challenge . . rop Challenge to Ushom, Io 21-28

sheep Untreated challenge Group 4 Challenge to Unshorn, 10 28-35 No.:= number; 2Chall. days = Challenge Days; 3N/A = Not Applicable

Group I animals were treated 7 days post-shearing. Groups 2 and 3 animals were treated within 4 hours post-shearing. The IVP was applied to the backline using a commercial pour-on applicator fitted with a'T-bar" shower nozzle with the full dose of IVP applied as a single strip from the poll to the tail base. Group arithmetic means, geometric means and treatment efficacies for each lice count day are detailed in Tables 18 and 19 below. This study confirmed, through elimination of sheep body lice (Bovicola ovis), as determined by whole body lice counts, aminimum 35 days (5 weeks) period of persistency following treatment with a single dose of 35mg/mL imidacloprid - 4mg/mL abamectin pour on formulation when applied at the proposed therapeutic dose level to naturally infected sheep within 24 hours off shears.

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StabilityStudies The 3.5% imidacloprid,/0.4% abamectin topical formulation (according to Table 1A) packaged in HDPE containers, was found to be stable under long-term conditions at 30°C/60% RH for at least 36 months, accelerated conditions at 40°C/75% RH through 12 months, VICH light study conditions and temperature cycling conditions, and remains stable throughout the shelf life of the product. The stability studies support a shelf life of 36 months when the product is stored below 30°C (Room Temperature). The specification for the shelf life is provided inTable 20:

Table-20. Shelf LifeSpecification Acceptance Criteria Tests Release Expiry Appearance Blue to dark blue clear Blue to dark blue clear solution solution

Integrity of pack Absence of leakage Absence of leakage

FilVolume Not less than the nominal Not less than the nominal volume volume

Viscosity using J tube(cps) 3-6 2-6 Density at 20 0.95-1.05 0.95-1.05 Identification tests 1. The retention time of 1. The retention time of Imidacloprid in the Imidacloprid Imidacloprid in the sample sample should match that of standard within by HPLC and PDA UV should match that of +5%. spectrum standard within ±5%. 2. PDA UV spectrum of the peak should closely match

authentic spectrum of Imidacloprid Assay Imidacloprid 3.325 - 3.675%wv 3150 - 3.850 % w/v (95 to 105 % *LC) (90 to 110 % *LC)

Imidacloprid Degradation Products Individual: < 1% Individual: < 1%

(wrt Imidacloprid) Total: < 5% Disregard: < Total: < 5% Disregard < 0.3% by HPLC 0.3% Identification tests 1 The retention time of 1. The retention time of Abamectin in the

Abamectin Abamectin in the sample sample should match that of standard within

by HPLC and PDA UV should match that of t5%. spectrum standard within +5%.

2.PDA UV spectrum of the peak shouldclosely match

authentic spectrum of Abamectin Assay Abamectin by HPLC 0.38 --- 0.42 % w/v 0.36 - 0.44 % w/v (95 to 105 % *LC) (90 to 110% *LC) ibamectin Degradation Products (wrt Abanecin) Individual: < 1% Individual: 5 1% by IPLC Total: 5 5% Disregard: < Total:55%Disregard :0.3% 0.3% Identification tests 1 The retention time of 1. The retention time of BHT in the sample

Butylated lhvdroxytoluene BHT in the sample should should match that of standard within+5% (BHT) match that of standard by HPLC and PDA UV within ±5%. 2. PDA UV spectrum of

the peak should closely

match authentic spectrum ofBHT Assay Butylated )ydroxytohiene 0.09 - 0.11 %w/v 0.08 - 0.12 % w/v (BHT) (90 to I10 % LC) (80 to 120 % LC) *LC = Label content

As the non-limiting examples above demonstrate, the stable, extended shelf-life compositions of the invention comprising at least one macrocyclic lactone (e.g. abamectin) and at least one neonicotinoid compound (e.g. imidacloprid) show efficacy against both ectoparasites and endoparasites in a mammal (e.g., Merino sheep).

Having thus described in detail various embodiments of the present invention, it is to be understood that the invention defined by the above paragraphsis not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention.

Claims

WHAT IS CLAIMED IS:

1. A topical veterinary composition for treating or preventing a parasitic infection or infestation in an animal comprising: (a) a combination of at least one macrocyclic lactone active agent and at least one neonicotinoid active agent; (b) a pharmaceutically acceptable carrier comprising a combination of a pyrrolidone solvent and a glycol ether solvent; (c) optionally an antioxidant; aid (d) optionally a dye.

2. The topical veterinary composition of claim 1, wherein the macrocyclic lactone active agent is an avermectin or milbemy cin active agent.

3. The topical veterinary composition of claim 2, wherein the avermectin ormilbemycin activeagent is selected from the group consisting of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin, or a mixture thereof

4. The topical veterinary composition of claim 1, wherein the neonicotinoid active agent is selected from the group consisting of acetamiprid, clothianidin, dinotofuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam, or a mixture thereof.

5. The topical veterinary composition of claim 4, wherein the neonicotinoid active agent is imidacloprid.

6. The topical veterinary composition of amy of the preceding claims, wherein the pyrrolidone solvent is selected from the group consisting of 2-pyrrolidone, N

methylprrolidone, 1-ethlpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1 isopropylpyrrolidone, 1-sec-butylpyrrolidone, 1-t-butylpyrrolidone, 1-n-butylpyrrolidone, 1 hexylpyrrolidone, I-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1-(2-hy droxyethyl) pyrrolidone, 1-3-hydroxvpropyl)pyrrolidone, 1-(2-methoxVethyl)-pyrroidone, 1-(3 methoxypropyl)-pyrrolidone or 1-benzylpyrrolidone.

7. The topical veterinary composition of any preceding claim, wherein the glycol ether solvent is propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethl ether, ethylene glycol monomethyl ether or diethvlene glycol monoethvl ether, or a combination thereof.

8. The topical veterinary composition of any preceding claim, wherein the carrier comprises a combination of N-methylpyrrolidone and dipropylene glycol monomethyl ether.

9. The topical veterinary composition of claim 1., wherein the composition comprises: (a) a combination of imidacloprid and abamectin; (b) a pharmaceutically acceptable carrier comprising a combination of a N methylpyrrolidone and dipropylenegycoimonomethylether.

10. A topical veterinary composition for treating or preventing a parasitic infection or infestation in an animal comprising: (a) a combination of an effective amount of inidacloprid and an effective amount of abamectin; (b) a pharmaceutically acceptable carrier comprising a combination of N methylpyrrolidone and dipropylene glycol monomethyl ether; and (c) optionally an antioxidant.

IH. A topical veterinary composition for treating or preventing a parasitic infection or infestation in an animal comprising: (a) a combination of about 3.5% (w/v) imidacloprid and about 0.4% (w/v)abamectin; (b) a pharmaceutically acceptable carrier comprising about 30% (w/v) N methylpyrrolidone and QS dipropylene glycol monomethyl ether; and (c) optionally an antioxidant.

12. The topical veterinary composition of claim 11, wherein the composition comprises about 0. 1% (w/v)butylated hydroxytoluene.

13. A topical veterinary composition for treating or preventing a parasitic infection or infestation in an animal consisting essentially of:

(a) a combination of about 3.5% (w/v) imidacloprid and about 0.4% (w/v) abamecun; (b) a pharmaceutically acceptable carrier comprising about 30% (w/v) N methiylpyrrolidone and QS dipropylene glycol monomethyl ether.

14. The topical veterinary composition of claim 13, wherein the composition comprises about 0.1% (w/v) butylated hydroxytoluene.

15. A topical veterinary composition for treating or preventing a parasitic infection or infestation in ananimal consisting of: (a) a combination of about 3.5% (w/v) imidacloprid and about 0.4% (w/)abamectin; (b) about 0.1% (w/v) butylated hydroxytoluene; (c) about 0.01% of a dye; and (b) a pharmaceutically acceptable carrier comprising about 30% (w/v) N methylpyrrolidone and QS dipropylene glycol monomethyl ether.

16. The topical veterinary composition of any preceding claim, wherein the composition is a pour-on composition.

17. A method for the treatment or prevention of a parasitic infestation or infection in an animal comprising administering to the animal in need thereof an effective amount of the topical veterinary composition of any one of claims I to 16.

18. The method of claim 17, wherein the parasite is an endoparasite.

19. The method of claim 17, wherein the parasite is an ectoparasite.

20. The method of claim 19, wherein the ectoparasite are lice.

21. The method of claim 19, wherein the ectoparasite are fly.

22. The method of claim 17, wherein the animal isa sheep.

23. The method of claim 22, wherein the topical veterinary composition is administered at a dosage of about 1 ml per kg of body weight.