Parasiticidal compositions comprising multiple active agents, methods and uses thereof

The present invention provides veterinary compositions comprising at least one 1-laripyrazole as an active agent, at least one macrocyclic lactone as an active agent, at least one insect growth regulator (IGR) as an active agent and at least one anti-worm agent as an active agent for controlling external parasites and internal parasites in animals; the use of these compositions against external parasites and internal parasites and methods of preventing or treating infections and parasitic infestations in animals.

BACKGROUND OF THE INVENTION [0002] Animals, such as mammals and birds, are often sensitive to infestations / parasitic infections. These parasites may be external parasites, such as insects and internal parasites such as nematodes and other worms. Domesticated animals, such as cats and dogs, are often infected with one or more of the following external parasites:

· Fleas (e.g., Ctenocephalides spp., Such as Ctenocephalides felis, etc.), · ticks (e.g., Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., Etc.), · mites (e.g., Demodex spp. Sarcoptes spp., Otodectes spp., Etc.), · lice (e.g., Trichodectes spp., Cheyletiella spp., Lignonathus spp., Etc.), · mosquitoes (Aedes spp., Culux spp., Anopheles spp., Etc.) and flies (Hematobia spp., Musca spp., Stomoxys spp., Dematobia spp., Coclyomia spp., etc.).

[0003] Fleas are particularly problematic because they not only have a deleterious effect on the health of an animal or a human, but also contribute to great psychological stress. In addition, fleas are also pathogenic vectors in animals and humans, such as tapeworms (Dipylidium caninum).

[0004] Similarly, ticks are also harmful to the physical and psychological health of an animal or human being. Nevertheless, the most serious problem associated with ticks is that they are vectors of pathogens in both humans and animals. The main diseases that are caused by ticks include Lyme disease (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.) And rickettsia (also known as Rocky Mountain spotted fever). Ticks also release toxins that cause inflammation or paralysis in the host. Occasionally, these toxins are lethal to the host.

[0005] Similarly, farm animals are also sensitive to parasite infestations. For example, cattle are attacked by a large number of parasites. A parasite that is very widespread among farm animals is the tick of the genus Boophilus, especially those of the species microplus (bovine tick), decoloratus and annulatus. Ticks, such as the Boophilus microplus, are particularly difficult to control because they live in a pasture where grazing animals are grazed.

[0006] Animals and humans also suffer from internal parasitic infections including, for example, helmintosis, which is most often caused by a group of parasitic worms categorized as tapeworms (tapeworms), nematodes (roundworms) and flukes (flatworms or flukes). These parasites adversely affect the animal's nutrition and contribute to severe economic losses in pig, sheep, horse and cattle breeding, also by attacking domestic animals and poultry. Other parasites that occur in

The gastrointestinal tract of animals and humans includes Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius and parasites found in the blood or other tissues and organs, such as pillar and additional intestinal stages Strogyloides, Toxocara and Trichinella [0007] 1-arylpyrazoles as a class of chemicals are well known in the art and certain compounds of this class have been found to be highly active against a wide range of pests and parasites that are detrimental to animals and plants. For example, 1-arylpyrazole derivatives are known in the art to prevent, treat or control infestations with extraneous parasites in mammals, such as cats, dogs and cattle. Certain 1-arylpyrazoles and their use against pests are described in published US patent applications. Ser. No. US 2005/0182048; US 2006/0135778; US 2008/0132487; US 2008/0031902; in US Pat. Ser. U.S. Patent No. 4,963,575; US 5,122,530; US 5,232,940; US 5,236,938; US 5,246,255; US 5,547,974; US 5,567,429; US 5,576,429; US 5,608,077; US 5,714,191; US 5,814,652; US 5,885,607; US 5,567,429; US 5,817,688; US 5,885,607; US 5,916,618; US 5,922,885; US 5,994,386; US 6,001,384; US 6,010,710; US 6,057,355; US 6,069,157; US 6,083,519; US 6,090,751; US 6,096,329; US 6,124,339; U.S. 6,180,798; US 6,335,357; US 6,350,771; US 6,372,774; US 6,395,906; US 6,413,542; US 6,685,954; and US 7,468,381. See also: EP 0 234 119, EP 0 295 117, EP 0 352 944, EP 0 500 209, EP 0 780 378,

[0008] The compounds of the families defined in these patents are very active and one of these compounds, 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulphinylpyrazole, or fipronil, is particularly effective against pests, including fleas and ticks.

[0009] These compounds have been described as having activity against a very large number of parasites, including insects and mites, in fields as diverse as agriculture, healthcare and veterinary medicine. General information from these documents indicates that these active compounds can be administered in various ways: orally, parenterally, percutaneously and topically. Topical administration includes, in particular, solutions for use on the skin (pour-on (for pouring) or spot-on (for dripping)), sprays, for spraying (preparations for spraying devices), baths, showers, sprays, powders, ointments, shampoos, creams, etc. Pour-on solutions for use on the skin can be designed for percutaneous administration.

[0010] Other compounds that are known in the art to prevent, treat or control infestation with internal and external parasites include milbemycin or avermectin derivatives that are natural or semi-synthetic compounds containing a 16-membered macrocyclic ring. The series of avermectin and milbemycin compounds are powerful anthelmintics and antiparasitic agents against a wide range of internal and external parasites. The natural product of avermectin is disclosed in US Pat. Ser. No. 4,310,519, Albers-Schonberg et al. And compounds 22, 23-dihydroavermectin are disclosed in Chabala et al., US Pat. Ser. North America, No. 4,199,569. A general discussion of avermectins, which covers a discussion of their uses in humans and animals, can be found in 'Ivermectin and Abamectin', WC Campbell, ed., Springer-Verlag, New York (1989). The naturally occurring milbemycins are described in: Aoki et al., U.S. Ser. U.S. Patent No. 3,950,360.

[0011] U.S. Pat. Ser. No. 20081031902 describes certain 1-arylpyrazole compounds that are substituted at the 5-position of the pyrazole ring by alkyl groups or C groups₁-C₄haloalkyl. These compounds have also proved to be particularly effective against fleas and ticks.

[0012] Patent descriptions Ser. No. 6,096,329 and US 6,685,954 describe synergistic combinations of 1-arylpyrazole compounds and an insect growth regulator (IGR) as an active agent, such as (S) -methoprene, which are very effective against external parasites.

[0013] Other pharmaceutical or therapeutic agents include those known in the art for the treatment of parasitic infections caused by nematodes and flukes. For the treatment of tapeworm (and carrier) infections in warm-blooded animals, it is known to use 2acyl-4-oxo-pyrazinoisoquinoline in this animal as a drug (see, e.g., US Patent No. 4,001,441).

[0014] A compound of this class that is often used to treat tapeworms and nematodes is praziquantel, which has the following structure:

<img file="PL2552201T3_D0001.tif" />

[0015] Praziquantel (praziquantel) can be used to treat infections with internal parasites including infections by hepatocytes or flukes (schistosoma). Praziquantel works by causing severe cramps and paralysis of the worm's muscles.

[0016] Patent descriptions Ser. No. 6,482,425; US 6,426,333; US 6,962,713 and US 6,998,131 describe compositions comprising combinations of arylpyrazole compounds and macrocyclic lactone active agents that are effective against external parasites and intestinal parasites.

[0017] International patent application No. WO010109214 describes a local parasiticidal agent comprising (i) phenylpyrazole and / or neonicotinoid (ii) a macrocyclic lactone and / or an aminoacetonitrile derivative, (iii) an insect growth regulator, and (iv) a 2-acyl-4-oxo derivative. -1,2,3,6,7,11b-4Hpirazyno [2,1-a] isoquinoline.

[0018] Patent description Ser. No. 20040167175 describes a method for preventing or interfering the transmission of arthropod and mosquito-related diseases comprising the use of a formulation comprising at least one 1-N-arylpyrazole.

[0019] International patent application WO2004016252 describes chewing veterinary preparations.

[0020] Patent description Ser. No. 2004198676 describes veterinary preparations for topical use that are used in the treatment, control and prevention of infection by internal and external parasites in warm-blooded animals or birds, containing at least one macrolide anthelmintic compound and a second anthelmintic agent.

[0021] In addition to compositions containing arylpyrazole active agents, alone or in combination with other active agents described in the above documents, there is still a need for

The veterinary compositions and methods with improved efficiency and range of action for protecting animals against both internal parasites and external parasites.

[0022] Citation or identification of any document in the present application is not an admission that such a document is available as prior art to the present invention.

SUMMARY OF THE INVENTION [0023] The present invention provides a veterinary composition for topical application in the form of a spot-on solution (dripping), said composition being intended for treating or preventing a parasitic infection (infection) or infestation (invasion, parasite infection) an animal, and said composition comprises:

(a) a combination of at least one 1-arylpyrazole active agent of the formula (I),

<img file="PL2552201T3_D0002.tif" />

wherein:

R₁ is hydrogen, cyano, nitro, halogen, R₃, R₈, formyl, -C (O) R₈, -C (O) OR₈, C (O) NR₉R₁₀, -C (= NOH) NH₂, -C (= NNH₂) R₉ or -C (S) NH₂;

R₂ means R₈, halogen, cyano, nitro, -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁;

R₃ is hydrogen, halo, alkyl, haloalkyl, OH, OR₈, S (O)_mR₁₁, -C (O) R₈, C (O) OR 8, NR 9 R 10, -N = C (R 9) (R 14), -N = C (R 10) -Z- (R 9), -N = C (R 10) -NR 9 R 10, -N (R 8) - C (R10) = NR 9, N (R₁₁) C (O) CR₁₅R₁₀R₁₁, -N (R.₁₁) C (O) aryl, -N (R₁₁) C (O) heteroaryl or -N (R.₁₁) C (O) OR₁₀;

R₄, R₅ and R₇ independently are hydrogen, halo, alkyl, haloalkyl, cyano or nitro;

R₆ halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, -C (O) R₁₂, S (O)_nR₁₂ or SF₅;

X is a nitrogen or CR₁₃;

Z is O, S (O)_m or NR₉

R₈ is alkyl or haloalkyl;

R₉ is hydrogen, alkyl, haloalkyl, or alkoxy;

R₁₀ is hydrogen, alkyl, haloalkyl, alkoxy or -C (O) R₈;

R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxyalkyl or haloalkoxyalkyl;

R₁₂ is alkyl or haloalkyl;

PZ / 4348 / AGR EP2 552 201 B1

R₁₃ is hydrogen, halo, cyano, nitro, alkyl, haloalkyl, alkoxy or haloalkoxy;

R₁₄ is optionally substituted aryl or optionally substituted heteroaryl;

R₁₅ is hydrogen, halo, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, formyloxy, alkycarbonyloxy, haloalkylcarbonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino, di (haloalkyl) amino, aryloxy or aralkoxy;

wherein said alkyl, haloalkyl, or alkoxy groups are optionally substituted with alkyl, haloalkyl, alkoxy, aryl or heteroaryl; said aryl or heteroaryl groups are optionally substituted with one or more groups, such as alkyl, haloalkyl, aryl, halogen,

C (O) R₈, -C (O) OR₈, -C (O) NR₉R₁₀, - C (S) NH₂ or -S (O)_mR₁₁ m is 0, 1 or 2; and n is 0, 1 or 2; or a pharmaceutically acceptable salt, hydrate or solvate thereof;

at least one macrocyclic lactone as an active agent that is avermectin or milbemycin;

at least one insect growth regulator as an active agent selected from the following (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron and novaluron;

and at least one anti-worm agent as an active agent selected from the following thiabendazole, oxybendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, aminoacetonitrile active agent and arylazol-2-ilycyanoethylamine active agent;

(b) a pharmaceutically acceptable carrier which contains formal glycerol and dimethyl isosorbide; and (c) optionally a crystallization inhibitor; its use or veterinary uses for the treatment or prophylaxis of infections and parasitic infestations in animals (wild or domesticated), including livestock and pets, such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle, in order to deprive these parasite hosts commonly found in such animals. The veterinary composition for topical use according to the invention is preferably in the form of a spot-on formulation for use on localized surfaces on the animal to be treated.

[0024] Surprisingly, it has been found that the compositions and formulations of the invention described herein have a broader spectrum of efficacy against harmful internal parasites and external parasites for a long duration compared to compositions known in the art.

[0025] In one embodiment, the invention provides veterinary compositions for topical use comprising effective amounts of at least one 1-arylpyrazole of formula (I) or formula (IA) shown below, wherein the variables X, R₁, R₂, R_2a, R₃, R_3a, R₄, R_4a, R₅, R₆, R_6a R₇ and

PZ / 4348 / AGR EP2 552 201 B1

R_13a are as defined herein, in combination with at least one IGR as an active agent, at least one macrocyclic lactone as the active agent and at least one anti-worm agent as an active agent and a pharmaceutically or veterinarily acceptable liquid carrier as defined above.

<img file="PL2552201T3_D0003.tif" />

[0026] In certain preferred embodiments, the veterinary compositions for topical use include fipronil. The macrocyclic lactone as an active agent is an avermectin or milbemycin active agent including, but not limited to, eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime or moxidectin.

[0027] Compositions of the present invention include IGR as active agents such as (S) methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novaluron. The compositions further include at least one of the following thiabendazole, oxybendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triklabendazol, febantel, levamisole, pyrantel, morantel, praziquantel (praziquantel), closantel, clorsulon, aminoacetonitrile active agent or aroyl-2-cyanoethylamine active.

[0028] It is intended that the present invention does not include within its scope any previously known product, method for producing a product or method of using a product such that the Applicant reserves the right and hereby discloses the exclusion of any previously known product, process or method. It should be further noted that the invention is not intended to encompass the scope of the present invention any product, process or method of producing a product or use of a product that does not meet the USPTO requirements (35 USC §112, first paragraph) or EPO (Article 83 EPC) regarding written description and disclosure such that the Applicant reserves the right and hereby discloses the exclusion for any product previously described, the method of manufacturing the product or the use of the product.

[0029] These and other solutions are disclosed herein or are obvious on the basis and covered by the following Detailed Description.

DETAILED DESCRIPTION [0030] The present invention provides new compositions of the invention as defined in the claims.

[0031] The compositions are in a form that is suitable for topical administration, more particularly in the form of spot-on formulations (spot-on), which are applied to the localized surface at

PZ / 4348 / AGR EP2 552 201 B1 animal. These preparations provide unexpectedly effective protection of animals against both external parasites and internal parasites for a prolonged period of time.

[0032] The compositions of the present invention comprise at least one avermectin or milbemycin compound. In another embodiment, the at least one avermectin or milbemycin compound component of the composition is abamectin, dimementectin, doramectin, emamectin, eprinomectin, ivermectin, latideectin, lepimectin, selamectin, milbemectin, milbemycin D, moxidectin or nemadectin.

[0033] Also provided are uses for the treatment and / or prophylaxis of infections and parasitic infestations in animals, comprising administering an effective amount of the formulation of the invention to an animal.

[0034] The invention includes at least the following elements:

(a) The subject of the invention are new compositions as defined herein, which show better activity against animal parasites.

[0035] In the present disclosure and in the claims, terms such as &amp; quot; comprising &amp; quot; &amp; quot; including &amp; quot; &amp; quot; including &amp; quot; and &amp; quot; having &amp; quot; and the like may have the meanings ascribed to them in US Pat. Ser. North America and can mean "covers", "covering", etc .; the terms "consisting essentially of" or "consist essentially" have the same meaning assigned to them in patent law Ser. North America and these terms are open terms that allow the presence of what is mentioned above, as long as the basic or new properties that are mentioned are not changed by presence over what is mentioned, but exclude solutions known in the art.

[0036] It should also be noted that in the present disclosure and in the claims and / or paragraphs, the compounds of the present invention are intended to include all their stereoisomers and crystalline forms (which include hydrated forms, polymorphic forms and amorphous forms with up to 15% crystal structure by weight). ).

Definitions [0037] Unless otherwise specified, the terms used herein will have their usual meanings in the art. The organic groups mentioned in the definitions of the variables in formula (I) or (IA) are similarly to the term halogen atom - collective terms for individual combinations of members of a particular group. Prefix C_n-C_m indicates in each case the possible number of carbon atoms in the group.

[0038] As used herein, the term "animal" includes all mammals, birds and fish, and also includes all vertebrate animals, including humans. Animals include humans, cats, dogs, cattle, chickens, cows, cervids, goats, horses, llamas, pigs, sheep and how. The term also includes the individual animal at all stages of development, including embryonic and fetal stages.

[0039] The term "alkyl" refers to saturated straight, branched, cyclic, primary, secondary or tertiary hydrocarbons, including those having from 1 to 20 atoms. In some embodiments, the alkyl groups will include C groups₁-C₁₂, C₁₀, C₁C₈, C₁-C₆ or C₁-C₄ alkyl. Examples of C₁-C₁₀ alkyl include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1.27

PZ / 4348 / AGR dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2 , 3-dimethyl-butyl, 3,3-dimethyl-butyl, 1-ethylbutyl, 2-butyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, heptyl , octyl, 2-ethylhexyl, nonyl and decyl, and isomers thereof. C₁-C₄alkyl is e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[0040] Cyclic alkyl groups that are included within the term alkyl include those containing from 3 to 10 carbon atoms and having single or multiple condensed rings. In some embodiments, the cycloalkyl groups include cyclic C groups₄-C₇ or C₃-C₄ alkyl. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The alkyl groups described herein may be unsubstituted or substituted with one or more groups selected from the group consisting of the following alkyl, halogen, haloalkyl, hydroxy, carboxy, acyl, acyloxy, amino, alkyl or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfonyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, a carbamate, phosphonic acid, phosphate, phosphonate or any other possible functional group that does not inhibit the biological activity of the compounds of the invention, unprotected or protected if necessary, as known to those skilled in the art, e.g., as Greene et al. in the Protective Groups in Organic Synthesis publication,

[0042] The term "alkenyl" refers to both straight and branched carbon chains that have at least one carbon-carbon double bond. In some embodiments, the alkenyl groups may include C groups₂-C₂₀ alkenyl. In other embodiments, alkenyl includes groups C₂-, C₂, C₂-, C₂-C₆ or C₂-C₄ alkenyl. In one alkenyl embodiment, the number of double bonds is 1-3, in another alkenyl solution, the number of double bonds is one or two. Other ranges of the number of carbon-carbon double bonds and the number of carbon atoms are also contemplated depending on the position of the alkenyl group on the molecule. Groups "C₂-C₁₀ alkenyl "may contain more than one double bond in the chain. Examples include, but are not limited to, groups such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl 2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl- 2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl 1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1- methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-methyl pentenyl, 4-methyl-2-pentenyl,

PZ / 4348 / AGr2 dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl -2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1 , 1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

[0043] The term "cycloalkenyl" refers to monovalent cyclic alkenyl groups containing from 4 to 10 carbon atoms, preferably from 5 to 8 carbon atoms having single or multiple condensed rings, wherein the fused rings may or may not be cycloalkenyl, the condition that the point of attachment is a cycloalkenyl ring atom. Examples of cycloalkenyl groups include, by way of example, cyclopenten-4-yl, cyclooctene-5-yl and the like. Alkenyl and cycloalkenyl groups can be unsubstituted or substituted with one or more substituents as described above for an alkyl group.

[0044] The term "alkynyl" refers to both straight and branched carbon chains that have at least one carbon-carbon triple bond. In one alkynyl embodiment, the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one or two. In some embodiments, the alkynyl groups include groups C₂-C₂₀ alkynyl. In other embodiments, the alkynyl groups may include C groups₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄alkynyl. Other ranges of numbers of carbon-carbon triple bonds and numbers of carbon atoms are also contemplated depending on the location of the alkynyl group in the molecule. For example, the term "C₂-C₁₀"alkynyl" refers to an unsaturated straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn1-yl, prop-2-yn-1- 1, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, npent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent- 2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yne 4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n- hex-2-yn-6-yl, n-hex-3yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1 yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4- yl or 4-methylpent-2-yn-5-yl, etc.

[0045] The term "haloalkyl" refers to an alkyl group, as defined herein, which is substituted with one or more halogen atoms. For example, C₁-C₄-haloalkyl, including, without limitation, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2, 2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like

[0046] The term "fluoroalkyl" as used herein refers to an alkyl wherein one or more hydrogen atoms are replaced by fluorine atoms, e.g. difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2 -trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.

[0047] The term "haloalkenyl" refers to an alkenyl group, as defined herein, which is substituted with one or more halogen atoms.

[0048] The term "haloalkynyl" refers to an alkynyl group, as defined herein, which is substituted with one or more halogen atoms.

[0049] "Alkoxy" refers to an alkyl-O- group wherein alkyl is as defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "haloycycloalkoxy", and "halocycloalkenyloxy" refer to alkenyl-O-, alkynyl groups, respectively. -O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, haloycycloalkyl-O- and haloycycloalkenyl-O-, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl , cycloalkyl, cycloalkenyl, halogenocycloalkyl and halogenocycloalkenyl are as defined above. Examples of C groups₁-C₆-alkoxy include, but are not limited to, methoxy, ethoxy, C₂H₅CH₂O-, (CH₃)₂CHO-, n -utoxy, C₂H₅-CH (CH₃) O-, (CH₃)₂CH-CH₂O-, (CH₃)₃CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpenoxy, 3 -methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1 , 1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, etc.

[0050] "Aryl" refers to a monovalent aromatic carbocyclic group containing from 6 to 14 carbon atoms having a single ring or multiple condensed rings. In some embodiments, the aryl groups include C groups₆-C₁₀ aryl. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl and indanyl. Aryl groups can be unsubstituted or substituted by one or more groups selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloocycloalkyl, haloocycloalkenyl, alkoxy; , alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, haloocycloalkoxy, haloocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, haloocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl,

[0051] The term "aralkyl" ("aralkyl") refers to an aryl group that is bonded to the parent compound via a diradical alkylene bridge, (-CH₂-)_nwherein n is 1-12 and wherein "aryl" is as defined above.

[0052] "Heteroaryl" refers to a monovalent aromatic group containing from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, having one or more oxygen heteroatoms, nitrogen and sulfur in the ring, preferably from 1 to 4 heteroatoms or from 1 up to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple condensed rings, provided that the point of attachment is a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxaline, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl and benzothiophenyl.

[0053] "Heterocyclyl", "heterocyclic" or "heterocyclo" refer to fully saturated or unsaturated cyclic groups, e.g. 3 to 7 membered monocyclic or 4 to 7 membered monocyclic; 7 to 11 membered bicyclic or 10 to 15 membered tricyclic ring systems that contain one or more oxygen heteroatoms, sulfur or nitrogen in the ring, preferably from 1 to 4 or from 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more groups as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limited to, such groups as pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxo-azepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxotienyl, triazolyl, triazinyl etc.

Exemplary bicyclic heterocyclic groups include, but are not limited to, groups such as indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4 -oxoquinazolinyl), tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthroline, acridinyl, phenanthridinyl, xantenyl and the like.

[0057] Alkoxycarbonyl refers to -C (= O) -O-alkyl, wherein alkoxy is as defined above;

[0058] Halogen atom means fluorine, chlorine, bromine and iodine atoms. The designation "halo" (e.g. as illustrated in the haloalkyl term) refers to all degrees of substitution from a single substitution to a perhalo substitution (e.g. as exemplified by the substitution of a methyl group - chloromethyl (-CH)₂Cl), dichloromethyl (-CHCl 3₂), trichloromethyl (-CCl₃)).

Stereoisomers and polymorphic forms [0059] It will be appreciated by one of ordinary skill in the art that certain compounds in the compositions of the present invention may exist and be isolated in optically active and racemic forms. Compounds having one or more chiral centers, including those at a sulfur atom, may exist as single enantiomers or diastereoisomers or as mixtures of enantiomers and / or diastereoisomers. For example, it is well known in the art that sulfoxide compounds may be optically active and may exist as single enantiomers or as racemic mixtures. In addition, the compounds in the compositions of the invention may include one or more chiral centers that theoretically provide a number of optically active isomers.

PZ / 4348 / AGR EP2 552 201 B1 up to 2ⁿ optical isomers. The present invention includes specific enantiomers or diastereoisomers of each compound as well as mixtures of various enantiomers and / or diastereoisomers of the compounds of the present invention that possess useful properties as described herein. Optically active forms can be prepared e.g. by resolution of racemic forms using selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, chromatographic separation, using a chiral stationary phase or by enzymatic separation.

[0060] The compounds in the compositions of the present invention may also exist in various solid forms, such as different crystalline forms or in the form of an amorphous (amorphous) solid. The present invention includes various crystalline forms as well as amorphous forms of the compounds of the present invention.

[0061] Furthermore, the compounds in the compositions of the present invention may exist in the form of hydrates or solvates in which a stoichiometric amount of water or solvent is associated with the molecule in a crystalline form. The compositions of the present invention may include hydrates and solvates of the active agents.

Salts [0062] Also within the scope of the present invention are salts with the acids or bases of the compounds of the invention provided herein, respectively.

[0063] The term "acid" includes 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. The 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, these acids are saturated or unsaturated C₁-C₂₀ aliphatic straight or branched chain carboxylic acids which are optionally substituted by halogen or by hydroxy or C₆-C₁₂ aromatic carboxylic acids. Examples of such acids include carbonic acid, formic acid, acetic acid, propionic acid, isopropic acid, valeric acid, α-hydroxy acids, such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic 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 from 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 phenyl stearic acid.

[0064] The term "base" includes all pharmaceutically acceptable inorganic or organic bases, including metal hydroxides, carbonates or bicarbonates and alkali or alkaline earth metals. Salts formed with such bases include, for example, alkali metal salts and alkaline earth metal salts, including but not limited to lithium, sodium, potassium, magnesium salts or calcium salts. salts

PZ / 4348 / AGR formed with organic bases include salts of common hydrocarbon amines and heterocyclic amines which include, e.g. ammonium salts (NH4)⁺), alkyl and dialkylammonium salts and cyclic amine salts, such as morpholine salts and piperidine salts.

[0065] 1-arylpyrazoles as a class of chemicals are well known in the art and it has been found that certain compounds in this class are highly active against a wide range of pests and parasites that are harmful to animals and plants. For example, 1-arylpyrazole derivatives are known in the art for the prevention, treatment or control of infestation with external parasites in mammals, such as cats, dogs and cattle. Certain 1-arylpyrazoles and their use against pests are described in published U.S. Pat. Ser. US Pat. No. 2008/0132487 and US 2008/0031902; in US Pat. Ser. U.S. Patent No. 4,963,575; US 5,122,530; US 5,232,940; US 5,236,938; US 5,246,255; US 5,547,974; US 5,567,429; US 5,576,429; US 5,608,077; US 5,714,191; US 5,814,652; US 5,885,607; US 5,567,429; US 5,817,688; US 5,885,607; US 5,916,618; US 5, 922.885; US 5,994,386; US 6,001,384; US 6,010,710; US 6,057,355; US 6,069,157; US 6,083,519; US 6,090,751; 6,096,329; 6,124,339; 6,180,798; 6,335,357; 6,350,771; 6,372,774; 6,395,906; 6,413,542; 6,685,954; and US 7,468,381, US 7,517,877 and US 7,514,561; and in European published patents EP 0 234 119, EP 0 295 117, EP 0 352 944, EP 0 500 209, EP 0 780 378, EP 0 846 686 and EP 0 948 485.

[0066] The compounds of the families defined in these patents are very active and one of these compounds, 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfinylpyrazole or fipronil, is particularly effective against pests, including fleas and ticks.

[0067] The present invention relates to compositions that comprise at least one 1-arylpyrazole compound of formula (I):

<img file="PL2552201T3_D0004.tif" />

wherein:

R₁ is hydrogen, cyano, nitro, halogen, R₃, R₈, formyl, -C (O) R₈, -C (O) OR₈, C (O) NR₉R₁₀, -C (= NOH) NH₂, -C (-NNH₂) R₉ or -C (S) NH₂;

R₂ means R₈, halogen, cyano, nitro, -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁;

R₃ is hydrogen, halo, alkyl, haloalkyl, OH, OR₈, S (O)_mR₁₁, -C (O) R₈, C (O) OR 8, NR 9 R 10, -N = C (R 9) (R 14), -N = C (R 10) -Z- (R 9), -N = C (R 10) -NR 9 R 10, -N (R 8) - C (R 10) = NR 9, N (R.₁₁) C (O) CR₁₅R₁₀R₁₁, -N (R.₁₁) C (O) aryl, -N (R₁₁) C (O) heteroaryl or -N (R.₁₁) C (O) OR₁₀;

R₄, R₅ and R₇ independently are hydrogen, halo, alkyl, haloalkyl, cyano or nitro;

PZ / 4348 / AGR EP2 552 201 B1

R₆ halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, -C (O) R₁₂, S (O) nR12 or SF5;

X is a nitrogen or CR₁₃;

Z is O, S (O)_m or NR₉R₈ is alkyl or haloalkyl;

R₉ is hydrogen, alkyl, haloalkyl, or alkoxy;

R₁₀ is hydrogen, alkyl, haloalkyl, alkoxy or -C (O) R₈;

R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxyalkyl or haloalkoxyalkyl;

R₁₂ is alkyl or haloalkyl;

R₁₃ is hydrogen, halo, cyano, nitro, alkyl, haloalkyl, alkoxy or haloalkoxy;

R₁₄ is optionally substituted aryl or optionally substituted heteroaryl;

R₁₅ is hydrogen, halo, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, formyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino, di (haloalkyl) amino, aryloxy or aralkoxy;

wherein said alkyl, haloalkyl, and alkoxy groups are optionally substituted with alkyl, haloalkyl, alkoxy, aryl or heteroaryl; said aryl or heteroaryl groups are optionally substituted with one or more groups, such as alkyl, haloalkyl, aryl, halogen,

C (O) R₈, -C (O) OR₈, -C (O) NR₉R₁₀, -C (S) NH₂ or -S (O)_mR₁₁ m is 0, 1 or 2; and n is 0, 1 or 2; or a pharmaceutically acceptable salt, hydrate or solvate thereof;

in combination with at least one macrocyclic lactone as an active agent, at least one IGR compound and at least one anthelmintic compound or pharmaceutically acceptable salts, hydrates or solvates thereof together with a pharmaceutically acceptable carrier or diluent as defined above.

[0068] In one embodiment, the invention provides a composition that comprises 1-arylpyrazole of formula (I) wherein R₁ means cyano, -C (O) R₈, -C (O) OR₈, -C (O) NR₉R₁₀, -C (= NOH) NH₂, C (= NNH₂) R₉ or -C (S) NH₂ and all other variables have the meanings defined above.

[0069] In another embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein R₃ is alkyl or haloalkyl.

[0070] In one embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano, -C (O) R₈, -C (O) OR₈, -C (O) NR₉R₁₀, -C (= NOH) NH₂, -C (= NNH₂) R₉, or-C (S) NH₂; and

R₂ means -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁.

[0071] In another embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano, -C (O) R₈, -C (O) OR₈, -C (O) NR₉R₁₀, -C (= NOH) NH₂, -C (= NNH₂) R₉, or-C (S) NH₂;

R₂ means -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁; and

R₃ is alkyl, haloalkyl, or NR₉R₁₀.

In another embodiment, the invention relates to a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁; and

R₃ means -N = C (R.₉) (R₁₄), -N = C (R.₁₀) -Z- (R₉), -N = C (R.₁₀) -NR₉R₁₀, -N (R.₈) -C (R₁₀) = NR₉.

In another embodiment, the invention relates to a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁; and

R₃ means -N (R.₁₁) C (O) CR₁₅R₁₀R₁₁, -N (R.₁₁) C (O) aryl, -N (R₁₁) C (O) heteroaryl or -N (R.₁₁) C (O) OR₁₀. [0074] In yet another embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁;

R₃ is alkyl, haloalkyl, or NR₉R₁₀;

R₄, R₅ and R₇ independently are hydrogen or halogen; and

X is CR₁₃.

[0075] In another embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -SCN, 4-5-dicyanoimidazol-2-yl or -S (O)_mR₁₁;

R₃ means C₁-C₄alkyl or C₁-C₄haloalkyl;

R₆ is halogen, haloalkyl, or SF₅; and

X is CR₁₃.

[0076] In one embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -S (O)_mR₁₁;

R₃ means C₁-C₄alkyl, C₁-C₄haloalkyl, or NR₉R₁₀;

R₄, R₅ and R₇ independently are hydrogen or halogen;

R₆ is halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, or SF5;

PZ / 4348 / AGR EP2 552 201 B1

X is CR₁₃; and

R₁₃ is halogen or C₁-C₄haloalkyl.

[0077] In another embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -S (O)_mR₁₁;

R₃ means -NH₂;

R₄, R₅ and R₇ independently are hydrogen or halogen;

R₆ means C₁-C₄alkyl, C₁-C₄haloalkyl, or SF₅;

X is CR₁₃; and

R₁₃ is hydrogen or halogen.

[0078] In yet another embodiment of the composition, a 1-arylpyrazole of formula (I) is provided wherein:

R₁ means cyano;

R₂ means -S (O)_mR₁₁;

R₃ means methyl, ethyl, propyl or C₁-C₄ haloalkyl;

R₄ is halogen;

R₅ and R₇ are hydrogen;

R₆ means C₁-C₄haloalkyl;

X is CR₁₃;

R₁₁ means -CF₃, -CClF₂ or CFCl₂; and

R₁₃ is halogen.

[0079] In yet another embodiment, the invention provides a composition comprising a 1-arylpyrazole of formula (I) wherein:

R₁ means cyano;

R₂ means -S (O)_mR₁₁;

R₃ means methyl or ethyl;

R₄ is a chlorine atom or a fluorine atom;

R₅ and R₇ are hydrogen;

R₆ means -CF₃;

X is CR₁₃;

R₁₁ means -CFCl₂ or CF₃; and

R₁₃ means a chlorine atom or a fluorine atom.

In another embodiment, the invention relates to a composition comprising a 1-aralkyl or a 5-haloalkylpyrazole of formula (IA) as shown below:

VP / 4348 / AGR

EP2 552 201 B1

<img file="PL2552201T3_D0005.tif" />

or its salt, in which:

R2a is -S (O) mR11a;

R_3a means methyl, ethyl or C₁-C₄ haloalkyl;

R_4a is halogen;

R_6a means C₁-C₄alkyl or C₁-C₄haloalkyl;

R_13a is halogen;

R_11a means C₁-C₄ haloalkyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt, hydrate or solvate thereof; in combination with at least one macrocyclic lactone as an active agent, at least one IGR compound and at least one anthelmintic compound or pharmaceutically acceptable salts, hydrates or solvates thereof together with a pharmaceutically acceptable carrier or diluent as defined above.

[0081] Compounds of formula (IA) as well as methods for the preparation of these compounds are described in US Patent Ser. US 2008/0031902 A1 and US Pat. Ser. No. 7,759, 381, Lee et al., Which are incorporated herein by reference in its entirety.

In another embodiment, the invention provides a composition that comprises a 1-aryl-5-alkylpyrazole compound of formula (IA), wherein:

R2a is -S (O) mR11a;

R_3a means methyl or ethyl;

R_4a is halogen;

R_6a means C₁-C₄ haloalkyl;

R_13a is halogen;

R_11a means -CF₃, -CClF₂ or -CFCl₂; and m is 0, 1 or 2.

In another embodiment, the invention provides a composition that comprises a 1-aryl-5-alkylpyrazole compound of formula (IA), wherein:

R2a is -S (O) mR11a;

PZ / 4348 / AGR EP2 552 201 B1

R_3a means methyl or ethyl;

R_4a is halogen;

R_6a means C₁-C₄ haloalkyl;

R_13a is halogen;

R_11a means -CF₃, -CClF2 or -CFCl₂; and m is 0, 1 or 2.

[0084] In yet another embodiment of the invention, there is provided a composition that comprises a 1-aryl-5-alkyl-pyrazole compound of formula (IA), wherein:

R2a is -S (O) mR11a;

R_3a means methyl;

R_4a means -Cl;

R_6a means -CF₃;

R_13a means -F;

R_11a means -CFCl₂ or CF₃; and m is 0, 1 or 2.

[0085] In a preferred embodiment, the invention provides compositions for treating or preventing parasitic infections or infections in an animal comprising at least one 1-axiarazole compound, at least one macrocyclic lactone as an active agent, at least one IGR, and at least one anti-worm compound together. with a pharmaceutically acceptable carrier as defined above in which the 1-arylpyrazole compound is 1- [2,6-dichloro-4-trifluoromethyl-phenyl] -3-cyano-4-trifluoromethylsulfinyl-5-aminopyrazole, which is also known as fipronil.

[0086] Macrocyclic lactone compounds are also well known in the art and can be obtained commercially or using known synthetic techniques. In the case of avermectins, ivermectin and abamectin, reference can be made, for example, to the publication of "Ivermectin and Abamectin", 1989, MH Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag., "Macrocyclic Lactones in Antiparasitic Therapy", 2002, J Vercruysse and RS Rew, published by CABI Publishing or AlbersSchanberg et al. (1981), "Avermectins Structure Determination", J. Am. Chem. Soc., 103, 4216-4221. In the case of doramectin, one can consult the publication "Veterinary Parasitology", volume 49, No. 1, July 1993, 5-15. In the case of milbemycin, one can refer, among others, to Davies HG 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, US Pat. Ser. No. 4,134,973 and European Patent No. EP 0 677 054.

[0087] Macrocyclic lactones include natural products or their semi-synthetic derivatives. The structures of avermectins and milbemycins are closely related, e.g. by dividing a complex 16-membered macrocyclic lactone ring; whereby milbemycins do not have a glycosidic group like avermectin. Natural avermectin products are disclosed in US Patent Ser. U.S. Patent No. 4,310,519, Albers-Schonberg et al. and 22, 23-dihydroavermectin compounds are disclosed in Chabala et al., description

Patent pending. Ser. U.S. Pat. No. 4,199,569. Mention has also been made, inter alia, to Kitano, US Pat. Ser. No. 4,468,390, Beuvry et al., US Pat. Ser. No. 5,824,653, European Patent Specification EP 0 007 812 A1, British Patent Specification UK 1 390 336, European Patent Specification EP 0 002 916 and Ancare in New Zealand Patent Specification No. 237,086. Milbemycins found in nature are described in Aoki et al. Patent description Ser. US 3,950,360, as well as various references cited in The Merck Index, 12th edition, S. Budavari, ed., Merck &amp; Co., Inc. Whitehouse Station, New Jersey (1996). Latideectin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, Vol. 17, No. 4, pp. 263- 286, (2003). Semi-synthetic derivatives of compounds of this class are well known in the art and described, e.g. in U.S. Pat. Ser. No. 5,077,308, in US Pat. Ser. No. 4,859, 6657, in U.S. Pat. Ser. No. 4,963,582, in U. S. Patent No. 4,963,582. Ser. No. 4,855,317, in U. S. Patent Ser. No. 4,871,719, in U.S. Pat. Ser. No. 4,874,749, in U.S. Pat. Ser. No. 4,427,663, in U. S. Patent Ser. U.S. Patent No. 4,310,519, in U.S. Pat. Ser. U.S. Pat. No. 4,199,569, in U.S. Pat. Ser. No. 5,055,596, in US Pat. Ser. No. 4,973,711, in U. S. Patent No. 4,973,711. Ser. No. 4,978, 677, in U.S. Pat. Ser. U.S. Patent No. 4,920,

[0088] Compositions of the present invention include at least one 1-arylpyrazole compound in combination with at least one avermectin or milbemycin compound, at least one IGR compound, and at least one antiviral active agent as defined above. Avermectin and milbemycin active agents include, but are not limited to, such as abamectin, dimadeectin, doramectin, emamectin, eprinomectin, ivermectin, latideectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin or nemadectin or mixtures of these active agents.

[0089] Agents of the acaricidal or insecticidal class known as insect growth regulators (IGRs) are well known in the art and represent a wide range of different chemical classes. The IGR compounds preferably form part of the composition of the present invention, providing better anti-parasitic efficacy. All these compounds act by interfering with the development or growth of harmful insects. For example, certain IGR compounds act by blocking the development of immature stages (eggs and larvae) to adult stages or by inhibiting chitin synthesis. Certain compounds in the IGR class mimic juvenile hormones. Insect growth regulators are described, e.g. in US Pat. Ser. U.S. Patent No. 3,748,356; in St. Ser. U.S. Patent No. 3,818,047; in St. Ser. U.S. Pat. No. 4,225,598; in St. Ser. U.S. Patent No. 4,798,837; in St. Ser. No. 4,751,225, EP 0 179 022 or UK Patent No. 2 140 010, as well as in US Pat. Ser. US 6,096,329 and US 6,685,954. Compositions of the invention include at least one IGR selected from (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron and novaluron.

[0090] In certain preferred embodiments, the compositions of the present invention include a metoprene comprising (S) -methoprene, pyriproxyfenes, hydropren, cyromazine and lufenuron.

[0091] Various types of anti-worm agent (in addition to one or more macrocyclic lactones) may be used in the compositions of the present invention.

[0092] The compositions of the invention also include at least one anti-worm agent as an active agent selected from the following: thiabendazole, oxybendazole, mebendazole, fenbendazole, oxfendazole, albendazol, triklabendazol, febantel, levamizol, pyrantel, morantel, praziquantel, closantel, clorsulon, aminoacetonitrile agent active and arylazol-2-ilo-cyanoethylamine active. [0093] In yet another embodiment, the invention provides a composition comprising at least one 1-arylpyrazole of formula (I):

<img file="PL2552201T3_D0006.tif" />

in which R₁ means cyano;

R₂ means -S (O)_mR₁₁;

R₃ means NR₉R₁₀;

R₄, R₅ and R₇ independently are hydrogen or halogen;

R₆ means C₁-C₄-haloalkyl, or SF₅;

X is CR₁₃;

R₁₁ means C₁-C₄-alkyl or C₁-C₄-haloalkyl;

[0094] R₁₃ is halogen; and R₉ and R₁₀ they have the meanings defined above for formula (I); in combination with at least one of the following eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novhaurone; and at least one of the following agents thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triblabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, aminoacetonitrile such as monepantel or an aryl azole-2-isocyanatoethylamine compound such as N- [2- (6-bromo-2H-pyrazolo [4,3-b] pyridin-2-yl) -2-cyano-2metyloetylo] -4-trifluoromethoxy-benzamide; in combination with a pharmaceutically acceptable carrier or diluent,

[0095] In yet another embodiment, the invention provides a composition comprising at least one 1-arylpyrazole of formula (I):

VP / 4348 / AGR

EP2 552 201 B1

<img file="PL2552201T3_D0007.tif" />

in which R₁ means cyano;

R₂ means -S (O)_mR₁₁;

R₃ means NR₉R₁₀;

R₄, R₅ and R₇ independently are hydrogen or halogen;

R₆ means C₁-C₄-haloalkyl, or SF5;

X is CR₁₃;

R₁₁ means C₁-C₄-alkyl or C₁-C₄-haloalkyl;

[0096] R₁₃ is halogen; and R₉ and R₁₀ they have the meanings defined above for formula (I); in combination with at least one of the following eprinomectin, ivermectin, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen or lufenuron; and at least one of the following febantel, levamisole, pyrantel or praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

In another embodiment, the invention provides a composition comprising a 1-aralkyl or a 5-haloalkylpyrazole of formula (IA) as shown below:

<img file="PL2552201T3_D0008.tif" />

or its salt, in which:

R2a is -S (O) mR11a;

R_3a means methyl, ethyl or C₁-C₄ haloalkyl; R_4a is halogen;

R_6a means C₁-C₄ alkyl or haloalkyl;

PZ / 4348 / AGR EP2 552 201 B1

R_13a is halogen;

R_11a means C₁-C₄ haloalkyl; and m is 0, 1 or 2; in combination with at least one of the following eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novhaurone; and at least one of the following thiabendazole, oxybendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, aminoacetonitrile such as monepantel, an amiZol-2-ilo cyanethylamine compound such as N- [2- (6-bromo2H-pyrazolo [4,3-b] pyridin-2-yl) -2-cyano-2-methylethyl] -4-trifluoromethoxybenzamide; in combination with a pharmaceutically acceptable carrier or diluent,

In another embodiment, the invention provides a composition comprising a 1-aralkyl or a 5-haloalkylpyrazole of formula (IA) as shown below:

<img file="PL2552201T3_D0009.tif" />

or its salt, in which:

R2a is -S (O) mR11a;

R_3a means methyl or ethyl;

R_4a is halogen;

R_6a means C₁-C₄ haloalkyl;

R_13a is halogen;

R_11a means -CF₃, -CClF2 or -CFCl₂; and m is 0, 1 or 2; in combination with at least one of the following eprinomectin, ivermectin, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen or lufenuron; and at least one of the following febantel, levamisole, pyrantel or praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0099] In another embodiment, the invention provides a composition comprising a 1-aralkyl or a 5-haloalkylpyrazole of formula (IA) as shown below:

VP / 4348 / AGR

EP2 552 201 B1

<img file="PL2552201T3_D0010.tif" />

or its salt, in which:

R2a is -S (O) mR11a;

R_3a means methyl;

R_4a means -Cl;

R_6a means -CF₃;

R_13a means -F;

R_11a means -CFCl₂ or CF₃; and m is 0, 1 or 2; in combination with at least one of the following eprinomectin, ivermectin, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen or lufenuron; and at least one of the following febantel, levamisole, pyrantel or praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0100] In a preferred embodiment, the invention provides a composition comprising 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethylsulphinylpyrazole (fipronil) in combination with at least one of the following eprinomectin, ivermectin , selamectin, milbemectin, milbemycin D, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novhaurone; and at least one of the following thiabendazole, oxybendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triblabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, aminoacetonitrile such as monepantel, an arylazol-2-cyanoethylamine compound such as N- [2 - (6-bromo-2H-pyrazolo [4, 3-b] pyridin-2-yl) -2-cyano-2-methylethyl] -4trifluorometoksybenzamid; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0101] In another preferred embodiment, the invention provides a composition comprising 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethylsulphinylpyrazole (fipronil) in combination with at least one of the following eprinomectin, ivermectin, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novhaurone; and at least one agent out of

The following albendazole, triclabendazole, levamisole, pyrantel or praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0102] In yet another preferred embodiment, the invention provides a formulation comprising amino-3- (cyclo-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethylsulphinylpyrazole) (fipronil) in combination with at least one of the following eprinomectin , ivermectin, milbemycin oxime or moxidectin; at least one of the following (S) -methoprene, pyriproxyfen, lufenuron or novaluron; and at least one of the following levamisole, febantel, pyrantel or praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0103] In another preferred embodiment, the invention provides a composition comprising 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethylsulphinylpyrazole (fipronil) in combination with at least one of the following eprinomectin, ivermectin, milbemycin oxime or moxidectin; (S) -metopren; and at least one of the following febantel, pyrantel or praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0104] In yet another preferred embodiment, the invention provides a composition comprising 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulphinylpyrazole (fipronil) in combination with at least one of the following eprinomektyna ivermectin or milbemycin oxime; (S) -metopren; and praziquantel; in combination with a pharmaceutically acceptable carrier or diluent as defined above.

[0105] It has surprisingly been found that compositions of the invention that contain at least four different active agents in a carrier system that is compatible with each active agent are stable and effective against a broad spectrum of parasites and internal parasites. It will be obvious to those skilled in the art that the combination of many active agents in a single composition without affecting the stability of the active agents during storage or the effectiveness of each active agent after administration is very difficult and unpredictable. The four classes of active agents contained in the compositions of the present invention have significantly different structures and consequently different solubility and durability requirements. The introduction of many active agents into a single preparation is a significant problem, especially for formulations that require four active agents to be in solution, such as in spot-on or pour-on formulations. The solubility, logP, molecular weight and other physical properties of each active agent in the carrier system affect the ability to deliver the drug to the animal's hair or to penetrate the skin as required. Identification of a suitable carrier system that will dissolve each active agent into a stable solution, and at the same time be capable of delivering active agents to the target position on the animal at the desired concentration is a very difficult task and is not predictable or obvious. the molecular weight and other physical properties of each active agent in the carrier system affect the ability to deliver the drug to the animal's hair or to penetrate the skin as required. Identification of a suitable carrier system that will dissolve each active agent into a stable solution, and at the same time be capable of delivering active agents to the target position on the animal at the desired concentration is a very difficult task and is not predictable or obvious. the molecular weight and other physical properties of each active agent in the carrier system affect the ability to deliver the drug to the animal's hair or to penetrate the skin as required. Identification of a suitable carrier system that will dissolve each active agent into a stable solution, and at the same time be capable of delivering active agents to the target position on the animal at the desired concentration is a very difficult task and is not predictable or obvious.

[0106] Furthermore, the identification of a suitable carrier system to produce a stable composition comprising four different classes of active agents is a challenge and is not self-evident.

[0107] It is well known in the art that it is very difficult to form macrocyclic lactones as active agents together with some other active agents due to different requirements

PZ / 4348 / AGR EP 2 552 201 B1 and the sensitivity of macrocyclic lactones to degradation in certain solvents. Avermectins and milbemycins are poorly water-soluble and are not compatible with acidic conditions, while certain anthelmintics, such as levamisole, are more soluble in water and require an acidic pH for optimal stability (see US Pat. No. 2006 / 0128641 A1). For example, international patent application No. WO00 / 74489 describes liquid compositions comprising a macrocyclic lactone and another anti-worm agent (levamisole), which compositions contain separate phases that contain various active agents to meet various solubility and stability requirements of each active agent. In U.S. Patent Ser. No. 6,489,303 to Jancys, Jancys et al. it was described that mixtures of the macrocyclic lactone and other insoluble anti-worm agents resulted in an increase in the degradation rate of the macrocyclic lactone as an active agent, requiring the addition of an excess of antioxidant to stabilize the mixture. Thus, a combination of four active agents, including a macrocyclic lactone, in a single liquid composition that is both stable for a prolonged period of time and effective against a broad spectrum of parasites and internal parasites is a significant achievement in the field of veterinary medicine that is not predictable or obvious . requiring the addition of an excess of antioxidant to stabilize the mixture. Thus, a combination of four active agents, including a macrocyclic lactone, in a single liquid composition that is both stable for a prolonged period of time and effective against a broad spectrum of parasites and internal parasites is a significant achievement in the field of veterinary medicine that is not predictable or obvious . requiring the addition of an excess of antioxidant to stabilize the mixture. Thus, a combination of four active agents, including a macrocyclic lactone, in a single liquid composition that is both stable for a prolonged period of time and effective against a broad spectrum of parasites and internal parasites is a significant achievement in the field of veterinary medicine that is not predictable or obvious .

[0108] The compositions of the present invention combine active agents that are effective against both intrinsic parasites and external parasites. For example, 1-arylpyrazole and IGR compounds such as fipronil and metoprene are active against fleas and ticks on the coat of an animal, where fleas and ticks are contacted with these compounds. In contrast, macrocyclic lactones and anthelmintic compounds exert their action against intestinal parasites such as parasitic worms by systemic (systemic) exposure. Since the excipient carrier in the composition has a major impact on the distribution of active agents in the animal, it is very problematic to achieve a formulation containing a combination of active agents, which require systemic or local exposure to achieve the desired efficiency against both internal parasites and external parasites in one liquid carrier system. Thus, 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 long-term efficacy against external parasites, such as fleas and ticks, while effectively controlling intestinal parasites such as Dirofilaria immitis (nematode in the heart), roundworms and other parasitic worms. The compositions of the invention surprisingly achieve the required distribution of an effective amount of each particular active agent to the animal site required to achieve excellent efficacy against the harmful internal parasites and external parasites shown in the examples. In particular, excellent efficacy against Dirofilaria immitis (nematode in the heart), roundworms including T. cati, tapeworms including D. caninum and hookworms including A. tubaeforme, along with long-term efficacy against fleas and ticks is noteworthy and unique.

[0109] It is well known that active agents that are macrocyclic lactones and antiviral active agents must be absorbed into the blood stream to be effective against intestinal parasites. As such, preparations aimed at the treatment and control of internal parasites typically

PZ / 4348 / AGR include strong solvents and / or penetration enhancers that can interrupt the functional barrier of the stratum corneum to allow active agents to enter the bloodstream. Examples of solvents having this property include, but are not limited to, dimethyl sulfoxide and dimethyl isosorbide. Penetration enhancers include compounds having a polar head and long alkyl chains, inter alia, such as nonionic surfactants, oleic acid, decylmethyl sulfoxide and Azone.

[0110] However, this approach is not suitable for use with active agents such as 1-arylpyrazole or IGR active agents that must be present in effective concentrations on the surface (coat, coat) of the animal to be effective against external parasites, such as like fleas and ticks, because excessive passage of these active agents into the bloodstream would reduce the effectiveness against external parasites that occur on the surface of the animal. In addition, it is well known that high concentrations of certain arylpyrazoles in the bloodstream can lead to deleterious effects. Thus, the use of solvents or penetration enhancers,

[0111] It has surprisingly been found that the topical compositions of the present invention are capable of both effective percutaneous penetration of macrocyclic lactone and active agents against worms, while maintaining effective amounts of 1-arylpyrazole and IGR as active agents on the surface of the animal. This result is unexpected, as it would be expected that the use of solvents, which are known to act as penetration enhancers, would rather also carry larger proportions of 1-arylpyrazole and

IGR as an active agent for the circulatory system rather than maintaining effective concentrations of the active agent against external parasites on the surface of the animal. By achieving effective concentrations of all active agents at the desired site of the animal, the compositions of the present invention are capable of effectively controlling both internal parasites and external parasites.

[0112] In a preferred embodiment of the composition according to the invention, the composition will be in the form of a liquid solution or suspension.

[0113] The carrier comprises glycerol formal. Formal glycerol 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 an alcohol group . Formal glycerol is a solvent with low odor and low toxicity for a wide range of applications in the pharmaceutical and cosmetics industries, including antiparasitic veterinary preparations.

[0114] The vehicle also contains dimethyl isosorbide. Dimethyl isosorbide (DMI) is a solvent and carrier of high purity that provides a safe, effective mechanism for enhancing the delivery of active ingredients in personal care products and preparations

Pharmaceutical. Pharmaceutical. In addition, dimethyl isosorbide is sometimes used as a means of enhancing epidermal penetration to obtain increased penetration of active agents into the epidermis. It can also provide delivery of active agents to the skin, while preventing the crystallization of the active agent, which will seriously limit the effectiveness of the preparation. Dimethyl isosorbide is soluble in various components 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).

[0115] Dyes may be added to the formulations of the invention. The dyes considered by the present invention include those commonly known in the art. Specific dyes include, for example, dyes, FD &amp; C Blue # 1 Aluminum Lake, caramel, an iron oxide-based dye or a mixture of any of the above. Organic dyes and titanium dioxide are particularly preferred. Preferred ranges include from about 0.5% to about 25%.

[0116] The compositions of the present invention are intended for topical administration to an animal. The topical application of the compositions of the present invention can be made possible for the delivery of active agents and their distribution in the sebaceous glands of an animal or coat and / or allows certain active agents to achieve a systemic effect (blood plasma concentration). When the compound is distributed in the sebaceous glands, sebaceous glands can act as a reservoir, so that you can get a long-lasting, eg 1-2-month effect or longer.

Cotchet et al. Described the distribution of fipronil, a 1-arylpyrazole compound in the stratum corneum, living epidermis and sebaceous glands and beagle epithelial layers after spot-on administration (see Cochet et al., Eur. J. Drug Metab. Pharmacokinet., 1997, 22 (3), 211-216). Using radiologically marked drug 14¹⁴C, the publication shows that fipronil is moved from the application site and distributed to the entire skin, where it was continuously detected up to 56 days after treatment.

[0117] The compositions of the present invention are in the form of a spot-on preparation (for spot-on) that is applied to the localized surface on the animal rather than to the entire animal's fur or a large part of the animal's fur. In one solution of the localized area, it is located between the arms (vanes). The spot-on formulation of the present invention provides a long-term and broad-spectrum efficacy against external parasites and internal parasites when the solution is used in a mammal or bird. The spot-on formulations provide a concentrated solution for topical administration, for intermittent use to the spot on the animal, generally between the two arms (spot-on solution).

[0118] Spot-on (dripping) formulations are well-known techniques for locally delivering an antiparasitic agent to a limited host area. For example, patents St. Ser. U.S. Patent No. 5,045,536; US 6,426,333; US 6,482,425; US 6,962,713; and US 6,998,131, describe spot-on formulations. International patent application No. WO01 / 957715, describes a method for controlling parasites external to small rodents, as well as interfering with or preventing arthropod diseases in small rodents, which comprises applying a topical formulation, such as spot-on compositions, to the skin or fur rodents. In the case of spot-on formulations, a pharmaceutically acceptable carrier may be a liquid vehicle carrier as described herein and other carriers described in the art,

Patent Pending. Ser. US Patent No. 6,426,333. In some embodiments, the liquid vehicle carrier may optionally contain a crystallization inhibitor such as crystallization inhibitors described below, or mixtures thereof, to inhibit the formation of crystals or precipitation of active ingredients.

[0120] The veterinary acceptable carrier will generally contain a diluent or excipient in which the active agents are soluble. It will be apparent to those skilled in the art that the carrier or diluent of the topical composition must be capable of delivering the active agents to the target site without precipitating the active agents from solution or crystal formation. In some embodiments, the carrier or diluent of the composition will be suitable to avoid the precipitation or crystallization of the active agents. In other embodiments, in addition to the carrier or diluent, the compositions may include a crystallization inhibitor.

[0121] Compositions for topical administration include formal glycerol and dimethyl isosorbide.

[0122] Spot-on preparations (for spot-on instances), described e.g. in US Pat. Ser. No. 7,262,214, can be prepared by dissolving active ingredients in a pharmaceutically or veterinarily acceptable excipient. Alternatively, the spot-on preparation can be prepared by coating the active ingredients to leave a therapeutic agent residue on the surface of the animal. These formulations will vary with respect to the weight of the therapeutic agent in combination depending on the species of host animal to be treated, the severity and type of infection, and the host's weight.

[0123] Typically, the 1-arylpyrazole active agent (active agents) is present in the formulation at a concentration of about 1 to about 25% (w / v (weight / volume)). In certain embodiments of the invention, the 1-arylpyrazole active agent (s) is present in the formulation at a concentration of about 1 to about 20% or about 5 to about 15% (w / v). In yet another embodiment of the invention, the 1-arylpyrazole active agent (active agents) is present in the formulation at a concentration of about 8-12% (w / v).

[0124] Typically, the formulations of the present invention will comprise from about 0.01 to about 10% (w / v) of the macrocyclic lactone as the active agent (active agents). More typically, the formulations will contain from about 0.01 to about 5% or from about 0.01% to about 2% (w / v) of the macrocyclic lactone as an active agent (active agents). Preferably, the formulations will contain from about 0.1 to about 5% or from about 0.1 to about 1% (w / v) of the macrocyclic lactone as active agent (active agents).

[0125] New and innovative formulations will typically contain from about 1 to about 30% (w / v) of at least one IGR compound. In other embodiments, the formulations will contain from about 1 to about 20% (w / v), about 5 to about 15% (w / v) of one or more IGR compounds. More typically, the active agent is present in the formulation at a concentration of about 8-12% (w / v).

[0126] The amount of worm active in the formulations of the present invention will typically be from about 1 to about 30% (w / v). More typically, the formulations will contain from about 1 to about 20% (w / v), about 5 to about 15% (w / v), or from about 8 to about 12% (w / v).

[0127] In one embodiment, the formulations of the present invention will comprise from about 5 to about 15% of at least one 1-arylpyrazole (1-arylpyrazole), from about 0.01 to about 5% at least

PZ / 4348 / AGR of one macrocyclic lactone (macrocyclic lactones), from about 5 to about 15% (w / v) of at least one active IGR agent (active IGR agents) and from about 5 to about 15% (w / v) at least one antiviral active agent (active agents).

[0128] In yet another embodiment, the compositions of the present invention will comprise from about 5 to about 15% (w / v) of at least one 1-arylpyrazole (1-arylpyrazole), from about 0.01 to about 2% ( w / v) at least one agent from the following eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime or moxidectin; from about 5 to about 15% (w / v) of at least one of the following (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novhaurone; and from about 5 to about 15% (w / v) of at least one of the following thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, triclabendazole, febantel, tetramisole, levamisole, pyrantel , morantel, praziquantel,

[0129] In a preferred embodiment, the compositions of the present invention comprise from about 5 to about 15% (w / v) of fipronil, from about 0.01 to 2% (w / v) of at least one of the following eprinomectin , ivermectin, milbemycin oxime or moxidectin; from about 5 to about 15% (w / v) of at least one of the following (S) -methoprene, pyriproxyfen or lufenuron; and from about 5 to about 15% (w / v) of at least one of the following febantel, levamisole, pyrantel or praziquantel. In another preferred embodiment, the compositions of the present invention will comprise from about 8 to about 12% (w / v) of fipronil, from about 0.1 to about 1% (w / v) of at least one of the following eprinomectin , ivermectin, milbemycin oxime or moxidectin; from about 8 to about 12% (w / v) ) at least one of the following (S) -methoprene, pyriproxyfen or lufenuron; and from about 8 to about 12% (w / v) of at least one of the following febantel, levamisole, pyrantel or praziquantel.

[0130] In certain embodiments of the invention, a softening agent and / or a spreading agent and / or a film former may be added to the topical compositions of the invention. In certain embodiments, a softening agent and / or a spreading agent and / or film-forming agents include:

(a) poly (vinylpyrrolidone), poly (vinyl alcohols), copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylated sorbitol esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane oils (PDMS)), e.g. those containing silanol functional groups or 45V2 oil, (b) anionic surfactants, such as alkaline stearates, sodium, potassium stearates or ammonium; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (e.g., sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids (e.g. those derived from coconut oil), (c) cationic surfactants,⁺R'R "R" 'R "" Y^-wherein the radicals R are optionally hydroxylated radicals

PZ / 4348 / AGR hydrocarbons and Y^- is a strong acid anion such as a halogen anion, a sulphate anion and a sulfonate anion; Cetyltrimethylammonium bromide is one of the cationic surfactants that can be used, (d) Amine salts of Formula N⁺ R'R "R" 'wherein the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants that can be used, (e) non-ionic surfactants, such as sorbitol esters, which are optionally polyoxyethylated (e.g., polysorbate 80), polyoxyethylene alkyl ethers; polyoxypropylated fatty alcohols, such as polyoxypropylene-styrene ether; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, (f) amphoteric surfactants, such as lauryl-substituted betaine compounds, and (g) a mixture of at least two of these funds.

[0131] In one embodiment, the softening agent is used in a proportion of about 0.1 to about 10% or from about 0.25 to about 5% (w / v).

[0132] In one embodiment of the present invention, the composition may be in the form of a ready-to-use solution as described, e.g. in U.S. Pat. Ser. No. 6,395,765, which is incorporated herein by reference. In addition to the active agents, the ready-to-use solution may contain a carrier or diluent, including an organic solvent (organic solvents) and a crystallization inhibitor.

[0133] In certain embodiments, the crystallization inhibitor may be present in a proportion of about 1 to about 30% (w / v). Typically, the crystallization inhibitor may be present in a proportion of about 1% to about 20% (w / v) or from about 5% to about 15% (w / v). Acceptable inhibitors include those that when added to the formulation inhibit the formation of crystals of the active agents when the formulation is in use. In certain embodiments, the formulations may contain compounds that act as crystallization inhibitors other than those specified herein. In these embodiments, the suitability of the crystallization inhibitor can be determined by testing whether it will sufficiently inhibit the formation of crystals such that a sample containing 10% (w / v) 1-arylpyrazole in a solvent as described above with 10% (w / v).

[0134] Crystallization inhibitors that are useful for the invention include, but are not limited to, the following:

(a) poly (vinylpyrrolidone), poly (vinyl alcohols), copolymers of vinyl acetate and vinyl pyrrolidone, 2-pyrrolidone comprising N-methylpyrrolidone, dimethyl sulfoxide, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylated sorbitol esters; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as polymers derived from acrylic monomers including polyacrylates or polymethacrylates; and, a solvent as described herein that inhibits the crystallization of the active agent and similar compounds;

(b) anionic surfactants, such as alkaline stearates (e.g. sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include, but are not limited to, such as sodium lauryl sulfate and sodium cetyl sulfate;

Sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids (e.g. coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammonium salts of formula N⁺R'R "R" 'R "" Y^-wherein the radicals R are identical or different and represent optionally hydroxylated hydrocarbon radicals and Y^- is a strong acid anion such as a halogen anion, a sulphate anion and a sulfonate anion; Cetyltrimethylammonium bromide is one of the cationic surfactants that can be used;

(d) the amine salts of formula N⁺R'R "R" 'in which the radicals R are identical or different and represent optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants that can be used;

(e) non-ionic surfactants, such as optionally polyoxyethylated sorbitol esters, e.g. polysorbate 80 or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, glycerol polyesters, polyoxyethylene fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and propylene oxide;

(f) amphoteric surfactants such as lauryl-substituted betaine compounds; or (g) a mixture of at least two compounds specified in (a) - (f) above.

[0135] In one embodiment of the crystallization inhibitor, a pair of crystallization inhibitors will be used. Such vapors include, for example, a combination of a polymeric type film-forming agent and a surfactant. These agents can be selected from the compounds listed above as crystallization inhibitors.

[0136] In one embodiment of the film-forming agent, the agents are of the polymeric type, which include, but are not limited to, such as various classes of poly (vinylpyrrolidone), poly (vinyl alcohols) and copolymers of vinyl acetate and vinylpyrrolidone.

[0137] In one embodiment of surfactants, they include, but are not limited to, agents such as those made from non-ionic surfactants. In another embodiment of surfactants, the agent is a polyoxyethylene sorbitan ester. In yet another embodiment of the surfactant, these include various classes of polysorbate, e.g. polysorbate 80.

[0138] In another embodiment of the invention, the film-forming agent and surfactant may be incorporated in similar or identical amounts within the limits of the total amount of crystallization inhibitor mentioned above.

[0139] The volume of topical compositions used is not limited as long as the amount of the substance being administered is safe and effective. Typically, the volume used depends on the size and weight of the animal as well as the concentration of the active agent, the degree of infestation by the parasites and the type of administration. In the case of spot-on compositions (for spot-on), the volume used is typically in the order of from about 0.1 to about 1 ml, or from about 0.1 ml to about 5 ml, or from about 0.1 ml to about 10 ml. In other embodiments, the volume can be from about 4 ml to about 7 ml. In the case of larger animals, the volume may be larger and may be up to 10 ml, up to 20 ml or up to 30 ml or more, among others. In one volume solution, the volume is of the order of from about 0.5 ml to about 1 ml, or from about 0.5 ml to about 2 ml for cats and a range of about 0,

[0140] Dosage forms may contain from about 0.5 mg to about 5 g of a combination of active agents. In one embodiment of the dosage form, the dosage is from about 1 mg to about 500 mg of active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg or from about 1000 mg.

Methods of treatment [0141] According to another aspect, a method of preventing or treating a parasitic infection / infestation in an animal, comprising administering a composition of the invention is provided. The compositions or formulations of the present invention have long-lasting effectiveness against external parasites (e.g., fleas and ticks) and are also active against intestinal parasites that harm animals. [0142] In one aspect, methods are provided for treating or preventing parasitic infections or infections in a pet that comprise administering the composition as defined above to an animal. External parasites against which the compositions of the present invention are effective include, but are not limited to, such as fleas, ticks, mites, mosquitoes, flies and lice.

[0143] In one aspect, methods are provided for treating and preventing infections and parasitic infestations in animals (wild or domesticated), including livestock and pets, such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys, and cattle, in order to deprive the hosts of parasites commonly found in such animals.

[0144] In a preferred embodiment, the invention provides compositions for treating or preventing infections and parasitic infestations in domestic animals including, but not limited to, cats and dogs. In a particularly preferred embodiment of the invention, the compositions described herein are used to prevent or treat parasitic infections or infestations in cats.

[0145] "Treating" or "treating" or "treating" is intended to apply or administer a composition of the present invention to an animal that suffers from a parasitic infection to control the parasite or to reduce the number of parasites infecting the animal undergoing treatment. It should be noted that the compositions of the present invention can be used to prevent such parasitic infections.

[0146] It will be appreciated by the skilled person that the methods of the invention comprise administering a 1-arylpyrazole compound (s), a macrocyclic lactone as an active agent (s), an IGR compound (s) and an active agent (s). the worms together in the same carrier or diluent.

[0147] In another aspect, the method comprises administering each of the 1-arylpyrazole (1-arylpyrazole), macrocyclic lactone (lactones), IGR compound (s) and anti-worm agent (s) simultaneously.

[0148] In yet another aspect, the method comprises administering each of the 1-arylpyrazole (1arylpyrazole), macrocyclic lactone (s), IGR compound (s), and worm agent (s) simultaneously in the same carrier or diluent.

[0149] In another aspect of the invention, there is provided a kit for treating or preventing parasitic infestations in an animal that comprises at least one 1-arylpyrazole (1-arylpyrazole), at least one macrocyclic lactone (lactones). at least one IGR compound (s) and at least one anti-worm agent (s) together with a pharmaceutically acceptable carrier as defined above and a dispensing device for topical application of the composition. The dispensing device can be a pipette, syringes, roll on dispensers, instillation pipettes, capsules, film packages, vials, screw caps and other single-dose and multi-dose containers that contain an effective dose of each active in a pharmaceutically acceptable carrier or diluent.

Additional active agents [0150] Additional veterinary / pharmaceutical active ingredients may be used with the compositions of the present invention. In certain embodiments, additional active agents may include, but are not limited to, acaricides, anti-worm agents, anti-parasitic agents, and insecticides. Antiparasitic agents may include both anti-parasitic agents and anti-parasitic agents.

[0151] Veterinary pharmaceuticals that may be included in the compositions of the invention are well known in the art (see e.g. Plumb 'Veterinary Drug Handbook, 5th edition, edited by Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th Edition, (January 2005)) and include, but are not limited to, the following acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide, 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 besilate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B desoxycholate,amphiperine B embedded in lipids, ampicillin, amprolium, antacids, aparminine, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atypamezole, atracine benzenesulphonate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, Baclofen, barbiturates, benazepril, betamethasone, betanochol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone sulphate, bromides, bromocriptine mesylate, budenozide, buprenorphine, buspiron, busulfan, butorphanol tartrate, cabergoline, calcitonin from salmon, calcitrol, calcium salts, captopril , carbenicillin, sodium indanyl, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, disodium cefotethane, sodium cefoxitine,cefpod oxime-proxetine, ceftazidime, ceftiofur sodium, ceftiofur, cefthiaxone sodium, cefalexin, cepfalosporins, cefapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- bromide clidinium, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline , chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium clorazepan, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporin, cyproheptadine, cytarabine, dacarbazine,charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clomidium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin , clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium clorazepan, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporin, cyproheptadine, cytarabine, dacarbazine,charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clomidium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin , clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium clorazepan, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporin, cyproheptadine, cytarabine, dacarbazine,cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium clorazepan, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporin, cyproheptadine, cytarabine, dacarbazine,cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium clorazepan, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporin, cyproheptadine, cytarabine, dacarbazine,

Pharmaceutical / actinycin D, sodium dalteparin, danazol, sodium dantrolene, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone perestalate, detomidine, dexamethasone, dexpanthenol, dexrazoxane, dextran, diazepam, diazoxide (oral), dichlorfenamide, diclofenac sodium, dicloxacillin, diethylcarbamizine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrin, dimercaprol / BAL, dimethyl sulfoxide, dinoprost dimethylamine, diphenylhydramine, disulfiramate phosphate, dobutamine, docsate / DSS, dolasetron mesilate, domperidone, dopamine, doramectin, docsapram, doxepin, doxorubicin, doxycycline, calcium and disodium edetate, calcium EDTA, edrofonium chloride, enalapril / enalaprilat, enoxaparin sodium,enrofloxacin, ephedrine sulfate, adrenaline (epinephrine), epoetin / erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid / sodium ethacryrate, ethanol (alcohol), sodium etidronate, etodolac, etomidate, eutanasis / w / pentobarbital agents, famotidine, fatty acids (essential / omega), felbamate, fentanyl, iron (II) sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumetasone, flunixin meglumin, fluorouracil (5-FU), fluoxetine , fluticasone propionate, fluvoxamine maleate, fomepizol (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamycin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents, glucosamine / chondroitin sulfate, glutamine, glyburide, glycerol (oral), glycopyrrolate, gonadorelin,griseofulvin, guaifenesin, halothane, glutamer-200 hemoglobin (OXYGLOBIN®), heparin, starch (hetastarch), sodium hyaluronate, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb imiptoic acid, impenium -clastatin sodium, imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium / potassium), ipekak (syrup), sodium iodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxuprine, itraconazole, ivermectin, kaolin / pectin, ketamine, ketoconazole, ketoprofen, ketorolac trometamine, lactulose, leuprolide, levetiracetam, sodium levothyroxine, lidocaine, lincomycin, liotyronine sodium, lisinopril, lomustine (CCNU), lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid .medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxalane, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, metazolamide, methanamine metastamine / methanamine methiplane, methimazole, methionine, methocarbamole, methoxylate, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaksol, mexiletine, mibolerlon, midazolam, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulphate, moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic (opiate) agonist agents analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, sodium novobiocin, nystatin, octreotide acetate,olsalysin sodium, omeprozole, ondansetron, opioid antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride, oxymorphone, oxytretracycline, oxytocin, disodium pamidronate, pankreplipaza, pankuronium bromide, paromomycin sulfate, parozetine, pencellamine, penicillin with general action, penicillin G, potassium potassium, pentazocine, pentobarbital sodium, pentosan polysulfate, pentoxyphenyl, pergolide mesylate, phenobarbital, phenoxybenzamine, feylobutazone, phenylephrine, phenylpropanolamine,penicillin G, potassium V penicillin, pentazocine, pentobarbital sodium, pentosan polysulfate, pentoxyphenyl, pergolide mesylate, phenobarbital, phenoxybenzamine, feylobutazone, phenylephrine, phenylpropanolamine,penicillin G, potassium V penicillin, pentazocine, pentobarbital sodium, pentosan polysulfate, pentoxyphenyl, pergolide mesylate, phenobarbital, phenoxybenzamine, feylobutazone, phenylephrine, phenylpropanolamine,

Phenytoin sodium, pheromones, parenteral phosphate, phytonadione / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfate glycosaminoglycan, ponazuryl, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone , primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, propionibacterium acnes for injection, propofol, propranolol, protamine sulphate, pseudoephedrine, hydrophilic mucilloid psyllium, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosylmethionine ( SAMe), brine / hyperosmotic defendant, selamectin, selegiline / I-deprenyl, sertraline, sevelamer, sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulphate,sodium thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, dimercaptosuccinic acid, succinoylcholine chloride, sucralfate, sufentanil citrate, sodium sulfachloropyridazine, sulfadiazine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadimethoxine, sulfadimethoxin / ormetoprim, sulfasalazine, taurine, tepoxaline , terbinafline, terbutaline sulphate, testosterone, tetracycline, sodium thiacetearamide, thiamine, thioguanine, thiopental sodium, thiotepa, trotropine, tiamulin, disodium ticarcyline, tiletamine / zolazepam, tilmicosin, thiopronin, tobramycin sulfate, tokainide, tolazoline, telfenamic acid, topiramate, tramadol , triamcinolone acetonide, trientin, trilostane, trimmedrine tartrate w / prednisolone, tripelennamine, tylosin, urdosiol (ursodeoxycholic acid), 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.

[0152] In yet another embodiment of the invention, additional insecticides and acaricides may also be added to the compositions of the invention. These include pyrethrins (which include cinerin I, cinerin II, jasmoline I, jasmoline II, pyrethrin I, pyrethrin II and mixtures thereof) and pyrethroids and carbamates (which include, but are not limited to, the following benomyl, carbanolane, carbaryl, carbofuran, methiocarb, metolcarb, promacyl , propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxim and thiophan).

[0153] Suitable organophosphorus agents include, but are not limited to, the following: cumafos, trichlorfon, haloxone, naphthalophos and dichlorwos, heptenophos, mevinfos, monocrotophos, TEPP and tetrachlorwinfos.

[0154] In still other embodiments, the compositions of the invention may include other active agents that are effective against parasitic arthropods. Suitable active agents include, but are not limited to, the following bromocyclene, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbofenothio, chlorphenvinphos, chlorpyrifos, crotoxyfos, cationtate, diazinon, dichlorention, diemtoat, dioxation, ethion, famfur, fenitrotione, fention, fospirat, iodophenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucytryrate, permethrin, phenothrin, pyrethrines, resmethrine, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanoacetate, monosulfiram,

PZ / 4348 / AGR dibenzofurancaraldehyde (MGK-11), 2- (2-ethylhexyl) -3a, 4,7,7a-tetrahydro-4,7-methane-1H-isoindolo -1,3 (2H) dione ( MGK-264), dipropylene-2,5-pyridinedicarboxylate (MGK-326) and 2- (octylthio) ethanol (MGK-874). [0155] An insecticide that can be combined with a compound of the invention to form a composition may be a substituted pyridylmethyl derivative such as imidacloprid. The agents of this class have been described above and, e.g. in U.S. Pat. Ser. No. 4,892,060 or in EP 0 892 060. In terms of skill, the practitioner will be able to decide which particular compound can be used in the formulation of the invention for the treatment of a given insect infection.

[0156] In some embodiments, the insecticide that can be combined with the compositions of the present invention is semicarbazone, such as metaflumizone.

[0157] In general, the additional active agent is included in the composition in an amount between about 0.1 μg and about 1000 mg. More typically, the additional active agent can be included in a dosage of about 10 μg to about 500 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or from about 10 mg to about 100 mg. In one embodiment of the invention, the additional active agent is contained in a dose comprised between about 1 μg and about 10 mg. In other embodiments of the invention, the additional active agent may be included in a dosage of about 5 μg / kg to about 50 mg / kg per animal weight. In other embodiments, the additional active agent may be present in a dosage of about 0.01 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg animal weight. In other solutions, the additional active agent may be present in a dosage of about 5 μg / kg to about 200 μg / kg or from about 0.1 mg / kg to about 1 mg / kg animal weight. In yet another embodiment of the invention, the additional active agent is contained in a dose comprised between about 0.5 mg / kg to about 50 mg / kg.

[0158] Optionally, an aroma-giving agent (fragrance) may be added to any composition of the invention. Aroma-giving agents that are useful in the present invention include, but are not limited to:

(i) esters of carboxylic acid, such as octyl acetate, isoamyl acetate, isopropyl acetate and isobutyl acetate;

(ii) fragrance oils such as lavender oil.

[0159] The compositions of the invention are prepared by mixing appropriate amounts of active agents, a pharmaceutically acceptable carrier or diluent and optionally a crystallization inhibitor, an antioxidant, a preservative, a film former, etc., to form a composition of the invention. The compositions may be obtained in a variety of forms (e.g., such as tablets, pastes, pour-ons, spot-ons, collars, etc.) by following the method of preparing these forms described above as a description of the preparation of these forms that can be found in the descriptions. regarding general formulation principles known in the art, e.g. Remington - The Science and Practice of Pharmacy (21st edition) (2005), Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics (11th edition) (2005) and Ansel '

[0160] The formulations of the present invention may contain other inert ingredients, such as antioxidants, preservatives or pH stabilizers. These compounds are well known in the art of formulation. An antioxidant such as alpha tocopherol, acid may be added to the formulation

Ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulphate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene, butylhydroxytoluene), monothioglycerol, etc. Antioxidants it is generally added to the formulation in amounts ranging from about 0.01 to about 2.0%, based on the total weight of the formulation, with an amount of about 0.05 to about 1.0% being particularly preferred.

[0161] Preservatives, such as parabens (methyl paraben and / or propyl paraben), are suitably used in the formulations in amounts ranging from about 0.01 to about 2.0%, an amount from about 0.05 to about 1, 0% is particularly beneficial. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butyl paraben, cetrimid, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethyl paraben, imidourea, methyl paraben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, nitrate phenylmercury, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, etc. Preferred ranges for these compounds include from about 0.01 to about 5%.

[0162] Compounds that stabilize the formulation pH are also included. Again, such compounds are well known to the practitioner in the art as well as how to use these compounds. Buffering systems include, for example, systems selected from the group consisting of the following acetic acid / acetate, malic acid / malate, citric acid / citrate, tartaric acid / tartrate, lactic acid / lactate, phosphoric acid / phosphate, glycine / glycine, tris, glutamic acid / glutamates and sodium carbonate.

[0163] The compositions of the invention are administered in parasiticidally effective amounts that are defined by the mode of administration. In each aspect of the invention, the compounds and compositions of the invention can be used against a single pest or combinations thereof.

[0164] The compositions of the invention may be administered continuously to treat or prevent parasitic infections or infestations. In this method, the compositions of the invention provide an effective amount of active compounds to an animal in need thereof to control the target parasites. The term "effective amount" is intended to refer to a sufficient amount of the composition of the invention to control or reduce the number of parasites that infect an animal. In certain embodiments, an effective amount of active agent achieves at least 70% efficacy against the target parasite. In other embodiments, an effective amount of active agent achieves at least 80% or at least 90% efficacy against target pests. Preferably, the effective amount of active agent will be at least 95%,

[0165] In general, a dosage of about 0.001 to about 100 mg per kg of body weight administered as a single dose or in divided doses over a period of 1 to 5 days will be satisfactory, but of course, there may be instances where greater or lesser ranges are indicated dosages and these also fall within the scope of the invention. In terms of routine skills, the practice is to determine a particular dosing schedule for a specific host and parasite.

[0166] In one treatment approach, treatment is carried out so that the drug is used in an animal, once, at a dose containing between about 0.001 and about 100 mg / kg of active agents. In another embodiment, the composition provided provides a dose of about 1 to 20

PZ / 4348 / AGR EP 2 552 201 mg / kg arylpyrazole, from about 1 to 20 mg / kg IGR, from about 0.01 to 5 mg / kg macrocyclic lactone as active agent and from about 1 to 20 mg / kg antimicrobial agent. worms. In a preferred embodiment, the compositions of the invention will provide from about 5 to 15 mg / kg of arylpyrazole, from about 5 to 15 mg / kg of IGR, from about 0.1 to 1 mg / kg of macrocyclic lactone and about 5 to about 15 mg / kg. active agent against worms.

[0167] Larger amounts may be provided for sustained release in or on the body of the animal. In another treatment approach, the amount of active agents for birds and other animals that are small is above about 0.01 mg / kg, and in another embodiment for treating small birds and other animals, the amount is between about 0.01 and about 20 mg / kg animal weight.

[0168] The solutions of the invention can be used by any means known per se, e.g. using a gun applicator or volumetric flask, pipette, syringes, roll on dispensers, instillation pipettes, capsules, foil packs, vials, twisted tip containers and other single-dose and multi-dose containers.

[0169] In one preferred embodiment of the method of use in cats, the composition comprising a 1-arylpyrazole compound, a macrocyclic lactone, an IGR and an anti-worm compound has an anti-flea efficacy of at least about 80.0% or more for at least about 43 days, at least about 50 days, at least about 57 days or at least about 63 days. In another embodiment of this method of use in cats, a composition comprising a 1-arylpyrazole compound, a macrocyclic lactone, an IGR and an anti-worm compound has an anti-flea efficacy of at least 90.0% or more for at least about 43 days, at least about 50 days, or at least about 57 days. In yet another embodiment of the invention for the treatment of cats, a composition comprising a 1arylpyrazole compound, a macrocyclic lactone,

[0170] In another embodiment for treating cats, a composition of the invention comprising a 1arylpyrazole compound, a macrocyclic lactone, an IGR, and an anti-worm compound has an efficacy of at least about 90% against ticks for at least about 30 or 37 days. In another embodiment for treating cats, a composition comprising a 1-arylpyrazole compound, a macrocyclic lactone, an IGR, and an anti-worm compound has an efficacy of at least about 95% against ticks for at least 30 days or 37 days. In each of these solutions for use against fleas and ticks, the arylpyrazole compound may be fipronil; the macrocyclic lactone compound may be ivermectin, eprinomectin or moxidectin; IGR is (S) -methoprene, pyriproxyfen, hydropren, cyromazine, fluazuron, lufenuron or novaluron;

[0171] In another embodiment for treating cats, a composition comprising a 1-arylpyrazole compound, a macrocyclic lactone, an IGR and an anti-worm compound has an efficacy of at least 90% when inhibiting the incubation of fleas for at least about 47 days, at least about 54 days, or at least about 61 days.

[0172] In yet another embodiment for treating cats, a composition of the invention comprising a 1-arylpyrazole compound, a macrocyclic lactone, an IGR, and an anti-worm compound has efficacy.

PZ / 4348 / AGR EP2 552 201 B1 of at least 90% against internal parasites including Dipylidium caninum and Taenia taeniaeformis. In another embodiment for treating cats, the composition of the invention has an efficacy of 100% against Taenia taeniaeformis.

[0173] In another embodiment for treating cats, a composition comprising a 1-arylpyrazole compound, a macrocyclic lactone, an IGR, and an anti-worm compound has an efficacy of at least 85%, at least 90%, at least 95%, or 100% against Toxocara cati (roundworm) ).

In another embodiment for treating cats, a composition of the invention comprising a 1arylpyrazole compound, a macrocyclic lactone, an IGR and an anti-worm compound has an efficacy of 100% against Ancylostoma tubaeforme.

[0175] In another embodiment for treating cats, a composition of the invention comprising a 1arylpyrazole compound, a macrocyclic lactone, an IGR, and an anti-worm compound has an efficacy of 100% against Dirofilaria immitis (nematode in the heart).

In another embodiment for the treatment of cats, a composition of the invention comprising a 1arylpyrazole compound, a macrocyclic lactone, an IGR and an anti-worm compound proves to be safe for use in cats infected with adult nematodes of Dirofilaria immitis (nematode in the heart).

[0177] In one embodiment of the administration site, a single formulation containing the active agent in a substantially liquid carrier and in a form that allows single application or repeated applications infrequently will be administered to the animal in the localized area of ​​the animal, e.g. between two arms. In one embodiment of the invention, the localized area has a surface area₂ about 10 cm² or more. In another embodiment of the invention, the localized area has a surface area between about 5 and about 10 cm² surface.

EXAMPLES [0178] The invention is further described by the following non-limiting examples, which further illustrate the invention and are not intended to be and should not be construed as limiting the scope of the invention. Example 1: Anti-flea efficacy [0179] The effectiveness of a spot-on composition (for dripping) containing fipronil, (S) -methoprene, eprinomectin and praziquantel in a pharmaceutically or veterinarily acceptable liquid carrier against adult fleas (Ctenocephalides felis), their efficacy was tested. eggs and larvae in cats. The compositions contained fipronil and (S) -methoprene at dose-delivering concentrations of 10 mg / kg of fipronil and 12 mg / kg of (S) -methoprene to cats infected with adult fleas. It was shown that at volumes of 0.10, 0.15 and 0.20 ml / kg and various concentrations of active agents,

[0180] All cats were infected with a specific number of fleas (e.g., 100) before treatment using the composition. On day 0, the cats were treated with the composition, with the exception of the control group. On day 1, all cats were combed to remove and count live fleas. Cats were later infected every week with a specific number of fleas (e.g., 100). All cats were combed to remove and count live fleas every week, 24 hours after being infected with fleas to determine the effectiveness of the composition over time. Efficacy or percent reduction in treatment is calculated at any given time point by comparing the mean flea numbers in the treatment group with the average number of fleas in the control group. The early time point (day 1) allows you to estimate

PZ / 4348 / AGR efficiency; and weekly time points allow you to estimate the duration of effectiveness.

[0181] Table 1 shows the efficacy (% reduction) of the spot-on composition of the invention comprising fipronil, (S) -methoprene, eprinomectin and praziquantel in the glycerol formal and dimethyl isosorbide at concentrations of 10 mg / kg fipronil, 12 mg / kg (S) -methoprene, 0.5 mg / kg eprinomectin and 10 mg / kg praziquantel to cats infected with adult fleas (adult stages of fleas) (Ctenocephalides felis). The volume of the composition administered was 0.2 ml / kg per animal weight.

Table 1: Effectiveness against adult fleas (% reduction)

<td></td><td>Day 1</td><td>Day 3</td><td>Day 15</td><td>Day 22</td><td>Day 29</td><td>Day 36</td><td>Day 43</td><td>Day 50</td>

<td>% reduction</td><td>96.1</td><td>99.8</td><td>99.9</td><td>98.1</td><td>99.3</td><td>99.6</td><td>98.3</td><td>91.6</td>

[0182] In another study, the efficacy of compositions against adult fleas and their ability to inhibit the development of flea eggs and larvae was examined. The efficacy against adult fleas was tested as described above in Example 1 until day 29, after which efficacy was estimated four days after each infestation (infection). During the 4-day period after flea infestation, flea eggs produced from cats were collected, counted and incubated. After the following specific incubation periods (approximately 3 days to estimate the incubation of the larvae and about 35 days to estimate the appearance of adults), the ratio of emerging larvae and / or emerging adults in the treatment group with the ratio of emerging larvae and / or emerging adults in the control group. Table 2 shows the inhibition of hatching of larvae by the composition described for Table 1 above. The effect of the excellent effectiveness of the composition was the absence of flea eggs before day 43 of the study. Efficacy of at least 90% inhibition of incubation of larvae was observed for 2 weeks after the reduction of efficacy against adult individuals, i.e. when flea eggs began to appear on day 43.

<td colspan="7">Table 2: Inhibition of incubation of larvae</td>

<td></td><td>Day 1</td><td>Day 15</td><td>Day 22 Day 29</td><td>Day 36</td><td colspan="2">Day</td>

<td></td><td colspan="6"></td>

<td>% reduction of adults</td><td>93.7</td><td>99.4</td><td>99.7 98.8</td><td>99.6</td><td>98.3</td><td>91.6</td>

<td>fleas</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>until day 47</td><td>Day 54</td><td>Day 61</td>

<td>braking</td><td></td><td></td><td></td><td>100</td><td>99.2</td><td>91.1</td>

<td>incubation of larvae (%)</td><td></td><td></td><td></td><td></td><td></td><td></td>

[0183] Table 3 below shows the efficacy of a spot-on composition of the invention containing fipronil, (S) -methoprene, eprinomectin and praziquantel in a pharmaceutically acceptable carrier (mixture of glycerol formal and dimethyl isosorbide) at concentrations of 10 mg / kg fipronil, 9 mg / kg (S) -methoprene, 0.4 mg / kg eprinomectin and 8 mg / kg praziquantel at volumes of 0.10 ml / kg per animal weight.

VP / 4348 / AGR

EP2 552 201 B1

Table 3: Effectiveness against adult fleas (%)

<td></td><td>Volume (Ml / kg)</td><td>Day 1</td><td>Day 15</td><td>Day 22</td><td>Day 29</td><td>Day 36</td><td>Day 43</td><td>Day 50</td><td>Day 57</td><td>Day 63</td>

<td>%</td><td>0.15</td><td>96.6</td><td>99.9</td><td>99.6</td><td>97.5</td><td>98.9</td><td>99.2</td><td>98.0</td><td>96.4</td><td>88.4</td>

<td>reduction</td><td>0.10</td><td>96.7</td><td>99.8</td><td>99.1</td><td>97.4</td><td>97.7</td><td>99.5</td><td>97.8</td><td>97.9</td><td>99.9</td>

Example 2: Tick efficacy [0184] The efficacy of the composition of the invention including fipronil, (S) -methoprene, eprinomectin and praziquantel in a pharmaceutically acceptable carrier (mixture of glycerol formal and dimethyl isosorbide) against ticks was investigated. The composition contained active agent concentrations delivering 10 mg / kg fipronil, 12 mg / kg (S) -methoprene, 0.45 mg / kg eprinomectin and 10 mg / kg praziquantel in a volume of 0.10 ml / kg per animal weight. The cats were infected with a certain number of ticks (eg 50 females, Ixodes ricinus) before treatment. On day 0, all cats were treated with a composition containing fipronil, (S) -methoprene, eprinomectin and praziquantel in the glycerol formal and dimethyl isosorbide. On day 2, tight or free ticks were removed from each cat and living ticks were counted. One week later, all cats were infected with a specified number of ticks (e.g., 50 females) and the attached and free ticks were removed and counted 48 hours later. Table 4 below shows the efficacy (% reduction) of the tick composition.

Table 4: Tick efficacy (% reduction)

<td></td><td>Day 2 Day 9 Day 16</td><td>Day 23</td><td>Day 30</td><td>Day 37</td>

<td>% reduction</td><td>97.2 100, 99.7</td><td>98.8</td><td>98.8</td><td>97.6</td>

<td colspan="5">Example 3: Effectiveness against internal parasites</td>

[0185] The efficacy of the composition comprising (S) -methoprene, eprinomectin and praziquantel in a pharmaceutically acceptable carrier (mixture of glycerol formal and dimethyl isosorbide) against intestinal parasites was investigated. The compositions contained active agent concentrations delivering 10 mg / kg of fipronil, 12 mg / kg of (S) -methoprene and different doses of eprinomectin and praziquantel.

[0186] Cats were infected with the infectious material (eggs, larvae) of the target parasite prior to treatment. The cats were examined and selected for further testing based on the positive diagnosis of the target parasite (eg identification of eggs in the feces). Alternatively, positive cats relative to the target parasite were harvested and confirmed to be infected with a parasite (e.g., identification of eggs in faeces). On day 0, the cats were treated with the test composition, with the exception of the control group. Approximately on day 7-10 (the time necessary to kill the parasite and to remove it from the body), the cats underwent an autopsy to recover the parasites and count them.

[0187] Compositions containing praziquantel providing doses of 6, 8 or 10 mg / kg were tested against Dipylidium caninum in 3 studies. The efficacy of the praziquantel-containing composition was also tested against T. taeniaeformis and T. cati at certain doses. Table 5 below shows the efficacy of compositions containing fipronil at a dose of 10 mg / kg, (S) -methoprene at 12 mg / kg and eprinomectin and praziquantel at varying doses against these three internal parasites.

Table 5: Effectiveness against internal parasites

<td>Study</td><td></td><td></td><td>% reduction</td><td></td><td></td>

<td></td><td>The dose of praziquantel (mg / kg)</td><td>Eprinomectin dose (mg / kg)</td><td>D. caninum</td><td>T. taeniaeformis</td><td>T. cati</td>

<td>1</td><td>6</td><td>2.5</td><td>64</td><td>100</td><td>AD</td>

<td></td><td>8</td><td>2.5</td><td>78</td><td>100</td><td>AD</td>

<td></td><td>10</td><td>2.5</td><td>92</td><td>100</td><td>AD</td>

<td>2</td><td>8</td><td>0.5</td><td>98</td><td>AD</td><td>95</td>

<td></td><td>10</td><td>0.5</td><td>98</td><td>AD</td><td>87</td>

<td>3</td><td>10</td><td>0.25</td><td>100</td><td>AD</td><td>95</td>

<td></td><td>10</td><td>0.5</td><td>91</td><td>AD</td><td>100</td>

ne = not estimated

Example 4: Effect of eprinomectin dose against internal parasites [0188] In 12 separate studies, the efficacy of compositions containing fipronil, (S) methoprene, praziquantel and varying eprinomectin doses against various internal parasites was investigated. The compositions contained concentrations of fipronil, (S) -methoprene and praziquantel providing doses of 10 mg / kg, 12 mg / kg and 10 mg / kg of each active agent, respectively. The eprinomectin concentration was varied to give doses ranging from 0.1 mg / kg to 10 mg / kg. Cats infected with natural or experimental A. tubaeforme, T. cati (capstone), D. caninum and various strains of D. immitis (nematode in the heart) were used for the study. The results from 12 studies are shown in Table 6 below.

Table 6: Effectiveness against internal parasites% Reduction

<td>Worm type Type of infection</td><td>Hookworm¹Infection experimental</td><td>roundworm ²Experimental infection</td><td>roundworm ³Experimental infection</td><td>roundworm ²Experimental infection</td><td>Hookworm¹Infection experimental</td><td>roundworm ³Natural infection</td>

<td>Dose eprinomectin (Mg / kg) 10</td><td>100</td><td>100</td><td></td><td></td><td></td><td></td>

<td>2.5</td><td>100</td><td>100</td><td>-</td><td>-</td><td>-</td><td>-</td>

<td>1.0</td><td>-</td><td>-</td><td>100</td><td></td><td></td><td></td>

<td>0.5</td><td>-</td><td>-</td><td>100</td><td>97</td><td>100</td><td>92</td>

<td>0.35</td><td>-</td><td>-</td><td>-</td><td>96</td><td>100</td><td>-</td>

<td>0.25</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td>

<td>0.2</td><td>-</td><td>-</td><td>-</td><td>92</td><td>100</td><td>-</td>

<td>0.1</td><td>-</td><td>-</td><td>-</td><td>73</td><td>100</td><td>-</td>

<td>1.A tubaeforme, 2</td><td colspan="3">. T. cati, 3. mixed D. caninum / T. cati</td><td></td><td></td><td></td>

[0189] Table 7 shows the effect of eprinomectin dose between 0.1 mg / kg and 0.5 mg / kg against roundworms, including the new T. cati strain and against two strains of nematode present in the heart. (D. immitis). Although the number of untreated (control) cats infected with D. immitis was insufficient (2/10) to calculate the percentage reduction, it was found that the lowest eprinomectin dose was effective against both strains of nematode present in the heart.

Table 7: Effectiveness against internal parasites

<td>Worm type</td><td>% Reduction roundworm⁴ roundworm²</td><td>roundworm⁵</td><td>Hookworm^{6 7}</td><td>Hw 7</td><td>HW8</td>

<td>Type of infection</td><td>Infection Infection</td><td>Infection</td><td>Infection</td><td>Infection</td><td>Infection</td>

<td></td><td>declared natural</td><td>experimental</td><td>experimental</td><td>experimental</td><td>natural</td>

Eprinomectin dose (mg / kg)

<td>0.5</td><td>-</td><td>100</td><td>100</td><td>100</td><td>0/10</td><td>0/10</td>

<td>0.4</td><td>100</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td>

<td>0.25</td><td>-</td><td>95</td><td>-</td><td>-</td><td>-</td><td>-</td>

<td>0.2</td><td>99.5</td><td>-</td><td>98</td><td>100</td><td>-</td><td>-</td>

<td>0.1</td><td>-</td><td>-</td><td>-</td><td>-</td><td>0/10</td><td>0/10</td>

4. a new T. cati strain, 2. T. cati,

5. immature stage of T. cati,

6. immature stage A. tubaeforme,

7. D. immitis strain EU, 8. D. immitis strain US [0190] In another study, the number of untreated cats (controls) infected with the US D. immitis strain was sufficient (12/14) to calculate the percent reduction that was 100% (0/14).

Example 5: Stability of the formulation at 30 ° C [0191] As discussed above, it is surprising that the formulations of the present invention containing at least one 1-arylpyrazole, at least one macrocyclic lactone, at least one IGR and at least one compound against worms with significantly different physicochemical properties, including solubility and compatibility with a solvent, could be successfully formulated into a stable composition in one pharmaceutically acceptable carrier system. The stability (stability) of each active agent in a preferred composition of the invention comprising fipronil, (S) -methoprene, eprinomectin and praziquantel in a carrier containing formal glycerol and dimethyl isosorbide was estimated at 30 ° C using high performance liquid chromatography (HPLC). The study showed

[0192] A plot of stability (stability) of one of the formulations up to 24 months at 30 ° C is shown below.

VP / 4348 / AGR

EP2 552 201 B1

DURABILITY At 30 ° C

<img file="PL2552201T3_D0011.tif" />

♦ Fiprontl 30 ° C · S-metoprene 30 ° CA eprnomectin 30 ° C ♦ praziquantel 30 ° C [0193] As demonstrated by the non-limiting examples described above, compositions of the invention containing at least one arylpyrazole active agent, at least one macrocyclic lactone, at least one IGR and at least one anthelmintic compound have more long-lasting efficacy, both against external parasites and intestinal parasites in mammals (cats).

VP / 4348 / AGR

EP2 552 201 B1