BR112017018442B1 - LONG-ACTING INJECTABLE COMPOSITIONS COMPRISING AN ISOXAZOLINE ACTIVE AGENT, METHODS AND USES THEREOF - Google Patents

Abstract

LONG-ACTING INJECTABLE COMPOSITIONS COMPRISING AN ACTIVE ISOXAZOLINE AGENT, METHODS AND USES THEREOF. This invention relates to long-acting injectable formulations to combat parasites in animals, comprising at least one active agent isoxazoline, a poloxamer and a co-solvent. This invention also provides improved methods for eradicating, controlling and preventing infections and parasite infestations in an animal comprising administering the long-acting injectable formulations of the invention to the animal in need thereof.

Description

CROSS REFERENCE TO RELATED ORDERS

[001] This application claims the benefit of North American Provisional Application No. 62/121,350, filed on February 26, 2015, which is incorporated herein by reference.

FIELD OF INVENTION

[002] The present invention provides long-acting injectable formulations containing at least one active agent isoxazoline, a copolymer of ethylene oxide and propylene oxide blocks (poloxamer) and, optionally, a co-solvent; the use of these formulations against parasites (including ectoparasites (e.g., fleas or ticks) and/or endoparasites), and methods for the prevention or treatment of infections and parasitic infestations in animals.

BACKGROUND OF THE INVENTION

[003] Animals such as birds and mammals are often sensitive to parasite infestations/infections. These parasites can be ectoparasites, such as fleas, ticks and parasitic flies, and endoparasites, such as nematodes and other worms. Domesticated animals, such as dogs and cats, are often infested with one or more of the following ectoparasites: - Fleas (e.g., Ctenocephalides spp., such as Ctenocephalides felis and the like); - Ticks (e.g., Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., and similar); - Mites (e.g. Demodex spp, Sarcoptes spp, Otodectes spp, and the like); - Lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp. and the like); - Mosquitoes (Aedes spp, Culex spp, Anopheles spp and similar ones); and - Flies (Haematobia spp, Musca spp, Stomoxis spp, Dermatobia spp, Cochliomyia spp and others).

[004] Fleas are a particular problem, not only because they negatively affect the health of the animal or human being, but they also cause a great deal of psychological stress. Furthermore, fleas can also transmit pathogens to animals and humans, such as tapeworm (Dipylidium caninum).

[005] Likewise, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are vectors of pathogens in humans and animals. Major diseases that can be transmitted by ticks include borrelioses (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.), and rickettsioses (e.g., Rocky Mountain spotted fever). Ticks also release toxins that cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.

[006] Likewise, farm animals are also susceptible to parasite infestation. For example, cattle are affected by a large number of parasites. One parasite that is prevalent among cattle in some regions are ticks of the genus Rhipicephalus, especially those of the species microplus (cattle tick), decoloratus and annulatus. Ticks such as Rhipicephalus microplus (ormerly Boophilus microplus) are difficult to control because they lay eggs in pasture where farm animals graze. This species of tick is considered a one-host tick and passes immature and adult stages on the same animal before it engorges the female and drops off the host to lay eggs in the environment. The tick's life cycle is about three to four weeks. In addition to cattle, Rhipicephalus microplus can infest buffaloes, horses, donkeys, goats, sheep, deer, pigs and dogs. A heavy tick load on animals can decrease production and damage hides as well as transmit diseases such as babesiosis ("cattle fever") and anaplasmosis.

[007] Animals and humans also suffer from endoparasite infections including, for example, helminthiasis, which is caused by parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flounder). These parasites adversely affect the animal's nutrition and cause serious economic losses in pigs, sheep, horses and cattle, as well as affecting companion animals and poultry. Other parasites that occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, and parasites that are found in the blood or other tissues and organs, such as filarial worms and the extra-intestinal stages of Strongyloides, Toxocara and Trichinella.

[008] Recently, isoxazole and isoxazoline-containing compounds have been shown to be effective against parasites that harm animals. For example, US 7,964,204 (to DuPont, incorporated herein by reference in its entirety), describes isoxazoline compounds according to Formula (I) below, which are active against ectoparasites and/or endoparasites.

[009] Furthermore, the patent application published nos. US 2010/0254960 Al, WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 Al, US7951828 & US7662972, US 2010/0137372 Al, US 2010/0179194 A2, US 201 1/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al and WO 2007/075459 A2 and US Patent Nos. 8,410,153; 7,947, 171; 8,618,126; 8,466, 115; 8,383,659; 8,853,186; 7,951,828 and 7,662,972 (all incorporated herein by reference in their entirety) describe various other parasiticidal isoxazoline compounds. Other published patent applications describing various other parasiticidal isoxazoline compounds and formulations comprising the same include WO 2007/079162 Al, WO 2008/154528 Al, WO 2009/002809 A2, WO 2011/149749 Al, WO 2013/078070, WO 2014/439475 Al, US 8 466, 115, WO 2012/120399, WO 2014/039484, WO 2014/189837, (Zoetis) and WO2012 120135A1 (Novartis). WO 2012/089623 describes topical localized isoxazoline formulations comprising glycofurol. WO 2013/039948 Al provides topical veterinary compositions comprising at least one isoxazoline active agent and WO 2013/119442 Al provides oral veterinary compositions such as a soft chew comprising at least one isoxazoline active agent. All of the foregoing publications are incorporated herein by reference in their entirety.

[0010] Furthermore, for topical and oral dosage forms, it is sometimes possible to formulate active agents as long-acting formulations, depending, for example, on the physicochemical properties of the individual active agent; These properties include, for example, solubility, bioavailability, etc. For example, US 6,733,767 and US 8,362,086 (both incorporated herein by reference in their entirety) to provide long-acting injectable formulations comprising a bioactive substance, such as, for example, an avermectin or a milbemycin and an acceptable biological polymer.

[0011] Notwithstanding the compositions comprising isoxazoline active agents alone or in combination with other active agents described in the documents above, there is a need for compositions and methods with improved efficacy, bioavailability, and spectrum of veterinary coverage to protect animals against endoparasites and / or ectoparasites. More specifically, there is a need to develop a long-acting injectable formulation comprising an isoxazoline compound, which has good bioavailability and exhibits reduced irritation at the injection site while continuing to be effective against parasites (e.g., fleas and ticks) to a long duration (e.g. from three (3) to six (6) months or more).

INCORPORATION BY REFERENCE

[0012] Any previous requests, and all documents cited herein or during their suppression ("application cited documents") and all documents cited or referenced in the request for cited documents, and all documents cited or referred to in this text (" documents cited herein"), and all documents cited or referenced in documents cited herein, together with any manufacturer's instructions, descriptions, product specifications, and product sheets of all products herein or in any document incorporated herein by reference, are incorporated herein by reference mentioned, and may be employed in the practice of the invention.

[0013] The citation or identification of any document in this patent application is not an admission that such document is available as prior art to the present invention.

SUMMARY OF THE INVENTION

[0014] The present invention provides new and inventive long-acting injectable formulations for the treatment or prevention of infections or parasite infestations in an animal comprising an effective antiparasitic amount of at least one isoxazoline compound, a poloxamer and, optionally, an co-solvent wherein the formulation does not contain a pharmaceutically acceptable polymer, as defined herein, other than a poloxamer. As used herein, the term "poloxamer" means a block copolymer of ethylene oxide and propylene oxide. Different classes, sources and types of block copolymers of ethylene oxide and propylene oxide can be used in long-acting injectable formulations of the invention. Likewise, for purposes of this application, liquid polyethylene glycols (PEGs) are considered to be a co-solvent and are not considered to be a pharmaceutically acceptable polymer.

[0015] In accordance with this invention, it has been discovered that the inventive formulations, in general, show desirable bioavailability and duration of effectiveness, while causing minimal irritation at the injection site. The compositions also provide desirable safety profiles toward warm-blooded animal and avian receptors. Furthermore, it has been found that a single administration of such formulations generally provides potent activity against one or more parasites (e.g., ectoparasites), while also tending to provide rapid onset of activity, long duration of activity, and/or desirable security profiles.

[0016] The invention encompasses veterinary uses or uses of isoxazoline compositions for the treatment or prevention or prophylaxis of infections and parasitic infestations of animals (both domestic and wild), including farmed and companion animals, such as cats, dogs, horses , chickens, sheep, goats, pigs, turkeys and cattle, with the aim of freeing these hosts from the most common parasites found by these animals.

[0017] The invention also provides methods for treating or preventing infections and parasitic infestations in animals, comprising administering an effective amount of long-acting injectable formulations comprising an antiparasitic effective amount of at least one isoxazoline compound together with a poloxamer and a co-solvent, wherein the formulation does not contain a pharmaceutically acceptable biodegradable polymer, as defined herein. Surprisingly, it has been found that the inventive isoxazoline-containing formulations described here exhibit superior broad-spectrum efficacy against harmful parasites (e.g., ectoparasites such as fleas and ticks) more quickly, and over a longer period compared to other formulations. injectables that contain isoxazoline active agents known in the art, although they exhibit minimal irritation at the injection site.

[0018] This invention also provides for the use of an isoxazoline in the preparation of a long-acting injectable formulation for treating or preventing an animal against parasites.

[0019] In one embodiment, the invention provides for long-acting injectable formulations comprising anti-parasitic effective amounts of at least one of isoxazoline of formula (I) below, in combination and a liquid pharmaceutically or veterinary acceptable carrier, wherein the variables A1, A2, A3, A4, A5, A6, B1, B2, B3,R1, R2, R4, R5, W and n are defined here.

[0020] In some embodiments, the long-acting injectable formulations and methods comprise 4- [5- [3-chloro-5- (trifluoromethyl) phenyl] -4,5-dihydro-5- (trifluoromethyl) -3- isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide as the active agent.

[0021] In other embodiments, long-acting injectable formulations may further comprise one or more additional active agents that are systemically active. Systemically-acting active agents may include, but are not limited to, isoxazoline active agents of different structure, a systemically-acting neonicotinide active agent, a systemically-acting 1-N-alylpyrazole active agent, macrocyclic lactones, such as the avermectin and milbemycin, a cyclic depsipeptide such as emodepside or PF1022A or its analogues, benzimidazoles, imidazothiazoles, a tetrahydropyrimidine active agent, an organophosphate active agent, Levamisole, a paraherquamide active agent and/or a marcfortin active agent, praziquantel , closantel, clorsulon, a spinosyn or spinosoid active agent, an amino acetonitrile active agent, an aryloazol-2-yl cyanoethyl active agent, a systemically acting insect growth regulator. In one embodiment, the long-acting injectable formulations comprise at least one macrocyclic lactone active agent, including, but not limited to, avermectins or milbemycins. In some embodiments, the active avermectin or milbemycin agent is eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin.

[0022] In other embodiments, the compositions and methods comprise at least one of thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levadamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, an active agent of amino acetonitrile, or an aryloazol -2-yl cyanoethylamino active agent.

[0023] It is an object of the invention to not include in the scope of the invention any previously known product, product manufacturing process, or method of using the product, such that applicants reserve the right and hereby disclose a notice of any previously known product, process, or method. It is further noted that the invention is not intended to include within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the written description and qualification requirements of the USPTO ( 35 USC §112, first paragraph) or EPO (EPC Article 83), such that applicants reserve the right to hereby disclose notice of any previously described product, process of manufacturing the product, or method of using the product.

[0024] These and other embodiments are disclosed or are obvious from, and covered by, the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides new and inventive long-acting injectable formulations treating or preventing infections or parasite infestations in an animal comprising an antiparasitic effective amount of at least one isoxazoline compound, a poloxamer and, optionally, an co-solvent, in which no other pharmaceutically acceptable polymers as defined herein are present.

[0026] Also provided are methods and uses for the treatment and/or prophylaxis of infections and parasitic infestations of animals, comprising administering to an animal in need thereof a long-acting formulation comprising an antiparasitic effective amount of at least one compound of isoxazoline, a poloxamer and optionally a co-solvent, in which no other pharmaceutically acceptable polymers are present.

[0027] In another embodiment, the present invention provides long-acting injectable formulations for the treatment and/or prophylaxis of infections and parasitic infestations of animals comprising an effective amount of antiparasites, at least one isoxazoline compound and an effective amount of hair. at least one additional systemically-acting active agent, a poloxamer and, optionally, a co-solvent, in which no other pharmaceutically acceptable polymers are present.

[0028] In a preferred embodiment of the invention, long-acting injectable formulations include liquid poloxamers at room temperature (20 - 25 ° C).

[0029] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prophylaxis of infections and parasitic infestations of animals comprising: a) an effective amount of antiparasites, at least one active agent isoxazoline, the which is: i) an isoxazoline compound of formula (I): (I) where:

[0030] A1, A2, A3, A4, A5 and A6 are independently selected from the group consisting of CR3 and N, provided that at most three of A1, A2, A3, A4, A5 and A6 are N;

[0031] B1, B2 and B3 are independently selected from the group consisting of CR 2 and N;

[0032] W is O or S;

[0033] R1 represents C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6;

[0034] each R2 independently represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1- C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamine, C2-C4 alkoxycarbonyl, - CN or - NO2;

[0035] each R3 is, independently, H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1C6 alkylthio, C1-C6 haloalkylthio , C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or-NO 2 ;

[0036] R4 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7-carbonyl;

[0037] R5 is H, OR10, NR11R12, or Q1; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or

[0038] R4 and R5 are taken together with the nitrogen to which they are bonded to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy; each R6 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, - CN or - NO2;

[0039] each R7 independently represents halogen; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxy, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, -NH2, -CN or -NO2; or Q2;

[0040] each R8 independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1- C6 alkylamino, C2-C6dialkylamine, C2-C4, -CN or-NO2;

[0041] each R9 independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1- C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6dialkylamino, - CN, - NO 2 , phenyl or pyridinyl;

[0042] R 10 is H; or C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl or C4-C7cycloalkylalkyl, each optionally substituted with one of more halogen;

[0043] R11 H, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl, C4-C7cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 - carbonyl;

[0044] R12 is H; Q3; or C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl or C4-C7cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or

[0045] R11 and R12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, -CN, -nO2 and C1-C2 alkoxy;

[0046] Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring or an 8-, 9- or 10-membered fused bicyclic ring system that optionally contains one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring system or ring optionally substituted with one or more substituents independently selected from R8;

[0047] each Q2 independently represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9;

[0048] Q 3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R 9; It is

[0049] n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

[0050] ii) an isoxazoline compound of formula (II): (II) where:

[0051] R1 represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl group, each of them being unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di( alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)- , R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2;

[0052] , haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)0-, R7C(O)NR8- , -CN or -NO2;

[0053] A1 is oxygen; It is

[0054] A2 is oxygen, NR 2 or CR 7 R 8

[0055] G is Gl or G-2;

[0056] B1, B2, B3, B4 and B5 are independently N or C-R9;

[0057] Y is hydrogen, halogen, -CN; or Y represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl group, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di (alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;

[0058] R2, R3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R10S(O)-, R1oS(O)2-, R1oC(O)- , R1oC(S)-, R10R11NC(O)-, R10R11NC(S)- R10OC(O)-;

[0059] R4, R5 and R 6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylakyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

[0060] R 7 and R 8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;

[0061] R9 is hydrogen, halogen, -CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of them being unsubstituted or substituted with one or more halogen, hydroxyl, amino , alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)- , R7R8NC(O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2;

[0062] R10, R11, R12 and R13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylakyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or

[0063] R10 together with R11 forms = 0, = S or = NR2; or

[0064] R12 together with R13 form = 0, = S or = NR2;

[0065] W is O, S or NR 2 ;

[0066] n is 1-4; It is

[0067] m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

[0068] iv) an isoxazoline compound of formula (III) or a pharmaceutically acceptable salt thereof; and/or

[0069] iv) an isoxazoline compound of formula (IV) or a pharmaceutically acceptable salt thereof; and/or

[0070] v) the isoxazoline compound of formula (V): wherein R1, R2 and R3 are independently H, Cl, F or CF3;

[0071] Y is the diradical group

[0072] T is a C1-C6 alkyl group that is unsubstituted or substituted by halogen, cyano, nitro, amino, hydroxyl, C1-C6 -alkoxy, C1-C6 -haloalkoxy, C1C6 -alkylthio, C1-C6 alkylthio, carboxy, carbamoyl or C2-C6alkanoyl group which may be unsubstituted or substituted on the alkyl moiety by halogen or a pharmaceutically acceptable salt thereof; and/or

[0073] vi) an isoxazoline compound of formula (VI) where Y is hydrogen, fluorine, chlorine or bromine;

[0074] R1 represents a phenyl group substituted with 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy;

[0075] R2 represents a methyl, fluoromethyl, trifluoromethyl or perfluoroethyl group;

[0076] R3a and R3b are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R3a and R3b together combine with the carbon to which they are attached to form a cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically acceptable salt thereof;

[0077] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[0078] c) optionally, at least one co-solvent;

[0079] d) optionally, an antioxidant; It is

[0080] e) acceptable additive, excipient, optionally, at least one pharmaceutical carrier or mixtures thereof;

[0081] in which no other pharmaceutically acceptable polymers are present.

[0082] In one embodiment, the co-solvent is a polar organic solvent that is miscible with water. In one embodiment, the co-solvent is a protic solvent such as an alcohol (e.g. ethanol or isopropanol). In another embodiment, the co-solvent is a polar aprotic solvent such as N-methyl-pyrrolidone, propylene carbonate, and the like. In another embodiment, the co-solvent is an organic solvent that is not miscible with water.

[0083] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) An antiparasitic effective amount of at least one isoxazoline compound of formula (I):

[0084] A1, A2, A3, A4, A5 and A6 are independently selected from the group consisting of CRa and N, provided that at most three of A1, A2, A3, A4, A5 and A6 are N;

[0085] B1, B2 and B3 are independently selected from the group consisting of CR 2 and N;

[0086] W is O or S;

[0087] R1 represents C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl or C4-C7cycloalkylalkyl, each optionally substituted with one or more substituents selected independently of R6;

[0088] each R2 independently represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1- C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6dialkylamine, C2-C4 alkoxycarbonyl, -CN or -N02;

[0089] each R3 independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1C6 alkylthio, C1-C6 haloalkylthio, C1- C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6dialkylamino, -CN or -N0 2;

[0090] R4 H, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl, C4-C7cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7-carbonyl;

[0091] R5 is H, OR10, NR11 R12 or Q1; or C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl or C4-C7cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or

[0092] R4 and R5 are taken together with the nitrogen to which they are bonded to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, -CN, -nO2 and C1-C2 alkoxy; each R 6 independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, - CN or - N0 2;

[0093] each R7 independently represents halogen; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8-dialkylamino, C3C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2 -C7 alkoxy, C2C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, -NH2, -CN or-N02; or Q2;

[0094] Each R is independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1 C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkoxycarbonyl, - CN or NO2;

[0095] each R9 independently represents halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio , C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6dialkylamine, - CN, - NO 2 , phenyl or pyridinyl;

[0096] R10 is H; or C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl or C4-C7cycloalkylalkyl, each optionally substituted with one of more halogen;

[0097] R11 is H, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7alkylcycloalkyl, C4-C7cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 - carbonyl;

[0098] R12 is H; Q3; or C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or

[0099] R11 and R12 are taken together with the nitrogen to which they are bonded to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy;

[00100] Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring or an 8-, 9- or 10-membered fused bicyclic ring system that optionally contains one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring system or ring optionally substituted with one or more substituents independently selected from R8;

[00101] each Q2 independently represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9;

[00102] Q3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; It is

[00103] n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof;

[00104] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00105] c) optionally, at least one co-solvent;

[00106] d) optionally, an antioxidant; It is

[00107] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00108] in which no other pharmaceutically acceptable polymers are present.

[00109] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) an iparasitic effective amount of an isoxazoline compound of formula ( there): or a pharmaceutically acceptable salt thereof

[00110] b) optionally, at least one pharmaceutically acceptable polymer that is a poloxamer;

[00111] c) optionally, at least one co-solvent;

[00112] d) optionally, an antioxidant; It is

[00113] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00114] in which no other pharmaceutically acceptable polymers are present.

[00115] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) an effective amount of antiparasites, at least one compound of isoxazoline of formula (II): on what:

[00116] R1 represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl group, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di( alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)- , R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2;

[00117] alkoxy, haloalkoxy, alkylthio haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)0-, R7C(O)NR8 -, -CN or -NO2;

[00118] A1 is oxygen; It is

[00119] A2 is oxygen, NR 2 or CR 7 R 8 ;

[00120] G is G-1 or G-2;

[00121]

[00122] B1, B2, B3, B4 and B5 are independently N or C-R9;

[00123] Y is hydrogen, halogen, -CN; or Y represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl group, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, -CN or -NO2; or Y is Y-1, Y-2, Y-3, Y-4, Y-5,Y-6, Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;

[00124] R2, R3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R10S(O)-, R1oS(O)2-, R1oC(O)- , R1oC(S)-, R10R11NC(O)-, R10R1iNC(S)- R1oOC(O)-;

[00125] R4, R5 and R6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylakyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

[00126] R7 and R8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylakyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;

[00127] R9 is hydrogen, halogen, -CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of them being unsubstituted or substituted with one or more halogen, hydroxyl, amino , alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)- , R7R8NC(O)-, R7OC(O)-, R7C(O)0-, R7C(O)NR8-, -CN or - NO2;

[00128] R10, R11, R12 and R13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylakyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or

[00129] R10 together with the form R11 = O, = S or = NR2; or

[00130] R12 together with the form R13 = O, = S or = NR2;

[00131] W is O, S or NR2;

[00132] n is 1-4; It is

[00133] m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof;

[00134] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00135] c) optionally, at least one co-solvent;

[00136] d) optionally, an antioxidant; It is

[00137] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00138] in which no other pharmaceutically acceptable polymers are present.

[00139] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of the formulas II-1.001 to n- 1.025 and n-2.00-n-2.018: Compounds II-1,001 to II-1,025 Compounds II-2001 to II-2018 or a pharmaceutically acceptable salt thereof;

[00140] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00141] c) optionally, at least one co-solvent;

[00142] d) optionally, an antioxidant; It is

[00143] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00144] in which no other pharmaceutically acceptable polymers are present.

[00145] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) an effective amount of antiparasitic and isoxazoline compound of formula ( III) (III) or a pharmaceutically acceptable salt thereof;

[00146] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00147] c) optionally at least one co-solvent;

[00148] d) optionally, an antioxidant; It is

[00149] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00150] in which no other pharmaceutically acceptable polymers are present.

[00151] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising:

[00152] iv) an effective amount of an isoxazoline antiparasitic compound of formula (IV)

[00153] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00154] c) optionally at least one co-solvent;

[00155] d) optionally, an antioxidant; It is

[00156] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00157] in which no other pharmaceutically acceptable polymers are present.

[00158] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula (V): where R1, R2 and R3 are independently H, Cl, F or CF3; Y is the diradical group

[00159] T is a C1-C6 alkyl group that is unsubstituted or substituted by halogen, cyano, nitro, amino, hydroxyl, C1-C6 -alkoxy, C1-C6 -haloalkoxy, C1C6 -alkylthio, C1-C6 alkylthio, carboxy, carbamoyl or C2-C6alkanoyl group which may be unsubstituted or substituted on the alkyl moiety by halogen or a pharmaceutically acceptable salt thereof

[00160] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00161] c) optionally, at least one co-solvent;

[00162] d) optionally, an antioxidant; It is

[00163] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00164] in which no other pharmaceutically acceptable polymers are present.

[00165] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising a) an antiparasitic effective amount of an isoxazoline compound of formula (Va ):

[00166] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00167] c) optionally, at least one co-solvent;

[00168] d) optionally, an antioxidant; It is

[00169] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00170] in which no other pharmaceutically acceptable polymers are present.

[00171] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising a) an antiparasitic effective amount of at least one compound of formula (VI ): on what

[00172] Y is hydrogen, fluorine, chlorine or bromine;

[00173] R1 represents a phenyl group substituted with 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy;

[00174] R2 represents a methyl, fluoromethyl, trifluoromethyl or perfluoroethyl group;

[00175] R3a and R3b are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R3a and R3b together combine with the carbon to which they are attached to form a cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically acceptable salt thereof

[00176] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00177] c) optionally at least one co-solvent;

[00178] d) optionally, an antioxidant; It is

[00179] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00180] in which no other pharmaceutically acceptable polymers are present.

[00181] In another embodiment, the present invention provides a long-acting injectable formulation for the treatment and/or prevention (prophylaxis) of infections and parasitic infestations of animals comprising: a) an effective amount of antiparasites, at least one compound of formula (VIa):

[00182]

[00183] (Via)

[00184] b) at least one pharmaceutically acceptable polymer that is a poloxamer;

[00185] c) optionally at least one co-solvent;

[00186] d) optionally, an antioxidant; It is

[00187] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof;

[00188] in which no other pharmaceutically acceptable polymers are present.

[00189] In another embodiment, the long-acting injectable formulations of the present invention comprise an effective amount of antiparasites, at least one isoxazoline of Formula (I), which has the formula (lb): (1b) or a pharmaceutically acceptable salt thereof in which

[00190] R2 is, independently, halogen, C1-C6 alkyl or C1-C6 haloalkyl

[00191] R4 is H or C1-C6 alkyl;

[00192] R5 represents C1-C4 alkyl optionally substituted with one or more R 7 groups; and R 7 represents C2-C7 alkylcarbonyl, C2-C7 alkoxy, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7-haloalkoxy, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl (e.g. -CH2C(O)NHCH2CF3); It is

[00193] n is 0, 1 or 2.

[00194] In another embodiment, the long-acting injectable formulations of the present invention comprise an antiparasitic effective amount of 4- [5- [3-chloro-5- (trifluoromethyl) phenyl] -4,5-dihydro-5- (trifluoromethyl)-3isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide (Compound of formula Ia).

[00195] Compounds of formula (I) through formula (Via) can exist as stereoisomers, where there is a chiral center and these individual stereoisomers are encompassed by the structural formulas represented here. Thus, in another embodiment, the long-acting injectable formulations of the present invention comprise an antiparasitic effective amount of at least one isoxazoline of Formula (I), Formula (Ia), Formula (II), Formula (II-1, 1001) to Formula (II-1.025), Formula (π-2.001) to Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Via), which is enriched in an enantiomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the compounds of formula (I) of formula (Via) present in the compositions of the invention are enriched in one enantiomer (or (S) - or (reconfiguration) in a weightweight ratio of at least 1.5, at least two , at least five or at least 10. In another embodiment, the compounds of formula (I) to formula (Via) present in the compositions of the invention are essentially pure enantiomers.

[00196] Processes for preparing individual stereoisomers of the compounds of formula (I) through formula (route) (for example, the stereoisomers for formula I-la and formula I-lb below) from a racemic mixture comprising the even are fine with the common skill level skill in this art. Processes include, for example, recrystallization or chiral chromatography using, for example, a Chiralpak® AD column, and processes for preparing individual stereoisomers of an isoxazoline compound are found in the prior art (see, for example, WO 2014/090918 Al , WO 2011/104089 Al or US 2010/0254959 Al).

[00197] The various stereoisomers include enantiomers, diastereomers and atopisomers. One skilled in the art will understand that one stereoisomer may be more active and/or may exhibit beneficial properties when enriched relative to the other enantiomer. Furthermore, the person skilled in the art knows how to selectively separate, enrich and/or prepare a stereoisomer of the isoxazoline compounds described herein. The isoxazoline compounds of formula (I) in formula (Via) described herein contain a chiral carbon atom in the five-membered isoxazoline ring (shown by the asterisk (*), therefore the compounds will contain at least two possible stereoisomers (eg enantiomers). As an example for compounds of formula (la), the two possible quaternary carbon sterols are shown and (R) -Ia:

[00198] The compound of formula (S) -Ia above has the (S) configuration on the chiral carbon atom in the isoxazoline ring and the compound of formula (R) -Ia has the (R) configuration on the chiral carbon in the ring.

[00199] In one embodiment, the composition of the invention comprises a compound of formula (I), (Ia) or (lb) that is substantially enriched in one enantiomer. By the term substantially enriched is meant where the weight ratio is at least about 1.5 to 1 or greater in favor of the desired enantiomer. In another embodiment, the long-acting injectable compositions of the present invention comprise a compound of formula (I), (la) or (Ib) that is substantially enriched in the (S) enantiomer. In another embodiment, the long-acting injectable compositions of the present invention comprise a compound of formula (I), (Ia) or (lb) that is substantially enriched in the (R) enantiomer.

[00200] In another embodiment of the invention, the compositions comprise a compound of formula (I), (la) or (lb) which is enriched in the (S) enantiomer in a weight ratio of at least approximately 2 to 1, (S) -enantiomer for (R)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of formula (I), (la) or (lb) which is enriched in the (S) enantiomer in a weight:weight ratio of at least about 5 to 1, (S) - enantiomer to (R)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of formula (I), (la) or (lb) that is enriched in the (S) enantiomer in a weight:weight ratio of at least approximately 10 to 1, (S) - enantiomer for (R) - enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of formula (I), (la) or (lb) which is essentially the pure (S) enantiomer.

[00201] In another embodiment of the invention, the compositions comprise a compound of formula (I), (la) or (lb) that is enriched in the enantiomer (R) in a weight to weight ratio of at least approximately 2 to 1, O (R)-enantiomer for (, S)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of formula (I), (la) or (lb) which is enriched in the (R) enantiomer in a weight:weight ratio of at least about 5 to 1, (R) - enantiomer to (S)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of formula (I), (la) or (lb) that is enriched in the (R) enantiomer in a weight:weight ratio of at least about 10 to 1, (R) - enantiomer to (S)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of formula (I), (la) or (lb) which is essentially the pure (R) enantiomer.

[00202] The molecular representations drawn here follow standard conventions for describing stereochemistry. To indicate stereo configuration, bonds rising from the drawing plane and towards the observer are denoted by solid wedges, where the wide end of the wedge is connected to the crescent atom starting from the drawing plane towards the observer. Bonds going below the plane of the drawing and away from the viewer are denoted by dashed wedges, where the narrowest end of the wedge is bonded to the atom furthest from the viewer. Constant different line widths indicate connections in an opposite or neutral direction to connections shown with solid or dashed wedges; Constant different line widths also represent bonds in molecules or parts of molecules in which no particular stereo configuration is intended to be specified.

[00203] In one embodiment of the invention, it is considered that the most biologically active enantiomer is Formula I-la. Formula I-la has the (S) configuration on the chiral carbon of the isoxazoline ring and Formula I-lb has the (R) configuration on the chiral carbon. Similarly, biologically active enantiomers of isoxazoline compounds of formula (II) to (Via) are believed to have the (S) configuration at the chiral carbon of the isoxazoline ring. In certain embodiments, an isoxazoline compound of the invention or compositions comprising the compound that are enriched in one enantiomer that exhibits significant in vitro and in vivo activity (the eutomer) with a favorable toxicity profile while a compound or composition enriched in the other Corresponding enantiomer exhibits significantly less activity in vitro and in vivo (the distomer).

[00204] The present invention comprises racemic mixtures, for example, equal amounts of the enantiomers of isoxazoline compounds of Formulas (I) to (VIA). The invention includes compounds of Formula (I), Formula (Ia), formula (Ib), formula (II), formula (II-1.1001) to Formula (II-1.025), Formula (pi-2.001) to Formula ( 11- 018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (VIA) that are enriched in one enantiomer compared to the racemic mixture. Also included are the essentially pure enantiomers of the compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (II-1.1001) to Formula (II-1.025), Formula (π- 2.001) for Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI), or Formula (Via).

[00205] When enantiomerically enriched, one enantiomer is present in greater quantities than the other, and the degree of enrichment can be defined by an expression of enantiomeric excess ("ee"), which is defined as (2x-l) 100% , where x is the mole fraction of the predominant enantiomer in the mixture (for example, an ee of 20% corresponds to an enantiomer ratio of 60:40). In some embodiments, the compositions of the invention comprise compounds that have at least a 50% enantiomeric excess. In other embodiments, the compositions of the invention comprise compounds that have at least a 75% enantiomeric excess, at least a 90% enantiomeric excess, or at least a 94% enantiomeric excess of the most active isomer. Of particular interest are enantiomerically pure embodiments of the most active isomer (the eutomer).

[00206] The compounds of this invention can exist as one or more conformational isomers due to restricted rotation around the amide bond linked to the aryl or heteroaryl ring (for example, the amide linked to the naphthyl group in Formula (I)). This invention comprises mixtures of conformational isomers. Furthermore, this invention includes compounds that are enriched in one conformer relative to the others.

[00207] It will be appreciated that, in addition to the compounds of formula (Ia), the other isoxazoline compounds of general formula (I), Formula (Ib), formula (II), Formula (II- 1.1001) to Formula ( II-1.025), formula (π-2.001), formula (11-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) and formula (Via) will also have , at least two possible enantiomers, as a result of the quaternary carbon atom of the isoxazoline ring. Furthermore, certain compounds may include other chiral centers in one or more substituents.

[00208] In one embodiment, the composition of the invention comprises a compound of formula (la) that is substantially enriched in one enantiomer. By substantially enriched meaning, it means that the weight ratio is at least approximately 1.5 to 1 or more in favor of the desired enantiomer. In another embodiment, the long-acting injectable compositions of the invention comprise a compound of formula (la) that is substantially enriched in the (S) enantiomer. In another embodiment, the long-acting injectable compositions of the invention comprise a compound of formula (la) that is substantially enriched in the (R)-enantiomer.

[00209] Therefore, in one embodiment of the invention, the compositions comprise a compound of Formula (I), Formula (la), Formula (lb), Formula (II), Formula (II-1.1001) in Formula (II-1.025) , Formula (π-2.001) in Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Via) enriched in (S) - enantiomer in a weight:weight ratio of at least approximately 2 to 1, (S) enantiomer to (R) enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of Formula (I), Formula (la), Formula (lb), Formula (II), Formula (II-1.1001) in Formula (II-1.025), Formula (n- 2001) in Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Route), which is enriched in the (S) - enantiomer in a weight ratio: weight of at least about 5 to 1, (S) enantiomer to (R) enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of Formula (I), Formula (la), Formula (lb), Formula (II), Formula (II-1.1001) in Formula (II-1.025), Formula (II- 2001) in Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Route), which is enriched in the (S)-enantiomer in a weight ratio of at least approximately 10 to 1, (S)-enantiomer to (R)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of Formula (I), Formula (Ia), formula (Ib), formula (II), formula (II-1.1001) to Formula (II-1.025), Formula ( n-2.001) of formula (11-018), Formula (III), formula (IV), Formula (V), formula (Va), Formula (VI) or formula (Via), which is essentially the enantiomer ( S) -enantiomer.

[00210] In another embodiment of the invention, the compositions comprise a compound of Formula (I), Formula (la), Formula (lb), Formula (II), Formula (II-1.1001) in Formula (II-1.025) , Formula (II-2.001) to Formula (11018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Via), which is enriched in (R) in a weight ratio is at least approximately 2 to 1, (R)-enantiomer in (S)-enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of Formula (I), Formula (la), Formula (lb), Formula (II), Formula (n-1.1001) in Formula (II-1.025), Formula (n- 2001) in Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Route), which is enriched in the (R)-enantiomer in a weight weight ratio of at least about 5 to 1, (R) enantiomer to (S) enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of Formula (I), Formula (la), Formula (lb), Formula (II), Formula (n- 1.1001) in Formula (II-1.025), Formula (n- 2001) in Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Route), which is enriched in the (R)-enantiomer in a weight:weight ratio of at least approximately 10 to 1, (R) enantiomer to (S) enantiomer, or greater. In yet another embodiment, the compositions of the invention comprise a compound of Formula (I), Formula (II), Formula (II-1.1001) in Formula (II-1.025), Formula (II-2.001) in Formula (11-018), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (VI) or Formula (Via), which is essentially the pure (R) enantiomer.

[00211] In another embodiment, the long-acting injectable formulations of the present invention comprise an effective amount of antiparasites, at least one isoxazoline disclosed in US7,964,204, US 2010/0254960 Al, US2011/0159107, US2012/0309620, US2012/ 0030841, US2010/0069247, WO 2007/125984, WO 2012/086462, US 8318757, US 8466115, US 8618126, US 8822466, US8383659, US8853186, US 2011/01 44349, US 8053452; US 2010/0137612, US 2010/0254959, US 2011/152081, WO 2012/089623, WO 2012/089622, US 8, 119,671; US 7947715; WO 2102/120135, WO 2012/107533, WO 2011/157748, US 2011/0245274, US 2011/0245239, US 2012/0232026, US 2012/0077765, US 2012/0035122, US 2011/0251247, WO 2011/ 154433, WO 2011/154434, US 2012/0238517, US 2011/0166193, WO 2011/104088, WO 2011/104087, WO 2011/104089, US 2012/015946, US 2009/0 143410, WO 2007/123855 A2, US 2011/0118212, US7951828 and US7662972, US 2010/0137372 Al, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al, US 7,897 630 and US 7,951,828, all which are incorporated herein by reference in their entirety.

[00212] In yet another embodiment, the long-acting injectable formulations of the present invention comprise an effective amount of antiparasites, at least one isoxazoline compound described in WO 2009/02451A2 and WO 2011/075591 Al, both incorporated herein by reference in your totality.

[00213] In one embodiment, the compositions of the invention may comprise about 1 to about 50% (w/v) of an isoxazoline active agent. In another embodiment, the compositions comprise about 5 to about 50% (w/v) of an isoxazoline active agent. In another embodiment, the compositions of the invention comprise about 5 to about 40% (w/v) or about 5 to about 30% (w/v) of an isoxazoline active agent. In yet another embodiment, the compositions of the invention comprise about 5 to about 20% (w/v) of an isoxazoline active agent. In another embodiment, the compositions may comprise about 10 to about 50% (w/v) of an isoxazoline active agent. In another embodiment, the compositions may comprise about 10 to about 40% (w/v) of an isoxazoline active agent. In yet another embodiment, the compositions of the invention may comprise about 15% to about 40% (w/v), about 10% to about 35% (w/v), or about 15% to about 30%) (w/v) of an isoxazoline compound.

[00214] In one embodiment, the compositions of the invention may comprise about 1% to about 70%) (w/v) of a co-solvent or a mixture of co-solvents. In another embodiment, the compositions of the invention may comprise from about 1% to about 60% (w/v) of a co-solvent or a mixture of co-solvents. In another embodiment, the compositions of the invention may comprise about 1% to about 50%) (w/v) of a co-solvent or a mixture of co-solvents. In yet another embodiment, the compositions may comprise about 5% to about 50% (w/v), about 5% to about 40% (w/v), or about 5% to about 35% (w/v). / v) of a co-solvent or a mixture of co-solvents. In another embodiment, the compositions of the invention may comprise about 0.01% to about 10%) (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof. In other embodiments, the compositions may comprise about 0.01% to about 5% (w/v), about 0.1% to about 10%) (w/v), or about 0.1% (w/v) % to about 5% (w/v) of an additive, pharmaceutically acceptable excipient, or mixtures thereof.

[00215] In another embodiment, the compositions of the invention may comprise about 0.01% to about 3% (w/v) of an antioxidant. In other embodiments, the compositions may comprise about 0.01% to about 2% (w/v) of an antioxidant.

[00216] In certain embodiments of the present invention provides for long-acting injectable formulations for the treatment and/or prevention of infections and parasitic infestations of animals comprising: a) about 15 to 30% (w/v) of an active agent of isoxazoline, such as, for example, any of the isoxazoline compounds provided for in the above embodiments (for example, a compound of Formula I-Via); b) pharmaceutically acceptable polymer, which is a poloxamer; c) optionally, about 5% to 70% (w/v) co-solvent or a mixture of co-solvents, which is a water-miscible polar solvent; d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof

[00217] wherein the polymer present in just said pharmaceutically acceptable long-acting injectable composition is a poloxamer and wherein the poloxamer is present in the overall composition, in a proportion that represents the complement for 100% of the composition.

[00218] In certain embodiments of the present invention provides for long-acting injectable formulations for the treatment and/or prophylaxis of infections and parasitic infestations of animals comprising: a) about 10 to 30% (w/v) of an active agent of isoxazoline, such as, for example, any of the isoxazoline compounds provided for in the above embodiments (for example, a compound of Formulas I-Via), such as, a compound of the formula: (S)-(VIa) or a pharmaceutically acceptable salt thereof,

[00219] b) pharmaceutically acceptable polymer, which is a poloxamer;

[00220] c) optionally, about 5% to about 70% (w/v) co-solvent selected from the group consisting of ethanol, isopropanol, a liquid polyethylene glycol (e.g., PEG 400) or a mixture of any of the previous ones;

[00221] d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; It is

[00222] e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof;

[00223] wherein the polymer present in just said pharmaceutically acceptable long-acting injectable composition is a poloxamer and wherein the poloxamer is present in the overall composition, in a proportion that represents the complement for 100% of the composition.

[00224] Another embodiment of the present invention is a long-acting injectable formulation for the treatment and/or prevention of infections and parasitic infestations of animals consisting essentially of: a) an effective amount of antiparasites, at least one active agent isoxazoline, such as, for example, any of the isoxazoline compounds provided for in the above embodiments (e.g., a compound of Formulas I-Via), and, optionally, at least one additional active agent as identified in the present application; b) a poloxamer; c) optionally, at least one co-solvent wherein said co-solvent is a water-miscible polar solvent; d) optionally, an antioxidant; and e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof.

[00225] Another embodiment of the present invention is a long-acting injectable formulation for the treatment and/or prevention of infections and parasitic infestations of animals consisting of: a) an antiparasitic effective amount of at least one isoxazoline active agent, such as, for example, any of the isoxazoline compounds provided for in the above embodiments (e.g., a compound of Formulas I-Via), and optionally at least one additional active agent as identified in the present application;

[00226] b) a poloxamer;

[00227] c) at least one co-solvent wherein said co-solvent is a water-miscible polar solvent; d) optionally, an antioxidant; It is

[00228] e) optionally, acceptable additive, at least one pharmaceutical excipient or mixtures thereof.

[00229] In the present specification and the claims, terms such as "comprises", "comprising", "containing" and "having" and the like, may have the meaning assigned to them in U.S. Patent law and may mean " includes", "including," and similar; "Consisting essentially of or 'essentially consists' also has the meaning assigned in U.S. Patent law and the term is open-ended, allowing for the presence of more than what is recited as long as basic or novel features of what is recited is not altered by the presence of more than what is recited, but excludes prior art embodiments. The term "consisting of" excludes any element, step or ingredient not specified in the claims. Definitions

[00230] The terms used here will have their usual meaning in the art, unless otherwise specified. The organic moieties mentioned in the definitions of the variables of formula (I) are -like the term @halogen@ - collective terms for individual listings of the individual members of the group. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group.

[00231] The term "animal" is used herein to include all mammals, birds and fish and also to include all vertebrate animals. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also includes an individual animal at all stages of development, including embryonic and fetal stages. In some embodiments, the animal will be a non-human animal.

[00232] The term "essentially pure" is used herein to indicate that a compound or an enantiomer thereof is at least about 90% pure, at least about 95%, at least about 98% pure, or greater.

[00233] The term "alkyl" refers to primary, straight-chain, branched, cyclic, secondary or tertiary saturated hydrocarbons, including those having 1 to 20 atoms. In some embodiments, the alkyl groups include C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 or C 1 C 4 alkyl groups. Examples of C 1 -C 10 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, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C 1 -C 4 alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[00234] Cyclic alkyl groups or "cycloalkyl", which are covered by alkyl include those with 3 to 10 carbon atoms and which have single or multiple condensed rings. In some embodiments, cycloalkyl groups include C4-C7 or C3-C4 cyclic alkyl groups. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[00235] The alkyl groups described herein may be unsubstituted or substituted with one or more portions selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, arylamino , alkoxy aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine , carbamate, phosphoric acid, phosphate, phosphonate or any other viable functional group that does not inhibit the biological activity of the compounds of the invention, whether unprotected or protected if necessary, as is known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, incorporated herein by reference.

[00236] Terms including the term "alkyl" such as "alkylcycloalkyl", "cycloalkylalkyl", "alkylamino" or "dialkylamino" will be understood to include an alkyl group as defined above, attached to the other functional group, where the group is attached to the compound via the last listed group, as understood by those skilled in the art.

[00237] The term "alkenyl" refers to linear and branched carbon chains that have a double bond, at least one carbon-carbon bond. In some embodiments, the alkenyl groups may include C 2 -C 20 alkenyl groups. In other embodiments, it includes C 2 -C 12 alkenyl, C 2 -C 10 , C 2 -C8, C 2 -C6 or C 2 alkenyl groups. In one embodiment of alkenyl, the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one or two. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated, depending on the location of the alkenyl moiety on the molecule. "C 2 -C 1 o-alkenyl" groups may include more than one double bond in the chain. Examples include, but are not limited to, 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, 2-hexenyl, 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-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl , 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,

[00238] 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, 1-dimethyl-2-butenyl, 1, 1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1 , 2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2 ,2-dimethyl-3-butenyl, 2,3-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.

[00239] "Alkynyl" refers to linear and branched carbon chains that have a triple bond, at least one carbon-carbon bond. In an 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, alkynyl groups include from C 2 -C 20 alkynyl. In other embodiments, the alkynyl groups may include C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C6 or C 2 -C 4 alkynyl. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated, depending on the location of the alkenyl moiety on the molecule. For example, the term "C 2 -C 1 o-alkynyl" as used herein refers to a straight chain or unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop. -1-branched -yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1- y-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-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-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl , n-hex-1-yn-4-yl, n-hex-1-yn-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-3-yn-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 and the like.

[00240] The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted by one or more halogen atoms. For example, C 1 -C 4 haloalkyl includes, but is not limited to, 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.

[00241] The term "haloalkenyl" refers to an alkenyl group, as defined herein, that is substituted by one or more halogen atoms.

[00242] The term "haloalkynyl" refers to an alkynyl group, as defined herein, that is substituted by one or more halogen atoms.

[00243] "Alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Similarly, the terms

[00244] "alkenyloxy," alkynyloxy, ""haloalkoxy," "haloalkenyloxy," "haloalkynyloxy," "cycloalkoxy," "cycloalkenyloxy," "halocycloalkoxy," and "halocycloalkenyloxy" refer to alkenyl-0-, alkynyl- groups O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, C2H5-CH2O-, (CH3)2CHO, n-butoxy, C2H5-CH(CH3)0 -, (CH 3 ) 2 CH-CH 2 0- ; (CH 3 ) 3-CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1, 1-dimethylpropoxy, 1.2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1 -methylpentoxy, 2-methylpentoxy, 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 and the like.

[00245] The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above. Likewise, the terms "haloalkylthio," "cycloalkylthio," and the like, refer to haloalkyl-S- and cycloalkyl-S-, where haloalkyl and cycloalkyl are as defined above.

[00246] The term "alkylsulfinyl" refers to alkyl-S(O)-, where alkyl is as defined above.

[00247] Likewise, the term "haloalkylsulfinyl" refers to haloalkyl-S(O) - where haloalkyl is as defined above.

[00248] The term "alkyl sulfonyl" refers to alkyl-S(O)2-, where alkyl is as defined above.

[00249] Likewise, the term "haloalkylsulfonyl" refers to haloalkyl-S(O)2- where haloalkyl is as defined above.

[00250] The terms alkylamino and dialkylamino refer to alkyl-NH- and (alkyl) 2N- where alkyl is as defined above. Likewise, the terms "haloalkylamino" refer to haloalkyl-NH- where haloalkyl is as defined above.

[00251] The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino- C(O) - where alkyl, alkoxy, alkylamino and dialkylamino are as defined above.

[00252] Likewise, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl" and "dihaloalkylaminocarbonyl" refer to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O ) and dihaloalkylamino- C(O) - where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.

[00253] "Aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. In some embodiments, the aryl groups include C 6 -C 1 S aryl groups. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indanyl and phenylcyclopropyl. Aryl groups may be unsubstituted or substituted by one or more radicals selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, sulfinyl alkyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalken ilsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl -sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)amino, di(alkynyl)amino, or trialkylsilyl.

[00254] The terms "aralkyl" or "arylalkyl" refers to an aryl group that is linked to the parent compound through a di-radical alkylene bridge, (-CH 2 -) n , where n is 1-12 and where "aryl" is as defined above

[00255] "Heteroaryl" refers to a monovalent aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, having one or more oxygen, nitrogen, and sulfur heteroatoms within the ring, of preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. Nitrogen and sulfur heteroatoms can optionally be oxidized. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple fused rings, as long as the point of attachment is through a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, and benzothiophenyl. Heteroaryl rings may be unsubstituted or substituted by one or more radicals as described for aryl above.

[00256] "Heterocyclyl", "heterocyclic" or "heterocycle" refers to completely saturated or unsaturated cyclic groups, for example, 3 to 7 membered monocyclic or 4 to 7 membered monocyclic; 7 to 11 bicyclic members, or 10 to 15 tricyclic member ring systems, which have one or more oxygen, sulfur or nitrogen atoms in the ring, preferably 1 to 4 or 1 to 3 heteroatoms. nitrogen and sulfur heteroatoms can optionally be oxidized and nitrogen heteroatoms can optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted by one or more radicals as described for the aryl groups above.

[00257] Illustrative monocyclic heterocyclic groups include, but are not limited to, 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-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

[00258] Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinolinolyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as fur[2,3-c] pyridinyl, fur[3,2-b] pyridinyl] or fur[2,3b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl ( such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

[00259] Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[00260] Halogen means the atoms of fluorine, chlorine, bromine and iodine. The designation "halo" (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitution from a single substitution to a substitution, per-halo (e.g. as illustrated with methyl as chloromethyl (CH 2 C1), dichloromethyl (-CHCl 2 ), trichloromethyl (-CC1 3 )).

[00261] By the term "enriched" is meant when the weight to weight ratio is at least approximately 1.05 or greater, in favor of the enantiomer that exhibits significant in vitro and in vivo activity (the eutomer). Stereoisomers and polymorphic forms

[00262] As noted above, it will be appreciated by those skilled in the art that certain compounds within the scope of the compositions of the present invention can exist and be isolated in optically active form and racemic forms. Compounds having one or more chiral centers, such as those of formula (I) to formula (Via) above, including a sulfur atom, may be present as individual enantiomers or diastereomers, or as mixtures of enantiomers and/or diastereomers. For example, it is well known in the art that sulfoxide compounds can be optically active and can exist as individual enantiomers or racemic mixtures. Furthermore, compounds within the compositions of the invention may include one or more chiral centers, which results in a theoretical number of optically active isomers. When compounds within the compositions of the present invention include n chiral centers, the compounds may comprise up to 2n optical isomers. The present invention encompasses compositions comprising the specific enantiomers or diastereomers of each compound, as well as mixtures of different enantiomers and/or diastereomers of the compounds of the invention that have the properties described herein. Furthermore, the invention encompasses compositions comprising one or more conformational isomers (e.g., rotamers), as well as mixtures of conformational isomers. Conformational isomers of isoxazoline compounds can be produced by a rotation restriction around the amide bond attached to the aryl or heteroaryl ring (e.g., the amide bonded to the naphthyl group in Formula (I)). Optically active forms can be prepared, for example, by resolution of racemic forms by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution.

[00263] Furthermore, the compounds within the compositions of the present invention may exist in the form of hydrates or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in crystalline form. The compositions of the invention may include hydrates and solvates of the active agents. In some embodiments, the compositions of the invention may include up to 15% (w/w), up to 20% (w/w), or up to 30% (w/w) of a particular solid form.

Salts

[00264] Also contemplated within the scope of the invention are salts of acids or bases, if applicable, of the compounds of the invention provided for herein.

[00265] The term "acid salt" encompasses salts of compounds with all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalogenated acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment of the acids, the acids are straight or branched chain C1-C20 aliphatic carboxylic acids, saturated or unsaturated, which are optionally substituted by halogen or hydroxyl groups, or C6-C12 aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, 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 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 phenylesic acid. Other acids include gluconic acid, glycoheptonic acid and lactobionic acid.

[00266] The term "base salt" encompasses salts of compounds with all pharmaceutically acceptable inorganic or organic bases, including hydroxides, carbonates or bicarbonates of alkaline or alkaline earth metal metals. Salts formed with such bases include, for example, alkali metal and alkaline earth metal salts, including, but not limited to, lithium, sodium, potassium, magnesium or calcium salts. Salts formed with organic bases include the common hydrocarbon and heterocyclic amine salts, which include, for example, ammonium salts (NH4+), alkyl- and dialkyl ammonium salts, and cyclic amine salts, such as morpholine and piperidine salts. .

[00267] In another embodiment, the long-acting injectable formulations of the present invention comprise an effective amount of at least one isoxazoline or a pharmaceutically acceptable salt thereof, in combination with at least one other active agent. In one embodiment, the long-acting injectable compositions comprise an effective amount of at least one isoxazoline compound of formula (I) to (Via), or a pharmaceutically acceptable salt thereof, in combination with at least one other active agent that is systemically -active.

[00268] Additional veterinary/pharmaceutical active ingredients may be used with the compositions of the invention. In some embodiments, additional active agents may include, but are not limited to, acaricides, anthelmintics, antiparasitics and insecticides. Anti-parasitic agents may include both ectoparasiticidal and/or endoparasiticidal agents.

[00269] Veterinary pharmaceutical agents that can be included in the compositions of the invention are well known in the art (see for example the 'Veterinary Drug Handbook, 5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th Edition, (January 2005)) and include but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazol amide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, potassium clavulanate, amphotericin B with deoxycholate, read-based amphotericin B, ampicillin, amprolium, antacids (orally), antivenin, apomorphione, apramycin sulfate, ascorbic acid, asparaginase, aspirant, atenolol, atipamezole, besylate atracurium, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbituates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside , buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan di sodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, cefapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepid, chlordiazepoxide + /- clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarith romycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine , clomipramine, claonazepam, clonidine, cloprostenol sodium, dipotassium clorazepate, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium , dicloxacillin, diethylcarbamazine citrate, diethyl stilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprosttromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, disodium calcium edetate. Calcium EDTA, edrophonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid/ethacrinate sodium, ethanol (alcohol ), etidronate sodium, etodolac, etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, falepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, agents glucocorticoids, glucosamine/chondroitin sulfate, glutamine, glyburide, glycerin (orally), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXIGLOBIN®), heparin, hydroxyethyl starch, sodium hyaluronate, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate, impenemcilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium ), ipecac (syrup), sodium ipodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levadamisole, levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone acetate, medroxyprogesterone acetate megestrol, melarsomine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, mandela methenamine te/hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone, milbemycin midazolam oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics, sulfate neomycin, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprozole, ondansetron, anti-diarrheal opiates, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillamine, general information penicillins, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium , pentosan sodium polysulfate, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone, phenylephrine, phenypropanolamine, phenytoin sodium, pheromones, parenteral phosphate, a phytonadi / vitamin Kl, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated ponazuril, Glycosaminoglycan, Potassium Chloride, Pralidoxime Chloride, Prazosin, Prednisolone/Prednisone, Primidone, Procainamide, Procarbazine, Prochlorperazine, Propantheline Bromide, Propionibacterium Acnes Injection, Propofol, Propanolol, Protamine Sulfate, Pseudoephedrine, Hydrophilic Mucilloid Psyllium, Bromide pyridostigmine, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampicin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin, selegiline/1-deprenyl, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine/trimethoprim, trimethoprim/sulfamethoxazole, sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine, tepoxaline, terbinafline, terbutaline sulfate, testosterone, tetracycline, sodium thiacetarsamide, thiamine, thioguanine, sodium thiopental, thiotepa, thyrotropin, tiamulin, ticarcillin disodium, tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tocainide, tolazoline, telfenamic acid, topiramate, tramadol, trimcinolone acetonide, trientine, trilostane, trimepraxine tartrate w/prednisolone, tripelenamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), ethyl zinc/zinc sulfate, zonisamide and its mixtures.

[00270] In one embodiment of the invention, arylpyrazole compounds such as phenylpyrazoles, known in the art can be combined with isoxazoline compounds in the long-acting injectable compositions of the invention. Examples of such phenylpyrazol compounds include but are not limited to those described in US Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6, 174,540; 6,685,954 and 6,998, 131 (all of which are incorporated herein by reference, each assigned to Merial, Ltd., Duluth, GA).

[00271] In another embodiment of the invention, one or more macrocyclic lactones or lactams, which act as an acaricide, an anthelmintic agent and/or insecticide, can be added to the compositions of the invention.

[00272] Macrocyclic lactones include, but are not limited to, avermectins and avermectin analogs such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and ML-1, 694,554 and milbemycins and milbimycin analogs such as milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins. Examples of combinations of arylpyrazole compounds with macrocyclic lactones include, but are not limited to, those described in U.S. Patent Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998,131 (all incorporated herein by reference - each assigned to Merial, Ltd., Duluth, GA).

[00273] Macrocyclic lactone compounds are known in the art and can be easily obtained commercially or through synthetic techniques known in the art. Reference is made to widely available technical and commercial literature. For avermectins, ivermectin and abamectin, reference can be made, for example, to the work "Ivermectin and Abamectin", 1989, by H. MH Fischer and Mrozik, William C. Campbell, published by Springer Verlag., or by Albers-Schonberg et al. (1981), "Avermectin structure determination", J. Am. Chem. Soc, 103, 42164221. For doramectin, "Veterinary Parasitology", vol. 49, N ° 1, July 1993, 15/05 can be consulted. For milbemycins, reference may be made, among others, to HG Davies 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, 53335336, US Patent No. 4,134,973 and EP 0 677 054.

[00274] Macrocyclic lactones are natural products or semi-synthetic derivatives thereof. The structure of avermectins and milbemycins are closely related, for example, through sharing a 16-membered macrocyclic lactone ring complex. The natural avermectin products are described in US Patent No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosed in US Patent No. 4,199,569. Also refer to US Patent Nos. 4468390, 5824653, EP 0 007 812 Al, UK Patent Specification 1 390 336, EP 0 002 916, and New Zealand Patent No. 237 086, among other things. Naturally occurring milbemycins are described in US Patent No. 3,950,360, as well as in the various references cited in "The Merck Index" 12 Ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in the section "International non-proprietary names for pharmaceutical substances (INNs)," WHO Medicines Information, vol. 17, no. 4, pp. 263286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in US Patent Nos. 5077308, 4859657, 4963582, 4855317, 4871719, 4874749, 4427663, 4310519, 4, 199,569, 5,055,596, 4,973,711, 4,978,677, 492 0148 and EP 0 667 054.

[00275] In another embodiment of the invention, the invention comprises a long-acting injectable formulation comprising an isoxazoline compound in combination with compounds that act systemically from a class of acaricides or insecticides known as insect growth regulators (ICR). The compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. These compounds all act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in US Patent Nos. 3748356, 3818047, 4225598, 4798837, 4751225, EP 0 179 022 or UK 2 140 010, as well as US Patent Nos. 6096329 and 6685954 (all incorporated herein by reference).

[00276] In one embodiment, the IGR is a compound that mimics juvenile hormone. Examples of juvenile hormone mimics include azadirachtin, diophenolane, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy ) pyridazine-3(2H)-one.

[00277] In one embodiment, the long-acting injectable formulations of the present invention comprise an effective amount of at least one isoxazoline of Formula (I) for (Route), or a pharmaceutically acceptable salt thereof, in combination with methoprene or pyriproxyfen.

[00278] In another embodiment, the IGR compound is an inhibitor of chitin synthesis. Chi-tin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucicloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, triflumoron, novaluron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro- 4-(trifluoromethyl)phenylurea, l-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea and l-(2,6-difluorobenzoyl )-3-(2-fluoro-4-trifluoromethyl) phenylurea.

[00279] In yet another embodiment of the invention, adulticidal insecticides and acaricides can also be added to the long-acting formulations of the present invention. These include pyrethrins (which include cinerin I, cinerin II, jasmolin I, jasmolin II, Pyrethrin I, Pyrethrin II and mixtures thereof) and pyrethroids, and carbamates, including, but not limited to, benomyl, carbanolate, carbaryl, carbofuran, meththiocarb , metolcarb, promacil, propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxyme and thiophanox. In one embodiment, the compositions may include permethrin in combination with an isoxazoline active agent.

[00280] In some embodiments, the long-acting injectable formulations of the present invention may include one or more Antinematodes including, but not limited to, active agents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates and class of compounds. In some embodiments, benzimidazoles, including, but not limited to, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and its o, o-dimethyl analogue may be included in the compositions. .

[00281] In other embodiments, the long-acting injectable formulations of the present invention may include an imidazothiazole compounds including, but not limited to, tetramisole, levadamisole and butamisole. In still other embodiments, the long-acting formulations of the present invention may include tetrahydropyrimidine active agents including, but not limited to, pyrantel, oxantel and morantel. Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naphthalophos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

[00282] In other embodiments, the long-acting injectable formulations of the present invention may include the antinematodal compounds phenothiazine and piperazine as the neutral compound or in various salt forms, diethylcarbamazine, phenols such as desophenol, arsenides such as arsenamide, ethanolamines such as bephenium, thenyl closylate and methyridine; cyanine dyes including pyrhythium chloride, pyrimer pamoate and dithizanine iodide; isothiocyanates including bitoscanate, suramin sodium, phthalophin and various natural products including, but not limited to, hygromycin B, α-santonine and kainic acid.

[00283] In other embodiments, the long-acting injectable formulations of the present invention may include anti-sedmatological agents. Suitable antitrematodal agents include, but are not limited to, the miracils such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hcanthone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenol compounds known in the art including hexachlorophene, bithionol, bithionol sulfoxide and menichlopholan; salicylanilide various compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetolin and emetine.

[00284] Antiquestodal compounds can also be advantageously used in the long-acting formulations of the present invention, including, but not limited to, arecoline in various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.

[00285] In still other embodiments, the long-acting injectable formulations of the present invention may include other active agents that are effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, Carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxiphos, cythioate, diazinon, dichlorenthion, diemthoate, Dioxathione, ethion , famfur, fenitrothion, fenthion, fospirate, iodofenfos, malathion, naled, fosalone, phosmet, phoxim, propetanphos, Ronnel, stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucitrinate, permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate , carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, ethyl isobornyl thiocyanate, methoprene, monosulfiram, pyrenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, repellent, dimethyl phthalate, and compounds l, 5a, 6, 9,9a, 9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a, 4,7,7a-tetrahydro-4,7-methane- lH-isoindole-1, 3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarb oxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

[00286] An antiparasitic agent that can be combined with an isoxazoline compound in the long-acting formulations of the present invention can be a biologically active peptide or a protein including, but not limited to, depsipeptides, which act at the neuromuscular junction by stimulating the presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of parasites. The depsipeptide may be a cyclic depsipeptide. In one embodiment of the depsipeptide, the depsipeptide is emodepsid (see Willson et al., Parasitology, January 2003, 126 (Pt 1): 79-86). In another embodiment, the depsipeptide is PF1022A or a derivative thereof.

[00287] In another embodiment, the long-acting injectable formulations of the present invention may comprise an active agent from the neonicotinde class of pesticides. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticidal agent that can be combined with an isoxazoline compound to form a long-acting injectable formulation of the present invention is imidacloprid. Imidacloprid is a well-known neonicotinid active agent and is the essential active ingredient in the topical parasiticide products Advantage®, Advantage® II, K9 Advantix®, and K9 Advantix® II sold by Bayer Animal Health and the soft-chew oral formulation Advantus™ from Piedmont Animal health. Agents of this class are described, for example, in US Patent No. 4,742,060 or in EP 0 892 060.

[00288] In another embodiment, the long-acting injectable formulations of the present invention may comprise nitenpyram, another active agent from the neonicotinid class of pesticides. Nitenpyram has the following chemical structure and is the active ingredient in oral Capstar™ tablets marketed by Novartis Animal Health

[00289]

[00290] Nitenpyram is active against adult fleas when administered daily as an oral tablet. Nitenpyram works by interfering with normal nerve transmission and leads to the death of the insect. Nitenpyram has a very rapid onset of action against fleas. For example, Capstar™ tablets begin to work against fleas as early as 30 minutes after administration and are indicated for use as frequently as once daily. However, nitenpyram is only known to be effective when administered orally as a systemic parasiticide, such as with Capstar™ tablets.

[00291] In yet another embodiment, the invention provides long-acting formulations of the present invention comprising 4- [5- [3-chloro-5- (trifluoromethyl) phenyl] -4,5-dihydro-5- (trifluoromethyl) -3- isoxazolyl] - N- [2-oxo-2 - [(2,2,2-trifluoroethyl) amino] ethyl] -1- naphthalanecarboxamide (Compound of formula Ia) in combination with nitenpyram.

[00292] In yet another embodiment, the invention provides long-acting formulations of the present invention comprising 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl) -3- isoxazolyl] - N- [2-oxo-2 - [(2,2,2-trifluoroethyl) amino] ethyl] -1- naphthalanecarboxamide (Compound of formula Ia) in combination with imidacloprid.

[00293] In certain embodiments, an insecticidal agent that can be combined with the long-acting formulations of the present invention is a semicarbazone, such as metaflumizone.

[00294] In another embodiment, the long-acting injectable formulations of the present invention may, advantageously, include a combination of isoxazoline compounds known in the art. These active agents are described in US7,964,204, US 2010/0254960 Al, US2011/0159107, US2012/0309620, US2012/0030841, US2010/0069247, WO 2007/125984, WO 2012/086462 , US 8318757, US 8466115, US 8618126 , US 8822466, US8383659, US8853186, US 2011/0144349, US 8,053,452; US 2010/0137612, US 2010/0254959, US 2011/152081, WO 2012/089623, WO 2012/089622, US 8, 119,671; US 7947715; WO 2102/120135, WO 2012/107533, WO 2011/157748, US 2011/0245274, US 2011/0245239, US 2012/0232026, US 2012/0077765, US 2012/0035122, US 2011/0251247, WO 2011/ 154433, WO 2011/154434, US 2012/0238517, US 2011/0166193, WO 2011/104088, WO 2011/104087, WO 2011/104089, US 2012/015946, US 2009/0 143410, WO 2007/123855 A2, US 2011/0118212, US7951828 and US7662972, US 2010/0137372 Al, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al, US 7.89 7,630, and US 7,951,828, all of which are incorporated herein by reference in their entirety.

[00295] In another embodiment of the invention, nodulisporic acid and its derivatives (a class of known acaricidal, anthelmintic, antiparasitic and insecticidal agents) can be added to the long-acting formulations of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Patent Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are incorporated herein by reference in their entirety. The formulations may include one or more of the nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the patents cited above.

[00296] In another embodiment, anthelmintic compounds of the aminoacetonitrile (AAD) class of compounds such as monepantel (ZOLVIX) and the like can be added. long-acting formulations of the present invention These compounds are described, for example, in WO 2004/024704 and U.S. Patent No. 7,084,280 (incorporated by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, March 13, 2008, 176-181.

[00297] Compositions of the invention may also include aryloxazol-2-yl-cyanoethylamino compounds such as those described in US Patent No. 8,088,801 to Soil et al., which is incorporated herein in its entirety and thioamide derivatives of these compounds , as described in US Patent No. 7,964,621, which is incorporated herein by reference.

[00298] The long-acting injectable formulations of the present invention can also be combined with paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al. ., Medical and Veterinary Entomology 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds that include a spirodioxepine indole nucleus with activity against certain parasites (see Tet Lett 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44 , 492). Furthermore, the structurally related marcfortin family of compounds, such as marcfortines AC, are also known and can be combined with the formulations of the invention (see J. Chem Soc. -... Chem Comm 1980, 601 and Tet Lett. 1981, 22, 1977). Other references to paraherquamide derivatives can be found, for example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432, US Patent 5,703,078 and US Patent 5,750,695 , all of which are incorporated herein by reference in their entirety.

[00299] In another embodiment of the invention, the compositions may include a spinosyn active agent produced by the soil actinomycete Saccharopolyspora spinosa (see, for example, Salgado VL and Sparks TC, "The Spinosyns: Chemistry, Biochemistry, Mode of Action and Resistance ," in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi-synthetic prickly agent. Spinosyns are typically referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, 0, P, Q, R, S, T, U, V , W or Y, and any one of these components, or a combination thereof, can be used in the compositions of the invention. The spinosyn compound may be a 5,6,5 tricyclic ring system, fused to a 12-membered macrocyclic lactone, a neutral sugar (rhamnose), and an amino sugar (phorosamine). These and other natural spinosyn compounds, including 21-butenyl spinosyn produced by Saccharopolyspora pagona, which can be used in the compositions of the invention, can be produced by fermentation by conventional techniques known in the art. Other spinosyn compounds that can be used in the compositions of the invention are disclosed in U.S. Patent No. 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,880,861; 5,670,486; 5,631, 155 and 6,001,981, all incorporated by reference herein in their entirety. Spinosyn compounds may include, but are not limited to, Spinosyn A, Spinosyn D, Spinosad, Spinetoram or combinations thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spinetoram is a combination of 3'-ethoxy-5,6-dihydro spinosyn J and 3'-ethoxy spinosyn L.

[00300] In general, the additional active agent is included in the long-acting formulations of the present invention in an amount of between about 0.1 ug and about 1000 mg. More typically, the additional active agent may be included in an amount of about 10 mg to about 500 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 200 mg. of 100 mg.

[00301] In other embodiments of the invention, additional active agent may be included in the composition to provide a dose of about 5 ug/kg to about 50 mg/kg by animal weight. In other embodiments, the additional active agent may be present in an amount sufficient to provide a dose of about 0.01 mg/kg to about 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. kg, or about 0.1 mg/kg to about 10 mg/kg of animal weight. In other embodiments, the additional active agent may be present at a dose of about 5 ug/kg to about 200 ug/kg or about 0.1 mg/kg to about 1 mg/kg of animal weight. In yet another embodiment of the invention, the additional active agent is included at a dose of between about 0.5 mg/kg to about 50 mg/kg.

[00302] The long-acting formulations of the present invention, which include at least one isoxazoline active agent, a poloxamer and a co-solvent, have surprisingly been found to be stable and effective against a broad spectrum of ectoparasites, and possibly also endoparasites if another active is included for an extended period of time; for example, a period of three (3) to six (6) months while exhibiting favorable properties relative to the injection site.

[00303] Poloxamers are a family of synthetic block copolymers of ethylene oxide and propylene oxide. Poloxamers can be liquids, a milky white paste or a powder and are represented by the following structural formula:

[00304] where a is an integer between 2 and 130 and b is an integer between 15 and 67 (see, US 3740421). Poloxamer are available from commercial sources such as BASF and Croda. An example of a poloxamer is P-124, which is a solid at room temperature. In one embodiment, poloxamer P-124 has the values of a = 12 and b = 20. Other poloxamers include P-128 (a = 38 and b = 29), P-181 (a = 3 and b = 30) P-188 (a = 80 and b = 27), P-237 (a = 64 and b = 37), P338 (a = 141 b = 44 e,) and P407 (a = 101 and b = 56,).

[00305] except poloxamers, pharmaceutically acceptable polymers are specifically excluded from the long-acting formulations of the invention. For the purposes of this application, liquid polyethylene glycols, which function here as co-solvents, are not defined as or considered pharmaceutically acceptable polymers and thus their inclusion is permitted. Thus, the long-acting formulations of the present invention provide for the inclusion of liquid polyethylene glycols.

[00306] Examples of pharmaceutically acceptable polymers that are specifically excluded from the long-acting formulations of the invention include polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, poly- hydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malicacid), poly(amino acids), poly(vinyl methyl ether), poly(maleic anhydride), chitin, chitosan and copolymers, terpolymers or their combinations or mixtures thereof, including copolymers of polylactides, polycaprolactones, polyglycolides (e.g. poly(lactide-co-glycolide)

[00307] The co-solvents used in long-acting injectable compositions can be a single or a mixture of co-solvents. In one embodiment, the co-solvents used in the long-acting injectable formulations of the present invention include polar solvents that are miscible with water. Non-limiting examples of these co-solvents include ethanol, isopropanol, benzyl alcohol, glycol ethers (e.g., including, but limited to, diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether , ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether and the like), liquid polyethylene glycols (PEGs) (e.g. PEG 400), propylene glycol, carbonates (e.g. , propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, glycerol formal or a mixture of at least two of these solvents.

[00308] In one embodiment, the long-acting formulations of the present invention comprise a polar protic solvent including, but not limited to, an alcohol such as ethanol, isopropanol or a glycol or glycol ether.

[00309] In another embodiment, the long-acting injectable formulations of the present invention comprise a polar aprotic solvent, such as N-methyl-pyrrolidone, dimethyl isosorbide, dimethylacetamide or propylene carbonate.

[00310] In yet another embodiment of the invention, the compositions of the invention include non-miscible with water co-solvents. Examples of such non-limiting co-solvents include triacetin, triglyceride lipids, including medium chain triglycerides such as C8-C1o triglycerides such as capric/caprylic triglycerides, propylene glycol derivatives (e.g. propylene glycol monolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol) (water-dispersible nonionic surfactant, isopropyl myristate, or a mixture of at least two of these co-solvents.

[00311] In one embodiment, the compositions include a protic solvent that is not completely miscible with water, including, but not limited to, benzyl alcohol.

[00312] In another embodiment, the composition of the invention may include neutral oils as a co-solvent. Neutral oils are triglycerides of fractionated plant fatty acids with chain lengths from C8 to C1o. Two commercially available products are known as MIGLYOL® 810 and MIGLYOL® 812. In another embodiment, the neutral oil is a triglyceride of fractionated plant fatty acids with chain lengths of C8 and C10, combined with linoleic acid (about 4 -5%) . A commercially available product is known as MIGLYOL® 818. In yet another embodiment, the neutral oil is a glycerin ester of fractionated plant fatty acids with chain lengths of C8 and C10, combined with succinic acid. A commercially available product is known as MIGLYOL® 829. In another embodiment, the neutral oil may be a propylene glycol diester of saturated vegetable fatty acids with chain lengths of C8 and C10, combined with succinic acid. One commercially available product is known as MIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In yet another embodiment, the co-solvent may be a mixture of two or more neutral oils.

[00313] The formulations of the invention may contain other inert ingredients such as antioxidants, preservatives or pH stabilizers. These compounds are well known in the formulation art. Antioxidants such as vitamin E, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxy anisole) , BHT (butylated hydroxy toluene), BHA and citric acid, monothioglycerol, tert-butyl hydroquinone (TBHQ), and the like, can be added to the present formulation. Antioxidants are generally added to the formulation in amounts of about 0.01 to about 2.0%, based on the total weight of the formulation, with between about 0.05 and about 1.0% being especially preferred.

[00314] Preservatives, such as parabens (methylparaben and/or propylparaben), are suitably used in the formulation in amounts ranging from about 0.01 to about 2.0%, with between about 0.05 being especially preferred. and about 1.0%. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, ketemide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal and the like. Preferred ranges for these compounds include from about 0.01 to about 5%.

[00315] Compounds that stabilize the pH of the formulation are also contemplated. Again, such compounds are well known to a practitioner in the art, as is how to use these compounds. Buffer systems include, for example, systems selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tartic acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate.

[00316] Dosage forms can contain from about 0.5 mg to about 5 g of an active agent or a combination of active agents. More typically, the amount of active agent(s) in the compositions of the invention will be between about 1 mg to about 3 g. In another embodiment, the amount of active agent(s) in the compositions will be between about 20 mg to about 3 g. In another embodiment, the amount of active agent(s) present in the compositions will be from about 20 mg to about 2 g, about 20 mg to about 1.5 g, or about 20 mg to about 1 g. In other embodiments, the amount of active agent(s) in the compositions will be between about 20 mg to about 500 mg, about 30 mg to about 200 mg, or about 50 mg to about 200 mg. In yet another embodiment, the amount of active agent(s) present in the compositions will be from about 50 mg to about 2 g, about 50 mg to about 1 g, or about 50 mg to about 500 mg. In yet another embodiment of the invention, the amount of active agent(s) present will be between about 100 mg to about 2 g, about 100 mg to about 1 g, or about 100 mg to about 500 mg.

[00317] In another embodiment, the amount of active agent(s) present in an amount of from about 1 mg to about 500 mg of an active agent, about 1 mg to about 100 mg or about 1 mg to about 25 mg. In still other embodiments, the amount of active agent present in the compositions is from about 10 mg to about 50 mg or from about 10 mg to about 100 mg. In other embodiments, the amount of active agent present in the compositions is from about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 200 mg to about from 500 mg, about 300 mg to about 600 mg, about 400 mg to about 800 mg, or about 500 mg to about 1000 mg.

[00318] The compositions of the present invention are made by mixing the appropriate amount of the active agents, a poloxamer, a co-solvent and, optionally, an antioxidant, pharmaceutically acceptable additive and/or excipient to form a formulation of the invention. In some embodiments, formulations of the present invention can be obtained by following the method of making these forms described above by the description of making such forms found in general formulation texts known to those skilled in the art, e.g., Remington - The Science and Practice of Pharmacy (21st Edition) (2005), Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th Edition) (2005) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8th Edition), edited by Allen et al., Lippincott Williams & Wilkins, (2005). Treatment Methods

[00319] In another aspect of the invention, a method for preventing or treating a parasitic infestation/infection in an animal is provided, comprising administering to the animal a long-acting injectable formulation comprising an effective amount of at least one compound of isoxazoline, a poloxamer and a co-solvent. The formulations of the present invention have long-lasting efficacy against ectoparasites (e.g., fleas and ticks) and in certain embodiments may also be active against endoparasites that harm animals.

[00320] In one embodiment of the invention, there are provided methods for treating or preventing a parasitic infestation or infection in a domestic animal, which comprise administering a long-acting injectable formulation comprising an effective amount of at least one active agent. of isoxazoline to the animal. Ectoparasites against which the methods and compositions of the invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies and lice. In certain embodiments where the inventive formulations include one or more additional active agents that are active against internal parasites, the compositions and methods of the invention may also be effective against endoparasites including, but not limited to, cestodes, nematodes, hookworms and roundworms of the digestive tract of animals and humans.

[00321] In one embodiment for treatment against ectoparasites, the ectoparasite is one or more insects or arachnids, including those of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes , Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes and Felicola.

[00322] In another embodiment for treatment against ectoparasites, the ectoparasite is from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and / or Boophilus. Treated ectoparasites include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas {Ctenocephalides felis, Ctenocephalides sp. and the like), ticks {Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp. and the like), and mites (Demodex sp., Sar copies sp., Otodectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp., Linognathus sp., and the like), mosquitoes (Aedes sp., Culex sp. ., Anopheles sp., and the like) and flies (Haematobia sp. including Haematobia irritans, Musca sp., Siomoxis sp. including Stomoxis calciirans, Dermatobia sp., Cochliomyia sp., and the like).

[00323] Additional examples of ectoparasites include, but are not limited to the tick genus Boophilus, especially those of the species microplus (cattle tick), decoloratus and annulatus; myiasis such as Dermatobia hominis (known as Berna in Brazil) and Cochliomyia hominivorax (greenbottle); myiasis of sheep, such as Lucilia sericata, Lucilia cuprina (known as flystrike in Australia, New Zealand and South Africa). Suitable flies, namely those whose adults constitute the parasite, such as Haematobia irritans (horn fly) and Stomoxis calcitrans (stable fly); lice like Linognathus vituli, etc.; and mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art to be harmful to animals and humans. These include, for example, the migration of dipteran larvae.

[00324] In some embodiments of the invention, the composition can also be used to treat against endoparasites, such as those helminths selected from the group consisting of Anaplocephala, Ancylostoma, Necator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostomum, Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, and Trichostrongylus, among others.

[00325] In one embodiment, the invention provides methods for treating and preventing infections and parasitic infestations of animals (both domestic and wild), including farmed and companion animals, such as cats, dogs, horses, birds, including chickens , sheep, goats, pigs, deer, turkeys and cattle, with the aim of freeing these hosts from the most common parasites found by these animals.

[00326] In one embodiment, the invention provides methods and compositions for treating or preventing infections and parasitic infestations in companion animals, including, but not limited to, dogs and cats. The methods and compositions are particularly effective for preventing or treating parasite infestations of cats and dogs with fleas and ticks.

[00327] In another embodiment, the methods and compositions of the invention are used for the treatment or prevention of infections and parasitic infestations in cattle or sheep. When treating farm animals such as cattle or sheep, the methods and compositions are particularly effective against Rhipicephalus (Boophilus) microplus, Haematobia irritans (horn fly), Stomoxis calcitrans (stable fly), and sheep myiasis, such as Lucilia sericata, Lucilia cuprina (known as strike blowfly in Australia, New Zealand and South Africa).

[00328] The terms "treatment" or "treat" or "treatment" are intended to mean administering a long-acting formulation of the present invention to an animal that has a parasitic infestation, eradicating the parasite or reducing the number of parasites that infest the animal undergoing treatment. Note that the compositions of the invention can be used to prevent such parasitic infestation.

[00329] The terms "prevent", "prevention" or "prophylaxis" are intended to mean the administration of the long-acting formulations of the present invention to the animal before infection or parasitic infestation has occurred, in order to keep said infection or infestation from occurring.

[00330] The formulations of the invention are administered in effective amounts that are parasiticides that are suitable for controlling the parasite in question, to the desired extent, as described below. In each aspect of the invention, the compounds and compositions of the invention can be applied against a single pest or combinations thereof.

[00331] By "antiparasitic effective amount" is intended a sufficient amount of a composition of the invention to eradicate or reduce the number of parasites infesting the animal. In some embodiments, an effective amount of the active agent achieves at least 70% efficacy against the target parasite compared to an untreated control. In other embodiments, an effective amount of the active agent achieves at least 80%, or at least 90% effectiveness against the target pests. Preferably, an effective amount of the active agent will achieve an efficacy of at least 95%, at least 98% or 100% against the target parasites.

[00332] Generally, a dose 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 from 1 to 5 days, will be satisfactory, but, of course, there may be cases where higher or lower dosage ranges are indicated, and such are within the scope of the present invention. It is well within the routine skill of the clinician to determine a particular dosage regimen for a specific host and parasite.

[00333] In some embodiments for companion animals, the dose of the active agent isoxazoline administered from the topical compositions of the invention is between about 0.1 to about 50 mg per kg of body weight. More typically, the dose of active agent administered is about 0.5 to about 30 mg/kg isoxazoline or about 0.5 to about 30 mg/kg of body weight. In another embodiment, the dose of active agent administered is isoxazoline from about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, or about 20 to about 30 mg/kg of body weight.

[00334] In other embodiments, the dose administered may be lower, depending on the animal and the isoxazoline administered. For example, if the composition comprises the more active enantiomer of the isoxazoline compound a lower dose may be administered. In some embodiments, the dose is from about 0.1 to about 30 mg/kg of body weight. In another embodiment, the dose may be from about 0.1 to about 20 mg/kg or from about 0.1 to about 10 mg/kg of body weight. In other embodiments, the dose may be from about 1 to about 20 mg/kg of body weight or from about 1 to about 10 mg/kg. In yet another embodiment, the dose may be from about 5 to about 20 mg/kg or about 10 to about 20 mg/kg of body weight.

[00335] In other embodiments for treating farmed animals such as cattle or sheep, doses of the isoxazoline active agent administered can be from about 0.1 to about 40 mg/kg of body weight. More typically, doses will be administered at about 1 to about 30 mg/kg, about 1 to about 20 mg/kg, or about 1 to about 10 mg/kg of body weight. In yet another embodiment, the dose may be from about 10 to about 25 mg/kg, about 15 to about 30 mg/kg of body weight, or about 20-30 mg/kg of body weight.

[00336] In one embodiment of the method for use in dogs or cats, the long-acting formulations of the present invention comprising an isoxazoline compound have an efficacy against fleas and/or ticks of at least about 90.0% or more for about 3 months, or longer, compared to an untreated control. In another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks of at least 95.0% or more for about 3 months or more. In another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks of at least 90.0% or more for about 4 months or more. In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks of at least 95.0% or more for about 4 months or more. In another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks of at least 90.0% or more for about 5 months or more. In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks of at least 95.0% or more for about 5 months or more.

[00337] In another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on dogs and cats of at least about 80% for two months, or more. In another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on dogs and cats of about 90% for about 3 months, or longer. In yet another embodiment, the compositions provide an efficacy against fleas and/or ticks on dogs and cats of about 95% for about 3 months or more. In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on dogs and cats of at least 90% or greater for about 4 months, or longer. In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on dogs and cats of at least 95% or greater for about 4 months, or longer. In another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on dogs and cats of at least 90% or greater for about 5 months, or longer. In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on dogs and cats of at least 95% or greater for about 5 months, or longer.

[00338] In another embodiment, the long-acting formulations of the present invention have an efficacy of at least about 80% against fleas and/or ticks for about 3 months, or more. In yet another embodiment, the long-acting formulations of the present invention provide at least about 90% effectiveness against fleas and/or ticks for 3 months or more. In yet another embodiment, the long-acting formulations of the present invention provide at least about 95% efficacy against fleas and/or ticks for 3 months or more. In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on cats and/or dogs of at least 80% or at least 90% for about 3 months to about 6 months or longer. .

[00339] In yet another embodiment, the long-acting formulations of the present invention provide an efficacy against fleas and/or ticks on cats and/or dogs of at least 80% or at least 90% for about 7 months, 8 months, 9 months or longer.

[00340] In another aspect of the invention, a kit for treating or preventing a parasitic infestation in an animal is provided, which comprises a long-acting formulation of the present invention and a syringe. EXAMPLES

[00341] The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should it be construed to, limit the scope of the invention.

Formulation Examples

[00342] The following long-acting injectable formulations were prepared by mixing the following ingredients:

Example 1:

[00343] Compound of formula (Ia) 30% (w/v)

[00344] Ethanol 9% (w/v)

[00345] Poloxamer 124 QS.

Example 2

[00346] Compound of formula (Ia) 15% (w/w)

[00347] Poloxamer 124 85% (w/w)

Example 3

[00348] Compound of formula (Ia) 26% (w/w)

[00349] Poloxamer 124 10% (w/w)

[00350] PEG 400 64% (w/w)

Example 5

[00351] Compound of formula (Ia) 26% (w/w)

[00352] Poloxamer 124 66% (w/w)

[00353] Ethanol 8% (w/w)

Example 6

[00354] Compound of formula (Ia) 26% (w/w)

[00355] PEG 400 27% (w/w)

[00356] Poloxamer 181 39% (w/w)

[00357] Ethanol 8% (w/w)

Example 7

[00358] Compound of formula (Ia) 26% (w/w)

[00359] PEG 400 64% (w/w)

[00360] Poloxamer 181 10% (w/w)

Example 9

[00361] Compound of formula (Ia) 26% (w/w)

[00362] Poloxamer 124 63.4% (w/w)

[00363] Capryol 90 10.6% (w/w)

Example 10

[00364] Compound of formula (Ia) 26% (w/w)

[00365] Poloxamer 124 66% (w/w)

[00366] Benzyl alcohol 8% (w/w)

Example 11

[00367] Compound of formula (Ia) 15% (w/w)

[00368] Poloxamer 124 85% (w/w)

Example 12

[00369] Compound of formula (Ia) 26% (w/w)

[00370] Poloxamer 181 10% (w/w)

[00371] PEG 400 64% (w/w)

Example 13

[00372] Compound of formula (Ia) 26%

[00373] PEG 400 at 33% (w/w)

[00374] Poloxamer 124 33% (w/w)

[00375] Ethanol 8% (w/w)

Example 14

[00376] Compound of formula (S) - (Ia), 13% (w/w)

[00377] PEG 400 39.5% (w/w)

[00378] poloxamer 124 39.5% (w/w)

[00379] Ethanol 8% (w/w)

Example 15

[00380] Compound of formula (Ia) 26% (w/w)

[00381] PEG 400 at 33% (w/w)

[00382] Poloxamer 181 33% (w/w)

[00383] Ethanol 8% (w/w)

Example 16

[00384] Compound of formula (S) - (Ia), 13% (w/w)

[00385] PEG 400 39.5% (w/w)

[00386] Poloxamer 181 39.5% (w/w)

[00387] Ethanol 8% (w/w)

Example 17

[00388] Compound of formula (S) - (la) 13% (w/w)

[00389] PEG 400 27% (w/w)

[00390] Poloxamer 124 52% (w/w)

[00391] Ethanol 8% (w/w)

Example 18

[00392] Compound of formula (S)- (Ia), 26% (w/w)

[00393] PEG 400 52% (w/w)

[00394] Poloxamer 124 14% (w/w)

[00395] Ethanol 8% (w/w)

Example 19

[00396] Compound of formula (S) - (la) 26% (w/w)

[00397] PEG 400 at 33% (w/w)

[00398] Poloxomer 124 33% (w/w)

[00399] Ethanol 8% (w/w)

Examples of effectiveness

[00400] The following examples demonstrate the effectiveness of the long-acting injectable compositions of the present invention against ectoparasites in companion and farm animals.

[00401] Example 20

[00402] An efficacy study was performed to determine the effectiveness of the formula in Example 1, dosed at 20 mg/kg in beagles against Rhipicephalus sanguineus (tick) and Ctenocephalides felis (flea). Compared to an untreated control, efficacy against ticks on day 184 48 hours after infestation was 74%. On day 185, 72 hours after infestation, the effectiveness against ticks was 90.4%. Efficacy against fleas on day 193, 24 hours after infestation, was 85.6%.

Example 21

[00403] The effectiveness of a long-acting injectable composition of the present invention against Rhipicephalus (Boophilus) microplus in cattle was tested. Two groups of cattle were studied, an untreated control group and a test group treated with a long-acting injectable of the present invention comprising 15% (w/v) of general formula Ia in a vehicle consisting of a mixture of poloxamer. 124 (QS) and 20%) (w/v) ethanol to provide a dose of 5 mg/kg body weight. Cattle in the treatment group were treated on day 0 with the long-acting injectable composition. Each animal was infested with 5000 tick larvae on days 7, 21, and every 14 days thereafter. Adult ticks dropping from each animal are collected daily from day 1 until the end of the study. The effectiveness of the treatment is determined by collecting and counting the number of ticks dropped from each animal and comparing it to the number of ticks collected from the control group. The effectiveness of the long-acting composition was found to be nearly 100% for infestations performed on days 7, 21, 35, and 49; 95% in infestation carried out on Day 63; and greater than 70% in infestations conducted on Day 91.

Irritation at the injection site Example 22

[00404] The following example assessed the irritation of the long-acting injectable compositions of the invention (compositions of Treatment Group Nos. 2-6) in beagle dogs versus a placebo (Treatment Group No. 1).

[00405] Compositions were prepared according to the following treatment groups in Table 1: Table 1

[00406] All concentrations are in % w/w.

[00407] The composition of each of the treatment groups was injected subcutaneously into a dog at two sites and irritation to the two injection sites was monitored for 1 or two weeks, respectively, and evaluated according to the following criteria:

[00408] 0 no detectable reaction

[00409] 1 thickening of the injection site, no distinct nodule (non-floating).

[00410] (Pea-sized nodule) 2 small <about 0.5 - 2 cm in diameter

[00411] 3 medium (grape-sized) nodule > approximately 2-3 cm in diameter

[00412] 4 large (walnut size) nodule > 3 cm in diameter

[00413] 5 abscess formation

[00414] Criteria # a lower score is considered a better result (e.g. 0-2 vs. 3-5).

[00415] Table 2 provides the evaluation of the groups identified above at the first injection site on the injection days after indicated. Table 2

[00416] Table 3 provides the assessment for the treatment groups identified above at the second injection site on the day after indicated injection. Table 3

[00417] The data in Table 1 and 2 indicate that the inventive formulations exhibited no or very less injection site irritation and injection site irritation was comparable to placebo, which do not contain an isoxazoline active agent.

Assessment of Injection Efficacy and Site of Irritation. Example 23

[00418] The efficacy and injection site irritation of a long-acting injectable composition according to the invention (Treatment Group 5) were compared with placebo compositions (Treatment Groups 1 and 2) and an injectable composition comprising a PEG 400/ethanol (80:20 (v/v)) co-solvent mixture (Treatment Group 3). Eight dogs were evaluated in each of the treatment groups. Long-acting injectable compositions were administered on day 0.

[00419] Compositions were prepared according to the following treatment groups in Table 4 Table 4 Site of irritation

[00420] Treatment compositions Groups 1-5 were injected subcutaneously to beagle dogs on day 0 to evaluate injection site irritation for the compositions described in Table 5 -Table 5

[00421] The following criteria were used to evaluate irritation at the injection site:

[00422] 0 no detectable reaction

[00423] 1 - thickening of the injection site, no distinct nodule (non-floating).

[00424] 2 - (Pea-sized nodule) small <about 0.5 - 2 cm in diameter

[00425] 3 medium (grape-sized) nodule > approximately 2-3 cm in diameter

[00426] 4 - large (walnut size) nodule > 3 cm in diameter

[00427] 5 - formation of abscesses

[00428] Criteria A lower score is considered a better result (e.g., 0-2 vs. 3-5). The number of dogs assigned a given score is listed in parentheses.

Effective against Rhipicephalus sanguineus (ticks) and Ctenocephalides felis (fleas).

[00429] Dogs from Treatment Groups 3, 4 and 5 were infested with 50 Rhipicephalus sanguineus on Day 182. Thumb counts were performed on Day 184 and tick removal and counting on Day 185. Dogs were infested with 100 Ctenocephalides felis on Day 192. Fleas were removed and counted on Day 193. The percent reduction in tick attachment (comb count) Days 184 and 185 for each of the treatment groups are shown in Fig. 1. The effectiveness against fleas for each of the treatment groups on Day 193 is shown in Fig. 2. Overall, the data demonstrate that the compositions of the present invention showed good bioavailability, close to six months of flea and tick efficacy, and minimal injection site reactions. The invention is further described in the following numbered paragraphs: A long-acting injectable composition for the treatment or prevention of parasite infestations or infections in an animal comprising an effective amount of antiparasitics, at least one active agent isoxazoline, a poloxamer and, optionally , a co-solvent, in which no other pharmaceutically acceptable polymers are present. 2. Long-acting injectable composition, according to claim 1, comprising: a) an effective amount of antiparasitic, at least one isoxazoline active agent, which is: i) an isoxoazoline compound of formula (I): (I) where: A1, A2, A3, A4, A5 and A6 are independently selected from the group consisting of CR3 and N, provided that at most 3 of A1, A2, A3, A4, A5 and A6 are N ; B1, B2 and B3 are independently selected from the group consisting of CR2 and N; W is O or S; R1 represents C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents selected independently of R6; each R2 independently represents H, halogen, C1C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl , C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4, -CN or -NO2; each R3 independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C 1 -C 6 alkylthio, C1-C6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2; R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 -carbonyl; R5 is H, OR10, NR11R12, or Q1; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R4 and R5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy; each R6 independently represents halogen, C1-C6 alkyl, C1C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, - CN or - NO2; each R 7 independently represents halogen; C1C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2C7 alkylcarbonyl, C2- C7 alkoxy, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, -NH2, -CN or -NO2; or Q2; each R8 independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2- C6 dialkylamine, C2-C4, -CN or -NO2; each R9 independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C 1 -C 6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2 -C6 dialkylamino, -CN, -NO2, phenyl or pyridinyl; R10 is H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one more than halogen; R11 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7-carbonyl; R12 is H; Q3; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R11 and R12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1 -C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or a bicyclic fused 8-, 9- or 10-membered ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents selected independently of R8; each Q2 independently represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; Q3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; en is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or ii) an isoxazoline compound of formula (II): (II) wherein: R1 represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl group, each of them being unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC( O)-, R7OC(O), R7C(O)O-, R7C(O)NR8-, -CN or -NO2;; " , haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8 -, -CN or -NO2; A1 is oxygen; and A2 is oxygen, NR2 or CR7R8; G is Gl or L-2; B2, B3, B4 and B5 are independently N or CR9; Y is hydrogen, halogen, -CN; or Y represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl group, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di (alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13; R2, R3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R10S(O)-, R10S(O)2-, R10C(O)-, R10C( S)-, R10R11NC(O)-, R10R11NC(S)- R10OC(O)-; R4, R5 and R6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl; R7 and R8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxylalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; R9 is hydrogen, halogen, -CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC( O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2; R10, R11, R12 and R13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or R10 together with R11, form =0, =S or =NR2; or R12 together with R13, form =0, =S or =NR2; W is O, S or NR2; n is 1 - 4; in is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or iv) an isoxoazoline compound of formula (III) or a pharmaceutically acceptable salt thereof; and/or iv) an isoxazoline compound of formula (IV) or a pharmaceutically acceptable salt thereof; and/or v) an isoxazoline compound of formula (V): wherein R1, R2 and R3 are independently H, Cl, F or CF3; Y is the diradical group T is a C1-C6 alkyl group that is unsubstituted or substituted by halogen, cyano, nitro, amino, hydroxyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6 alkylthio, carboxy, carbamoyl or C2-C6 alkanoyl group which may be unsubstituted or substituted on the alkyl moiety by halogen or a pharmaceutically acceptable salt thereof; and/or vi) an isoxazoline compound of formula (VI): where Y is hydrogen, fluorine, chlorine or bromine; R1 represents a phenyl group substituted with 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy; R2 represents a methyl, fluoromethyl, trifluoromethyl or perfluoroethyl group; R3a and R3b are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R3a and R3b together combine with the carbon to which they are attached to form a cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically acceptable salt thereof; b) at least one pharmaceutically acceptable polymer, which is a poloxamer; c) optionally, at least one co-solvent; d) optionally, an antioxidant; and e) optionally at least one pharmaceutically acceptable carrier, additive, excipient or mixtures thereof in which no other pharmaceutically acceptable polymers are present. 3. Long-acting injectable composition according to claim 2, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula (I): where: A1, A2, A3, A4, A5 and A6 are independently selected from the group consisting of CR3 and N, provided that at most 3 of A1, A2, A3, A4, A5 and A6 are N; 81, B2 and B3 are independently selected from the group consisting of CR2 and N; W is O or S; R1 represents C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R2 independently represents H, halogen, C1C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1 -C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamine, C2-C4 alkoxycarbonyl, -CN or -NO2; each R is, independently, H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1C6 alkylthio, C1 -C6 haloalkylthio, C1 -C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2; R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7-carbonyl; R5 is H, OR10, NR11R12, or Q1; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R4 and R5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1C2 alkyl, halogen, -CN, -nO2 and C1-C2 alkoxy; each R6 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, -CN or -NO2; each R7 independently represents halogen; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2- C7 alkoxy, C2-C7 alkylaminocarbonyl, C3C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, - NH 2, - CN or - NO 2; or Q2; each R8 independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1 -C 6 alkylamino, C2 -C6 dialkylamine, C2-C4, -CN or -NO2; each R9 independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl , C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C 2 -C 6 dialkylamino, - CN, - NO 2 , phenyl or pyridinyl; R10 is H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one more halogen; R11 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7-carbonyl; R12 is H; Q3; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R11 and R12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2 alkyl, halogen, -CN, -nO 2 and C1-C2 alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or a bicyclic fused 8-, 9-, or 10-membered ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1, and S up to 3 N, each ring or ring system optionally substituted with one or more substituents selected independently of R8; each Q2 independently represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; Q 3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; en is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; b) at least one pharmaceutically acceptable polymer, which is a poloxamer; c) optionally, at least one co-solvent; d) optionally, an antioxidant; and e) optionally at least one pharmaceutically acceptable carrier, additive, excipient or mixtures thereof in which no other pharmaceutically acceptable polymers are present. 4. Long-acting injectable composition according to claim 3, wherein the active agent is an isoxazoline compound of formula or a pharmaceutically acceptable salt thereof wherein R2 is independently halogen, C1-C6 alkyl or C1-C6 haloalkyl R4 is H or C1-C6 alkyl; R5 represents a C1-C4 alkyl group optionally substituted with one or more R7 groups; and R7 represents C2-C7 alkylcarbonyl, C2-C7 alkoxy, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl; n is 0, 1 or 2. 5. Long-acting injectable composition according to claim 4, wherein the active agent is an isoxazoline compound of formula (Ia): or a pharmaceutically acceptable salt thereof. 6. Long-acting injectable composition according to claim 1 or 2, in which the active agent isoxazoline is enriched in one enantiomer. 7. Long-acting injectable composition according to claim 6, in which the active agent isoxazoline is enriched in a compound of formula (S) - (Ia) or (R) - (Ia): or a pharmaceutically acceptable salt thereof. 8. Long-acting injectable composition according to claim 2, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula (II): wherein: R1 represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl group, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di( alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)- , R7OC(O), R7C(O)O-, R7C(O)NR8-, -CN or -NO2; " , haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8 -, -CN or -NO2 ; A1 is oxygen; and A2 is oxygen is, NR2 or CR7R8; G is Gl or G-2; Gl G-2 B1, B2, B3, B4 and B5 are independently N or C-R9; Y is hydrogen, halogen, -CN; or Y represents an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl group, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di (alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC(O)-, R7OC(O), R7C(O)O-, R7C(O)NR8-, -CN or -NO2; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13; R2, R3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R10S(O)-, R10S(O)2-, R10C(O)-, R10C( S)-, R10R11NC(O)-, R10R11NC(S)- R10OC(O)-; R4, R5 and R6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl; R7 and R8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; R9 is hydrogen, halogen, -CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is unsubstituted or substituted with one or more halogen, hydroxyl, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S(O)-, R7S(O)2-, R7C(O)-, R7R8NC( O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2; R10, R11, R12 and R13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or R10 together with R11, form =0, =S or =NR2; or R 12 together with R13, form =0, =S or =NR2; W is O, S or NR2; n is 1-4; in is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; b) at least one pharmaceutically acceptable polymer which is a poloxamer; c) optionally, at least one co-solvent; d) optionally, an antioxidant; and e) optionally, at least pharmaceutically acceptable additives, excipients or mixtures in which no other pharmaceutically acceptable polymers are present. 9. Long-acting injectable composition according to claim 8, wherein isoxazoline agent is a compound of formulas II-1.001 to II-1.025 or II-2.00-II-2.018: Compounds II-1.001 to II-1.025 Compounds II-2.001 to II-2.018 or a pharmaceutically acceptable salt thereof. 10. Long-acting injectable composition according to claim 2, wherein the active agent isoxazoline is a compound of formula (III): (III) or a pharmaceutically acceptable salt thereof. 11. Long-acting injectable composition according to claim 2, wherein the isoxazoline compound is a compound of formula (IV): or a pharmaceutically acceptable salt thereof. 12. Long-acting injectable composition according to claim 2, wherein the isoxazoline compound is a compound of formula (Va): or a pharmaceutically acceptable salt thereof. 13. Long-acting injectable composition according to claim 2, wherein the isoxazoline compound is a compound of formula (VIa): (VIa) or a pharmaceutically acceptable salt thereof. 14. Long-acting injectable composition according to claim 1, wherein the poloxamer is poloxamer 124 or poloxamer P-181, P-188, P-237, P338 or P407. 15. Long-acting injectable composition according to claim 1, wherein the co-solvent is methanol, ethanol, isopropanol, benzyl alcohol or a liquid polyethylene glycol. 16. Long-acting injectable composition according to claim 1, comprising: a) about 5 to 30% (w/v) of an isoxazoline compound of general formula (I): (1) where: A1, A2, A3, A4, A5 and A6 are independently selected from the group consisting of CR3 and N, provided that at most 3 of A1, A2, A3, A4, A5 and A6 are N ; 81, B2 and B3 are independently selected from the group consisting of CR2 and N; W is O or S; R1 represents C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R2 independently represents H, halogen, C1C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamine, C2-C4 alkoxycarbonyl, -CN or -NO2; each R3 independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1 - C 6 alkylsulfinyl, C 1 -C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, - CN or - NO2; R4 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 -carbonyl; R5 is H, OR10, NR 11 R 12, or Q1; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R4 and R5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy; each R6 independently represents halogen, C1-C6 alkyl, C1C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, -CN or -NO2; each R7 independently represents halogen; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxy, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, -NH2, -CN or -NO2; or Q2; each R8 independently halogen, C1-C 6 alkoxy, C1C6 haloalkoxy, C1-C6 alkylthio, C 1 -C 6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C 6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamine, C2-C4 alkoxycarbonyl, -CN or -NO2; each R9 independently halogen, C 1 -C 6 alkyl, C1 -C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C 1-C6 alkoxy, C1-C6 haloalkoxy, C1-C 6 alkylthio, C 1-C6 haloalkylthio, C1 -C 6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN, -NO2, phenyl or pyridinyl; R10 is H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one more halogen; R 11 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 -carbonyl; R 12 be H; Q3; or C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R11 and R12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally an additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2 alkyl, halogen, -CN, -nO 2 and C1-C2 alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or a bicyclic fused 8-, 9-, or 10-membered ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1, and S up to 3 N, each ring or ring system optionally substituted with one or more substituents selected independently of R8; each Q2 independently represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; Q3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents selected independently of R9; en is 0, 1 or 2 or a pharmaceutically acceptable salt thereof; b) pharmaceutically acceptable polymer, which is a poloxamer; c) optionally, about 5% to 40% (w/v) of co-solvent selected from the group consisting of liquid polyethylene glycol, ethanol and isopropanol; d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and e) optionally, about 0.01% to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is a poloxamer and wherein the poloxamer is present in the overall composition, in a proportion that represents the complement for 100% of the composition. 17. The long-acting injectable composition of claim 1, wherein the composition treats or prevents parasites for about 3 to 6 months. 18. The long-acting injectable composition of claim 1, wherein the composition treats or prevents parasites for about 5 to 6 months. 19. The long-acting injectable composition of claim 1, wherein the composition treats or prevents parasites for about 6 months. 20. The long-acting injectable composition of claim 1, wherein the composition treats or prevents parasites for about 7 months or more. 21. Long-acting injectable composition according to any one of claims 17, 18 or 19, wherein the parasites are fleas or ticks. 22. A long-acting injectable composition according to claim 1, wherein it comprises: a) about 5 to 30% (w/v) of an active isoxazoline compound of formula (Ia) or a pharmaceutically acceptable salt thereof; b) pharmaceutically acceptable polymer, which is a poloxamer; c) optionally, from about 5% to 40% (w/v) of co-solvent selected from the group consisting of liquid polyethylene glycol, ethanol and isopropanol; d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and e) optionally, about 0.01% to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof; wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is a poloxamer, and wherein the poloxamer is present in the overall composition, in a proportion that represents the complement for 100% of the composition. 23. Long-acting injectable composition according to claim 19, wherein the isooxazoline compound is: or a pharmaceutically acceptable salt thereof. 24. A long-acting composition according to any one of claims 1 to 23, further comprising an effective amount of at least one additional pharmaceutically active agent. 25. The long-acting composition of claim 24, wherein the additional pharmaceutically active agent is a macrocyclic lactone. 26. Long-acting composition according to claim 25, wherein the macrocyclic lactone is abamectin, dimadectin, doramectin, emamectin, epnnomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1694,554, milbemectin, milbemycin D, moxidectin or nemadectin. 27. Method for treating or preventing parasites in an animal in need thereof for a period of 3 to 6 months, comprising administering the long-acting injectable composition as defined by claim 1, to said animal. 28. The method of claim 27, wherein the animal is a dog, cat, sheep or cattle. 29. Method according to claim 27, wherein the parasites are treated or prevented for about 5 to 6 months 30. Method according to claim 27, wherein the parasites are treated or prevented for about 6 months 31. The method of claim 27, wherein the parasites are fleas and/or ticks. 32. Use of an isoxazoline in which is the preparation of a long-acting injectable composition for the treatment or prevention of an infestation or parasitic infection in or on an animal.

[00430] Having thus described in detail several embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to the particular details set forth in the above description as many evident variations thereof are possible without departing from the spirit or scope of the present invention.

Claims (19)

1. Long-acting injectable composition for the treatment or prevention of parasite infestations or infections in an animal characterized by the fact that the parasites are fleas or ticks, wherein said composition comprises: a) an effective amount of antiparasitic, at least, an isoxazoline active agent of formula (Ib): or a pharmaceutically acceptable salt thereof wherein R2, independently, is halogen, C1-C6 alkyl or C1-C6 haloalkyl; R4 is H or C1-C6 alkyl; R5 is C1-C4 alkyl optionally substituted with further R7; and R7 is C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl; and is 0, 1 or 2; at least one pharmaceutically acceptable polymer P-181, poloxamer P-188, poloxamer P-237, poloxamer P338 or poloxamer P407; c) at least one co-solvent which is a polar organic solvent miscible with water and which is selected from methanol, ethanol, isopropanol, benzyl alcohol and a liquid polyethylene glycol; d) optionally, an antioxidant; and e) optionally, at least one pharmaceutically acceptable additive, excipient or mixtures thereof, in which no other pharmaceutically acceptable polymers are present. 2. Long-acting injectable composition according to claim 1, characterized by the fact that the active agent isoxazoline is a compound of formula (Ia): or a pharmaceutically acceptable salt thereof. 3. Long-acting injectable composition according to claim 1, characterized by the fact that the active agent isoxazoline is enriched in one enantiomer. 4. Long-acting injectable composition according to claim 3, characterized by the fact that the active agent isoxazoline is enriched in a compound of formula (S)-(Ia): or a pharmaceutically accepted salt thereof 5. Long-acting injectable composition, according to claim 1, characterized by the fact that it comprises: a) 5 to 30% (w/v) of compounds of an isoxazoline of formula (Ib) as defined in claim 1; b) a pharmaceutically acceptable polymer, which is a poloxamer selected from poloxamer 124, poloxamer P181, poloxamer P-188, poloxamer P-237, poloxamer P338 or poloxamer P407; c) 5% to 40% (w/v) of co-solvent selected from the group consisting of liquid polyethylene glycol, ethanol and isopropanol, or a mixture thereof; d) optionally, 0.01% to 2.0% (w/v) of an antioxidant; and e) optionally, 0.01% to 5.0% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof, wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is said poloxamers, and wherein the poloxamer is present in the overall composition, in a proportion that represents the complement for 100% of the composition. 6. Long-acting injectable composition according to claim 1, characterized by the fact that the composition treats or prevents parasite infestations or infections for 3 to 6 months. 7. Long-acting injectable composition according to claim 1, characterized by the fact that the composition treats or prevents infestations or infections by parasites for 5 to 6 months. 8. Long-acting injectable composition according to claim 1, characterized by the fact that the composition treats or prevents infestations or infections by parasites for 6 months. 9. Long-acting injectable composition according to claim 1, characterized by the fact that the composition treats or prevents parasite infestations or infections for 7 months or more. 10. Long-acting injectable composition according to claim 1, characterized by the fact that it comprises: a) 5 to 30% (w/v) of an active isoxazoline compound of formula (Ia) or a pharmaceutically acceptable salt thereof, b) pharmaceutically acceptable polymer, which is a poloxamer selected from poloxamer 124, poloxamer P181, poloxamer P-188, poloxamer P-237, poloxamer P338 or poloxamer P407; c) 5% to 40% (w/v) of co-solvent selected from the group consisting of liquid polyethylene glycol, ethanol and isopropanol; d) optionally, 0.01% to 2.0% (w/v) of an antioxidant; and e) optionally, 0.01% to 5.0% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof; wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is said poloxamer, and wherein the poloxamer is present in the overall composition, in a proportion that represents the complement for 100% of the composition. 11. Long-acting injectable composition, according to claim 10, characterized by the isoxazoline compound is: or a pharmaceutically acceptable salt thereof. 12. Long-acting composition, any one of claims 1 to 11, characterized in that it further comprises an effective amount of at least one additional pharmaceutically active agent. 13. Long-acting composition according to claim 12, characterized in that the additional pharmaceutically active agent is a macrocyclic lactone. 14. Long-acting composition according to claim 13, characterized by the fact that the macrocyclic lactone is abamectin, dimadectin, doramectin, emamectin, epnnomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1694,554, milbemectin, milbemycin D, moxidectin or nemadectin. 15. Use of the long-acting injectable composition as defined in claim 1 characterized by the fact that it is for the manufacture of a medicine to treat or prevent parasitic infestations for a period of 3 to 6 months in an animal in need thereof. 16. Use according to claim 15, characterized by the fact that the animal is a dog, cat, sheep or cattle. 17. Use according to claim 15, characterized by the fact that the medicine provides treatment or prevention of parasites for 5 to 6 months. 18. Use according to claim 15, characterized in that the medicine provides treatment or prevention of parasites for 6 months. 19. Use, according to claim 15, characterized by the fact that the parasites are fleas and/or ticks.