AU2020208145B2 - Topical compositions comprising a neonicotinoid and a macrocyclic lactone, methods and uses thereof - Google Patents

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 neomcotinoid 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

This application claims the benefit of priority to U.S. Provisional Application No. 62/793,301, filed January 16, 2019, which is incorporated herein by reference. 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. Ctenocephalides spp., such as Ctenocephalides felis and the like), - ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., 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 (Dipylidium caninum). 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 (Lyme disease caused by Borrelia burgdorferi), 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, Telodorsagia circumcinta and Trichostrongylus colubriformis. Sheep body lice are ubiquitous parasites of sheep and are estimated to cost Australian sheep 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 makes 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 microplus, 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 include Ancylostoma, 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 of internal and external parasites. The natural product avermectins are disclosed in U.S. Patent 4,310,519 to Albers-Schonberg, et al., and the 22, 23-dihydro-avermectin compounds are disclosed in Chabala, et al., U.S. Patent 4,199,569. For a general discussion of avermectins, which include a discussion of their uses in humans and animals, see“Ivermectin 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 B1a and isomer B1b, which differ by a single methylene group. The B_1a and B_1b isomers have the following structures:

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^® II 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 CAPSTAR™ Tablets sold by Novartis Animal Health. Nitenpyram has a very fast onset of action against fleas. For example, CAPSTAR™ 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 AVENGE™ by Bayer Australia Ltd. However, since imidacloprid is not active against internal nematodes, products containing imidacloprid only are not effective against internal parasites. AVENGE™ 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 in combination with other active agents described in the documents above, there is a 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 foregoing applications, 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, turkeys and cattle. In an embodiment, the topical veterinary composition of the invention are advantageously in the 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, milbemycin 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 acetamiprid, 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 known 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 or method 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 83 of the EPC), such that 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 yet 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 milbemycin 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, milbemycin oxime, moxidectin or nemadectin. In yet 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_n-C_m 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 and also 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 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.

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 2ⁿ 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 hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid. Organic acids include all pharmaceutically 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 C1-C20 aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, D-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 the morpholine 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 CABI Publishing or Albers-Schönberg et al. (1981),“Avermectins 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 Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Patent No.4,134,973 and EP 0677054, 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 and milbemycins 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-Schönberg et al., and the 22,23-dihydro avermectin compounds are disclosed in Chabala 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 0007812 A1, U.K. Patent Specification 1390336, EP 0002916, and Ancare New Zealand Patent No.237086, inter alia. 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^th 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 Information, 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.4,855,317, 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. 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^® II 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; 8,691,256 and 8,849,259, all incorporated herein by reference in their entirety. Another well-known neonicotinoid is nitenpyram. Nitenpyram is the active ingredient in the oral product CAPSTAR™ Tablets sold by Novartis Animal Health.

The avermectin and milbemycin active agents include, but are not limited to, abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin 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 guadipyr and huanyanglin (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, Li Z, Qian 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 Contam 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).

Pyrrolidone solvents that may be used in the compositions of the invention include, but are not limited to, 2-pyrrolidone, 1-(C1-20-alkyl)-2-pyrrolidone, in particular 1- methylpyrrolidone (also known as N-methylpyrrolidone), 1-ethylpyrrolidone, 1-n- propylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-(s- or t- or n-butyl)pyrrolidone, 1-hexylpyrrolidone, 1-(C₂-₂₀-alkenyl)-2-pyrrolidone such as 1-vinyl- 2-pyrrolidone, 1-(C3-8cycloalkyl)-2-pyrrolidone such as 1-cyclohexylpyrrolidone, 1-(C1-6- hydroxyalkyl)-2-pyrrolidone, 1-(C₁-₆-alkoxy-C₁-₆-alkyl)-2-pyrrolidone such as 1-(2- hydroxyethyl)-pyrrolidone, 1-(3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethy1)- pyrrolidone, 1-(3-methoxypropyl)pyrrolidone and 1-benzylpyrrolidone, 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 glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, 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, the pyrrolidone 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 (quantum sufficit 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, imidacloprid, 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 pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 of imidacloprid, or pharmaceutically acceptable salts, hydrates or solvates thereof, together with a pharmaceutically acceptable carrier that comprises a combination of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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 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 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, and an antioxidant.

In another embodiment, the invention provides topical compositions consisting essentially of an effective amount of an 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, 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, l- octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 imidacloprid, 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, l-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-benzylpyrrolidone; 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; and an antioxidant that is butylated hydroxytoluene or butylated hydroxyanisole.

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 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, 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, 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 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, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-benzylpyrrolidone; a glycol ether solvent, an antioxidant and a dye.

In still 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 selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-benzylpyrrolidone; 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; an 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-methylpyrrolidone, 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% (w/v) or about 1% to about 5% (w/v) of the neonicotinoid active agent. In another embodiment, the compositions of the invention may comprise 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 embodiments, the compositions will comprise about 0.1% to about 5% (w/v) or about 0.1 to about 2% (w/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 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 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 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 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 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 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 a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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% (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 a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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) 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 about 0.01% (w/v) to about 2% (w/v) of butylated hydroxytoluene or butylated hydroxyanisole.

In yet 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) 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) N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.) and about 0.01% (w/v) to about 2% (w/v) of butylated hydroxytoluene.

In yet another embodiment, the invention provides topical compositions that comprise about 0.1% (w/v) to about 2% (w/v) of an avermectin 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 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 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 abamectin and 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) 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-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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 comprises 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 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) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 1% (w/v) of butylated hydroxytoluene or butylated hydroxyanisole.

In yet 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) N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), and about 0.01% (w/v) to about 1% (w/v) of butylated hydroxytoluene.

In yet another embodiment, the invention provides topical compositions that comprise about 0.1% (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 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 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 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 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 about 35% (w/v) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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) of a pyrrolidone solvent selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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-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 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) 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.

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 0.01% (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% (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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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% (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 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 monomethyl ether (q.s.), and about 0.1% (w/v) 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 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 consists essentially of about 10% (w/v) to about 50% (w/v) of a pyrrolidone solvent and a glycol ether solvent (q.s., quantum sufficit), 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 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 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 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 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 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 selected from the group consisting of 2- pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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 selected from the group consisting of 2- pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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% (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 about 0.01% (w/v) to about 2% (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 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) N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.01% (w/v) to about 2% (w/v) of butylated 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 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 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 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, 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 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% (w/v) of abamectin and 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 consists essentially of about 20% (w/v) to about 40% (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 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, 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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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, together with a pharmaceutically acceptable carrier that 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, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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 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 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) N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.01% (w/v) to about 1% (w/v) of butylated hydroxytoluene.

In yet another embodiment, the invention provides topical compositions consisting essentially of about 0.1% (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 consists essentially of 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 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, 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 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 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 essentially of 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 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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 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 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 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 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.

In yet another embodiment, the invention provides topical compositions consisting essentially 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 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) 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 and a glycol ether solvent (q.s., quantum sufficit), 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 from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 from the group consisting of 2-pyrrolidone, N-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 0.4% (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 hydroxytoluene.

In yet another embodiment, the invention provides topical compositions consisting of 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 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 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, 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 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 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 a pharmaceutically 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, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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 pharmaceutically 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, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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 hydroxy anisole and a dye.

In 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 pharmaceutically acceptable carrier that consists of about 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 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) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.01% (w/v) to about 2% (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 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-methylpyrrolidone and dipropylene glycol monomethyl 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 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 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, 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 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 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) 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 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 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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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 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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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 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% (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 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 1% (w/v) of butylated hydroxy toluene and a dye.

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 pharmaceutically acceptable carrier that consists of about 20% (w/v) to about 40% (w/v) N-methylpyrrolidone and dipropylene glycol 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 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 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 1% (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 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 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) 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 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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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-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 0.1% (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 glycol monomethyl ether (q.s.), butylated hydroxy toluene or butylated 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 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 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 and dipropylene glycol monomethyl ether (q.s.), about 0.01% (w/v) to about 0.05% (w/v) of butylated hydroxytoluene 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 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-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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 0.4% (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-methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1- dodecylpyrrolidone, 1-isopropylpyrrolidone, l-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-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-methylpyrrolidone and 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) of N-methylpyrrolidone and dipropylene glycol monomethyl ether (q.s.), about 0.1% (w/v) of butylated hydroxytoluene 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 without affecting 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 the art 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 A1). 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 anthelmintic 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 macrocyclic 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 contortus, Telodorsagia circumcinta and 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, 16^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, fatty acid esters such as the dimethyl ester; dialkylesters of dicarboxylic acids including, but not limited to, diisobutyl adipate, diisopropyl adipate (also known as CERAPHYL 230), diethyl 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, dimethyl sulfoxide, ethylene glycol, propylene glycol, glycol carbonates, monomethylacetamide, liquid polyoxyethylene glycols (PEG) of different average molecular weight ranges, glycerol formal, dimethyl isosorbide, triacetin, C₁- C10 esters of carboxylic acids such as butyl or octyl acetate, benzyl acetate, aryl esters including 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-C10 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 C₁-C₁₀ alcohols or esters thereof (including acetates, such as ethyl acetate and the like), C10-C18 saturated fatty acids or esters thereof, C10-C18 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- hydroxymethyl-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 may 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 enhancer 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 myristate, 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 not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C₈ to C₁₂) 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, microemulsion 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, U.S. 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 pharmaceutically acceptable carrier may be a liquid carrier vehicle as described herein, and other carriers described in the art, for example in U.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, e.g. 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 are soluble. The formulations 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 location without the active agents precipitating 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- forming 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 a 45V2 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 and sodium cetyl sulfate); sodium dodecyl benzenesulfonate, sodium dioctylsulphosuccinate; fatty acids (e.g. those derived from coconut oil),

(c) cationic surfactants such as water-soluble quaternary 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% (w/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 size and 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 1 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, up to 20 ml or up to 30 ml, or higher. In one embodiment of the volume, the volume is on the order of about 0.5 ml to about 1 ml or about 0.5 ml to about 2 ml for cats, and on the order of about 0.3 to about 3 ml or 4 ml 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 ml to about 2 ml of the composition per kg of the animal is administered. In one embodiment, a volume of about 1 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 65ml. 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 macrocyclic lactone active agent in combination with at least one neonicotinoid agent, together with a pharmaceutically 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 Dirofilaria immitis (heartworm). In a particular embodiment, the methods of the invention exhibit excellent efficacy against sheep body lice (Bovicola ovis) while at the same time exhibiting superior efficacy against the gastrointestinal nematodes Haemonchus contortus, Telodorsagia circumcinta and Trichostrongylus colubriformis.

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 an animal that has a parasitic infestation for the eradication of the parasite or the reduction of the number of the parasites infesting 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 neonicotinoid active agent(s), or the macrocyclic lactone active agent(s) 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 macrocyclic 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 a pharmaceutically 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 Agents

Additional veterinary/pharmaceutical active ingredients may be used with the compositions of the invention. In some embodiments, the additional active agents may include, but are not limited to, acaricides, anthelmintics, anti-parasitics and insecticides. Anti-parasitic agents can include both ectoparasiticidal and endoparasiticidal agents.

Veterinary pharmaceutical agents that may be included in the compositions of the invention are well-known in the art (see e.g. Plumb’ Veterinary Drug Handbook, 5^th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9^th Edition, (January 2005)) and include but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, clavulanate potassium, amphotericin B desoxycholate, amphotericin B lipid-based, ampicillin, amprolium, 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, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime 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, clofazimine, 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, detomidine, 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, diphenylhydramine, 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 cypionate, 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, hyaluronate sodium, hydrazaline, 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, liothyronine sodium, lisinopril, lomustine (CCNU), lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone 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 decanoate, naproxen, narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprozole, 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 glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, 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, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine 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, trimcinolone acetonide, trientine, trilostane, trimepraxine tartrate w/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 adulticide insecticides and acaricides can also be added to the composition of the invention. These include pyrethrins (which include cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II 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 dichlorvos, heptenophos, mevinphos, 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 art, 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, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato acetate, monosulfiram, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, deet, dimethyl phthalate, and the compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)- dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano- 1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

In another 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 and US 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 actinomycete Saccharopolyspora spinosa (see, for example Salgado V.L. and Sparks T.C.,“The Spinosyns: Chemistry, Biochemistry, Mode of Action, 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 spinosyn 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; 5,767,253; 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 1000 mg. More typically, the additional active agent may be included in a dose of about 10 Pg/kg to about 500 mg/kg 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 Pg/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 weight 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 of weight of animal. In other embodiments, the additional active agent may be present in a dose of about 5 Pg/kg to about 200 Pg/kg or about 0.1 mg/kg to about 1 mg/kg of 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 by following 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 (21^st Edition) (2005), Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11^th Edition) (2005) and Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (8^th Edition), edited by Allen et al., 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, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Preferred ranges for these compounds include from about 0.01 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, glutamic acid/glutamates and sodium carbonate.

The compositions of the invention are 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 animal in 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 bodyweight. It is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific host and parasite.

For the macrocyclic lactone active agent(s), a dosage of about 1 mg/kg to about 10 mg/kg of bodyweight is administered. In some embodiments, a dosage of about 2 mg/kg to about 8 mg/kg or about 3 mg/kg to about 7 mg/kg of the macrocyclic 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 1A.

Table 1A. Topical formulation

1Butylated hydroxytoluene; ²N-methylpyrrolidone;

3 Dipropylene 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 minimum 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 in Table 1B. Table 1B. Manufacturing Process for Imidacloprid Abamectin Pour On

1N-methylpyrrolidone; ² Butylated hydroxytoluene ; ³ Dipropylene monomethyl ether Additional compositions according to the invention are shown in Table 1C. The results of a stress study on Composition 1C-a as shown in Table 1D indicated no significant loss of API after 4 weeks storage at at 55°C. Table 1C. Topical formulations

1Butylated hydroxytoluene; ²N-methylpyrrolidone; ³ Dipropylene monomethyl ether Table 1D. Stress study on Composition 1C-a

1API- Active Pharmaceutical Ingredient.

2Stability 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/mL imidacloprid + 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 mg imidacloprid/kg body weight and 5.32 mg abamectin/kg body weight. Study animals were dosed according to the treatment regime detailed in Table 2 shown below.

Table 2. Treatment regime

* 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 1 (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 in length. 20 partings were carried out on the left side of each sheep followed by 20 partings on the right 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 of the 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 that level throughout the 140 day study period.

Table 3. Group Mean Lice Counts

Table 4. Treatment Efficacies

Example 3: Efficacy against roundworms (Haemonchus contortus, Telodorsagia

circumcincta and Trichostrongylus colubriformis)

The Example 3 study was done to confirm the efficacy of a single dose of 35mg/mL imidacloprid + 4mg/mL abamectin pour-on formulation (Investigational Veterinary Product “IVP” see Table 1A) against adult and immature stages of macrocyclic-lactone susceptible strains of Haemonchus contortus, Telodorsagia circumcincta and Trichostrongylus colubriformis 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 their susceptibility to gastrointestinal 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 immature stages of macrocyclic- lactone susceptible strains of Haemonchus contortus, Telodorsagia circumcincta and Trichostrongylus colubriformis 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 8a and 9a), and mean faecal egg counts (FECs), in Tables 8b and 9b. Table 5. Treatment regime

Cohort A

Cohort B

pp

Table 6. Summary treatment data Cohort A

Table 7. Summary treatment data Cohort B

Table 8a. Group mean total worm counts (larval stages at treatment)

Table 8b. Efficacy (total worm count reduction) vs larval stages at treatment

Table 9a. Group mean total worm counts (adult stages at treatment)

Table 9b. Efficacy (total worm count reduction) vs adult stages at treatment

Example 4: Efficacy against roundworms (Haemonchus contortus, Telodorsagia circumcincta and Trichostrongylus rugatus and Nematodirus spp)

The Example 4 study was done to confirm the efficacy of a single dose of 35mg/ml imidacloprid + 4mg/ml abamectin pour-on formulation against adult and immature stages of macrocyclic-lactone susceptible strains of Haemonchus contortus, Telodorsagia circumcincta, Trichostrongy/us rugatus and Nematodirus 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:

H.contortus 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 blinded¹, 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 A and 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 1 with the following number of L3 larvae of the target parasites:

3_{,113 3} ^rd _{stage (L3) Telodorsagia circumcincta (3061strain) - Day 1}

3_{,913 3} ^rd _{stage (L3) Trichostrongylus rugatus (3061 strain) - Day 1}

3_{,603 3} ^rd _{stage (L3) Haemonchus contortus (TBZ strain) - Day 1}

6_{,000 3} ^rd _{stage (L3) Nematodirus spathiger (“NEM”) (SA strain) - Day -2}

¹ Personnel involved in performing artificial infection, post treatment FECs, cultures (CUL) or total worm 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 Oesophagostomum. Infection statistics indicated that all infection levels were adequate for the assessment of efficacy. Table 10. Treatment regime

pp Table 11. Summary treatment data means Cohort A

Table 12. Summary treatment data means Cohort B

This study confirmed the efficacy of a single dose of 35mg/ml imidacloprid + 4mg/ml abamectin pour-on formulation against adult and immature stages of macrocyclic-lactone susceptible strains of Telodorsagia circumcincta, Trichostrongylus axei, Trichostrongylus vitrinus and Nematodirus spathiger 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 Teladorsagia cirumcincta by total worm count reduction (TWCR). The larval differential results are shown in Table 14.

In this study, it appears that Haemonchus 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 H. contortus was isolated in 1976, prior to the introduction of macrocyclic- lactones, it appears 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 macrocyclic-lactone susceptible H. contortus in a field situation.

Control of adult Nematodirus 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 the immature 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 which N. 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 13A. Group Mean FEC Day 41 -42

Table 13B. Efficacy Day 41-42 (by faecal egg count reduction)

Table 14. Larval Differential Results (Day 41-42)

1

Haem = Haemonchus contortus, ²Trich. =Trichostrongy/us spp, ³Ost. = Telodorsagia spp. Table 15A. Group mean total worm counts (larval stages present at treatment)

Table 15B. Group mean total worm counts (adult stages at time of treatment)

Table 16A. Efficacy (total worm count reduction) vs larval stages at treatment

Table 16B. Efficacy (total worm count reduction) vs adult stages at treatment

1Investigational Veterinary Product according to Table 1A; ²Haemonchus contortus; ³Teldadorsagia spp.;⁴Trichostrongylus axei; ⁵Nematodirus spp.

Example 5: Persistency against sheep body lice

The Example 5 study was done to confirm the period of persistency (via reductions in 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 (Bovicola ovis) as determined by zero live lice counts at selection. Sheep were allowed to acclimatise for a minimum of 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 1 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 were weighed 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 1 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 1 (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 bodyweight 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 Day 20. 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 confirm no differences exist at p<0.05.

The Investigational Veterinary Product (“IVP”) for this study was the

imidacloprid/abamectin pour-on according to Table 1A having a composition of 35 g/L imidacloprid and 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 17A. Cohort A

Table 17B. Cohort B

Group 1 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, a minimum 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.

HA_E ^R

M

Stability Studies

The 3.5% imidacloprid/ 0.4% abamectin topical formulation (according to Table 1A) packaged in HDPE containers, was found to be stable under longterm 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 in Table 20: Table 20. Shelf Life Specification

*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 paragraphs is 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 (23)

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; and

(d) optionally a dye.

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

3. The topical veterinary composition of claim 2, wherein the avermectin or milbemycin active agent 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 any of the preceding claims, wherein the pyrrolidone solvent is selected from the group consisting of 2-pyrrolidone, N- methylpyrrolidone, 1-ethylpyrrolidone, l-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-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 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 monoethyl ether, ethylene glycol monomethyl ether or diethylene glycol monoethyl 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 dipropylene glycol monomethyl ether.

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 imidacloprid 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.

11. 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) abamectin; (b) a pharmaceutically acceptable carrier comprising about 30% (w/v) N- methylpyrrolidone 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 an animal consisting of:

(a) a combination of about 3.5% (w/v) imidacloprid and about 0.4% (w/v) 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 1 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 is a sheep.

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