Antiparasitic isoxazoline compounds, long-acting injectable formulations containing them, methods and uses thereof

Abstract

The present invention relates to a long-acting injectable composition for combating parasites in animals, which comprises at least one isoxazoline active agent, a liquid PEG and / or a neutral oil, an optional co-solvent, and an optional pharmaceutically acceptable additive or excipient. The present invention also provides a new isoxazoline active agent having a persistent effect against ectoparasites. The present invention further provides an improved method for eradicating, controlling and preventing parasite infections and infestations in animals, which method comprises administering to an animal in need thereof the new isoxazoline compound and the long-acting injectable composition of the present invention.

Description

[0001] This invention is a divisional application of Chinese Patent Application No. 201780018986.7 with a filing date of February 24, 2017. The original invention name was "Isoxazoline Compounds Against Parasites, Long-Acting Injectable Preparations Containing Them, Their Methods and Uses". Technical Field

[0002] The present invention provides insecticidal and antiparasitic isoxazoline compounds, and long-acting injectable compositions comprising at least one isoxazoline active ingredient, liquid polyethylene glycol (PEG), and optionally a co-solvent. The present invention also provides the use of these compounds and compositions against pests and parasites, including ectoparasites (such as fleas or ticks) and / or endoparasites, as well as methods for controlling pests and preventing or treating parasite infections and infestations in animals.

[0003] Cross-reference to related applications

[0004] This application claims the benefit of U.S. Provisional Application No. 62 / 299,333 filed on February 24, 2016 and U.S. Provisional Application No. 62 / 379,348 filed on August 25, 2016, both of which are incorporated herein by reference. Background Art

[0005] Animals, such as mammals and birds, are often vulnerable 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 cats and dogs, are often infested by one or more of the following ectoparasites:

[0006] - Fleas (e.g., Ctenocephalides spp., such as Ctenocephalides felis, etc.);

[0007] - Ticks (e.g., Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., etc.);

[0008] - Mites (e.g., Demodex spp., Sarcoptes spp., Otodectes spp., etc.);

[0009] -lice (e.g., Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.);

[0010] -mosquitoes (Aedes spp., Culex spp, Anopheles spp., etc.); and

[0011] -flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.).

[0012] Fleas are a particular problem because they not only adversely affect the health of animals or humans, but also create a great deal of psychological stress. In addition, fleas can transmit pathogenic agents to animals and humans, such as tapeworms (Dipylidium caninum).

[0013] Similarly, ticks are harmful to the physical and psychological health of animals or humans. However, the most serious problem associated with ticks is that they are vectors of pathogenic agents in humans and animals. The main diseases that ticks can transmit include Lyme disease (caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.), and rickettsiosis (e.g., Rocky Mountain spotted fever). Ticks also release toxins that cause inflammation or paralysis in the host. These toxins are sometimes fatal to the host.

[0014] Similarly, livestock are also vulnerable to parasite infestations. For example, cattle and other bovids are affected by a large number of parasites. Parasites prevalent in cattle in some regions are ticks of the genus Rhipicephalus, particularly those of the species Rhipicephalus microplus (cattle tick), Rhipicephalus decoloratus, and Rhipicephalus annulatus. Ticks such as Rhipicephalus microplus (formerly Boophilus microplus) are difficult to control because they lay eggs in the pastures where livestock graze. This species of tick is considered a one-host tick, which spends its immature and adult stages on one animal, and then the female tick becomes engorged and detaches from the host to lay eggs in the environment. The life cycle of the tick is approximately 3 to 4 weeks. In addition to cattle, Rhipicephalus microplus can also infest water buffalo, horses, donkeys, goats, sheep, deer, pigs, and dogs. A heavy tick burden on animals can reduce productivity and damage hides, as well as transmit diseases such as babesiosis ("cattle fever") and eperythrozoonosis.

[0015] Animals and humans also suffer from endoparasite infections, including, for example, helminthiases, which are caused by parasites classified as cestodes (tapeworms), nematodes (roundworms), and trematodes (flatworms or flukes). These parasites adversely affect the nutrition of animals and cause significant economic losses in pigs, sheep, horses, and cattle, as well as affect companion animals and poultry. Other parasites present in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, and the extraintestinal stages of parasites such as filaria and Strongyloides, Toxocara, and Trichinella present in the blood or other tissues and organs.

[0016] In recent years, it has been confirmed that compounds containing isoxazoles and isoxazolines are effective against parasites that harm animals. For example, US 7,964,204 (assigned to DuPont and incorporated herein by reference in its entirety) discloses isoxazoline compounds according to the following formula (I), which are active against ectoparasites and / or endoparasites.

[0017]

[0018] In addition, the published patent application numbers US2010 / 0254960 A1, WO 2007 / 070606A2, WO 2007 / 123855 A2, WO 2010 / 003923 A1, US7951828 and US7662972, US2010 / 0137372 A1, US2010 / 0179194A2, US2011 / 0086886 A2, US2011 / 0059988 A1, US2010 / 0179195A1 and WO 2007 / 075459 A2 and the US patent numbers 7,951,828 and 7,662,972 describe different other antiparasitic isoxazoline compounds. Other published patent applications that describe different other antiparasitic isoxazoline compounds and compositions containing them include WO 2007 / 079162A1, WO 2008 / 154528 A1, WO 2009 / 002809 A2, WO 2011 / 149749A1, WO2014 / 439475 A1, US 8,466,115, WO 2012 / 120399, WO 2014 / 039484, WO 2014 / 189837, (Zoetis) and WO2012 120135A1 (Novartis). WO 2012 / 089623 describes a topical isoxazoline composition containing glycogen. WO 2013 / 039948 A1 provides a topical veterinary composition containing at least one isoxazoline active agent, and WO 2013 / 119442 A1 provides an oral veterinary composition such as a soft chewable containing at least one isoxazoline active agent.

[0019] In addition to topical and oral dosage forms, sometimes it may be possible to formulate an active agent into a long-acting composition, depending on, for example, the physico-chemical properties of the various active agents; these properties include, for example, solubility, bioavailability, etc. For example, US 6,733,767 and US 8,362,086 provide long-acting injectable compositions containing a bioactive substance (e.g., avermectin or milbemycin) and a biologically acceptable polymer.

[0020] Although highly active isoxazoline actives and compositions comprising either a single isoxazoline active or isoxazoline actives in combination with other actives are described in the foregoing documents, there is still a need for more effective isoxazoline compounds and veterinary compositions and methods having improved efficacy, bioavailability, and coverage to protect animals from endoparasites and / or ectoparasites. More specifically, there is a need to develop long-acting injectable compositions comprising isoxazoline compounds that have good bioavailability, exhibit reduced injection site irritation, and are still effective against parasites (e.g., fleas and ticks) over a long duration (e.g., from three (3) months to six (6) months).

[0021] Incorporation by reference

[0022] Any of the foregoing applications and all documents cited in them or during their prosecution (“application-cited documents”), as well as all documents cited or referenced in the application-cited documents, and all documents cited or referenced herein (“herein-cited documents”), as well as all documents cited or referenced in the herein-cited documents, and any manufacturer's guidance, instructions, product specifications, and product inserts for any product mentioned herein or in any document incorporated herein by reference, are hereby incorporated by reference herein and may be used in the practice of the present invention.

[0023] The citation or identification of any document in this application is not an admission that the document is available as prior art for the present invention. SUMMARY OF THE INVENTION

[0024] In a first aspect, the present invention provides a novel and inventive long-acting injectable composition for treating or preventing parasite infections or infestations in animals, comprising an anti-parasite effective amount of at least one isoxazoline compound, liquid PEG and / or a pharmaceutically acceptable neutral oil, an optional co-solvent, and an optional pharmaceutically acceptable additive or excipient.

[0025] In accordance with the first aspect of the present invention, it has been found that the long-acting compositions of the present invention generally exhibit desirable bioavailability and duration of efficacy, while causing minimal irritation at the injection site. The compositions also provide a desirable safety profile to warm-blooded and avian animal recipients. Additionally, it has been found that a single administration of such compositions generally provides effective activity against one or more parasites (e.g., ectoparasites), while also tending to provide a rapid onset, long duration of activity, and / or a desirable safety profile.

[0026] The present invention includes the use or veterinary application of the isoxazoline compounds and compositions described herein for the treatment or prevention of parasite infections and infestations in or on animals (wild or domesticated), said animals including livestock and companion animals such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys, and cattle, with the aim of ridding these hosts of the parasites commonly encountered by these animals.

[0027] In addition, the compounds of formula (Id) described herein can be used to protect crops, plants, plant propagation materials, or materials containing or derived from wood from harmful pests.

[0028] The present invention also provides a method for the treatment or prevention of parasite infections and infestations in animals, said method comprising administering an effective amount of a long-acting injectable composition comprising an anti-parasite effective amount of at least one isoxazoline compound and at least one liquid PEG and / or a pharmaceutically acceptable neutral oil and an optional co-solvent, pharmaceutically acceptable additives, and / or excipients, wherein the composition does not contain a pharmaceutically acceptable biodegradable polymer as defined herein. It has surprisingly been found that the isoxazoline-containing compositions of the present invention described herein exhibit excellent broad-spectrum efficacy against harmful parasites (e.g., ectoparasites such as fleas and ticks) more rapidly and for a long duration compared to other injectable compositions containing isoxazoline active agents known in the art, while showing minimal irritation at the injection site.

[0029] The present invention also provides the use of isoxazoline in the preparation of a long-acting injectable composition for the treatment or prevention of parasites in animals.

[0030] In one embodiment, the present invention provides a long-acting injectable composition comprising an anti-parasite effective amount of a combination of at least one isoxazoline of formula (I) below and a pharmaceutically or veterinarily acceptable liquid carrier, wherein the variables A 1 、A 2 、A 3 、A 4 、A 5 、A 6 、B 1 、B 2 、B 3 、R 1 、R 2 、R 4 、R 5 、W and n are as defined herein.

[0031]

[0032] In another embodiment, the present invention provides a long-acting injectable composition comprising an isoxazoline compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0033]

[0034] wherein X 1 、X 2 and X 3 are each independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. It has been demonstrated that a long-acting composition comprising a compound of formula (Ic) wherein X 1 is chlorine, X 2 is fluorine, and X 3 is CF3) is surprisingly persistent and has excellent efficacy against Rhipicephalus microplus, with a rapid onset and a very long duration.

[0035] In another embodiment, the long-acting injectable composition and method 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-naphthamide as the active agent.

[0036] In other embodiments, the long-acting injectable composition may further comprise one or more additional systemically active agents. Systemically acting agents can include, but are not limited to: isoxazoline agents of different structures, systemically acting neonicotinoid agents, systemically acting 1-N-arylpyrazole agents, macrolides such as avermectin and milbemycin compounds, cyclic lipopeptides such as emamectin or PF1022A, or analogs thereof, benzimidazoles, imidazothiazoles, tetrahydropyrimidine agents, organophosphate agents, levamisole, paraherquamide agents and / or marcfortine agents, praziquantel, closantel, clorsulon, morantel, pyrantel, spinosyn or spinosoid agents, aminoacetonitrile agents, arylbenzoxazol-2-yl cyanoethyl agents and systemically acting insect growth regulators. In one embodiment, the long-acting injectable composition comprises at least one macrolide agent, including, but not limited to, avermectin or milbemycin. In certain embodiments, the avermectin or milbemycin agent is eprinomectin, ivermectin, selamectin, moxidectin, milbemycin D, demeton-S-methyl S-oxide or moxidectin.

[0037] In other embodiments, the composition and method comprise at least one of thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, carbendazim, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, aminoacetonitrile active agent or aryl-benzazol-2-yl cyanoethylamino active agent.

[0038] In a second aspect, the present invention provides novel and inventive insecticidal and antiparasitic isoxazoline compounds of the following formula (Id):

[0039]

[0040] wherein X 1 is bromine, chlorine, iodine or fluorine; and X 2 is chlorine, fluorine or CF3;

[0041] Y is group Y-1, Y-2, Y-3, Y-4 (where Z is N or CH), Y-5 or Y-6

[0042]

[0043]

[0044] and Q is OH, -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, -C(O)NHCH2CH2SCH3 or (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3.

[0045] The compounds of formula (Id) are highly active against arthropod pests and parasites and can be used to protect animals (including livestock and companion animals such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle) from infestation or infection by parasites that infest such animals. The present invention also provides insecticidal isoxazoline compounds of formula (Id) for protecting crops, plants, plant propagation materials or materials containing or derived from wood from harmful pests.

[0046] An object of the present invention is that within the present invention, any previously known product, process for manufacturing such product, or method of using such product is not included, such that the applicant reserves the right to disclaim any previously known product, process or method and hereby discloses the same. Further, it is pointed out that the present invention is not intended to include within the scope of the present invention any product, process for preparing such product, or method of using such product that does not meet the written description and enablement requirements of the USPTO (35 U.S.C. § 112, paragraph 1) or the EPO (Article 83 of the EPC), such that the applicant reserves the right to disclaim any previously described product, process for preparing such product, or method of using such product and hereby discloses the same.

[0047] The following detailed description discloses or reveals and includes these and other embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0049] Long-acting injectable compositions

[0050] In a first aspect, the present invention provides a novel and inventive long-acting injectable composition for treating or preventing parasitic infections or infestations in animals, comprising an anti-parasitically effective amount of at least one isoxazoline compound, liquid PEG and / or a pharmaceutically acceptable neutral oil, and optionally a co-solvent, pharmaceutically acceptable additives and / or excipients, wherein no other pharmaceutically acceptable polymers as defined herein are present.

[0051] Also provided are methods and uses for treating and / or preventing parasitic infections and infestations in or on animals, the method comprising administering to an animal in need thereof a long-acting composition comprising an anti-parasitically effective amount of at least one isoxazoline compound, liquid PEG and / or a pharmaceutically acceptable neutral oil, and optionally a co-solvent, pharmaceutically acceptable additives and / or excipients.

[0052] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on animals, comprising an anti-parasitically effective amount of at least one isoxazoline compound and an effective amount of at least one additional active agent, PEG and / or a pharmaceutically acceptable neutral oil, and optionally a co-solvent, pharmaceutically acceptable additives and / or excipients.

[0053] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on animals, comprising:

[0054] a) an anti-parasitically effective amount of at least one isoxazoline active agent, which is:

[0055] i) an isoxazoline compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0056]

[0057] Wherein:

[0058] A 1 、A 2 、A 3 、A 4 、A 5 and A 6 are independently selected from CR 3 and N, provided that A 1 、A2 、A 3 、A 4 、A 5 and A 6 at most 3 of which are N;

[0059] B 1 、B 2 and B 3 are independently selected from CR 2 and N;

[0060] W is O or S;

[0061] R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted by one or more substituents independently selected from R 6 ;

[0062] Each R 2 is independently 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 dialkylamino, C2-C4 alkoxycarbonyl, -CN or -NO2;

[0063] Each R 3 is 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-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2;

[0064] R 4 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 alkoxycarbonyl;

[0065] R 5 is H, OR 10 、NR 11 R 12 or Q 1; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted by one or more substituents independently selected from R 7 ; or

[0066] R 4 and R 5 together with the nitrogen to which they are attached form a ring containing 2-6 carbon atoms and optionally one additional atom selected from N, S and O, the ring optionally substituted by 1-4 substituents independently selected from C1-C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy;

[0067] Each R 6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, -CN or -NO2;

[0068] Each R 7 is independently 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 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, -NH2, -CN or -NO2; or Q 2 ;

[0069] Each R 8 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;

[0070] Each R 9is 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-C6 dialkylamino, -CN, -NO2, phenyl or pyridyl;

[0071] R 10 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 or more halogens;

[0072] R 11 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 alkoxycarbonyl;

[0073] R 12 is H; Q 3 ; 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 R 7 ; or

[0074] R 11 and R 12 together with the nitrogen to which they are attached form a ring containing 2-6 carbon atoms and optionally one additional atom selected from N, S and O, the ring optionally substituted with 1-4 substituents independently selected from C1-C2 alkyl, halogen, -CN, -NO2 and C1-C2 alkoxy;

[0075] Q 1 is a phenyl ring, 5- or 6-membered heterocycle or 8-, 9- or 10-membered fused bicyclic ring system, the ring or ring system optionally containing 1-3 heteroatoms selected from at most 1 O, at most 1 S and at most 3 Ns, each ring or ring system optionally substituted with one or more substituents independently selected from R 8 ;

[0076] Each Q 2 is independently a phenyl ring or 5- or 6-membered heterocycle, each ring optionally substituted with one or more substituents independently selected from R 9 ;

[0077] Q 3is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally being substituted by one or more substituents independently selected from R 9 and; and

[0078] n is 0, 1 or 2; and / or

[0079] ii) an isoxazoline compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0080]

[0081] wherein:

[0082] R1 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is unsubstituted or substituted by one or more of halogen, hydroxy, 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;

[0083] X is aryl or heteroaryl, which may be unsubstituted or substituted by one or more of halogen, hydroxy, 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;

[0084] A1 is oxygen; and

[0085] A2 is oxygen, NR2 or CR7R8;

[0086] G is G-1 or G-2;

[0087]

[0088] B1, B2, B3, B4 and B5 are independently N or C-R9;

[0089] Y is hydrogen, a halogen, -CN; or Y is an alkyl group, a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a haloalkynyl group, a cycloalkyl group, an alkylcycloalkyl group, a cycloalkylalkyl group, an aryl group or a heterocyclic group or a heteroaryl group, each of which is unsubstituted or substituted by one or more of a halogen, a hydroxyl group, an amino group, an alkyl- or di(alkyl)amino group, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a haloalkynyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, a haloalkylthio group, 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;

[0090]

[0091] R2 and R3 are independently hydrogen, an alkyl group, a haloalkyl group, a thioalkyl group, an alkylthioalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a haloalkynyl group, a cycloalkyl group, R 10 S(O)-, R 10 S(O)2-, R 10 C(O)-, R 10 C(S)-, R 10 R 11 NC(O)-, R 10 R 11 NC(S)-R 10 OC(O)-;

[0092] R4, R5 and R6 are independently hydrogen, an alkyl group, a haloalkyl group, an alkylthio group, an alkylthioalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a haloalkynyl group, a cycloalkyl group, an aryl group or a heteroaryl group;

[0093] R7 and R8 are independently hydrogen, an alkyl group, a haloalkyl group, an alkylthio group, an alkylthioalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group or a haloalkynyl group;

[0094] 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 of halogen, hydroxy, 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;

[0095] R 10 、R 11 、R 12 and R 13 are each independently hydrogen, alkyl, haloalkyl, alkanethio, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, or haloalkynyl; or

[0096] R 10 and R 11 together form =O, =S, or =NR2; or

[0097] R 12 and R 13 together form =O, =S, or =NR2;

[0098] W is O, S, or NR2;

[0099] n is 1 - 4; and

[0100] m is 0, 1, or 2; and / or

[0101] iii) an isoxazoline compound of formula (III) or a pharmaceutically acceptable salt thereof

[0102]

[0103] and / or

[0104] iv) an isoxazoline compound of formula (IV) or a pharmaceutically acceptable salt thereof

[0105]

[0106] and / or

[0107] v) an isoxazoline compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0108]

[0109] wherein R 1 、R 2and R 3 independently is H, Cl, F or CF3;

[0110] Y is a diradical group

[0111] and

[0112] T is an unsubstituted or C1-C6-alkyl substituted by the following groups: halogen, cyano, nitro, amino, hydroxy, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-alkylthio, carboxyl, carbamoyl or C2-C6-alkanoyl, which may be unsubstituted or substituted by halogen in the alkyl moiety; and / or

[0113] vi) an isoxazoline compound of formula (VI) or a pharmaceutically acceptable salt thereof:

[0114]

[0115] wherein Y is hydrogen, fluorine, chlorine or bromine;

[0116] R 1 is a phenyl substituted by 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy;

[0117] R 2 is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;

[0118] R 3a and R 3b independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R 3a and R 3b together with the carbon to which they are attached combine to form a cyclopentyl ring or a cyclohexyl ring;

[0119] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0120] c) optionally at least one co-solvent;

[0121] d) optionally an antioxidant; and

[0122] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0123] wherein there is no other pharmaceutically acceptable polymer.

[0124] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[0125] a) At least one isoxazoline active agent in an anti - parasite effective amount, which is:

[0126] i) An isoxazoline compound of formula (I) as described above or a pharmaceutically acceptable salt thereof; and / or

[0127] ii) An isoxazoline compound of formula (II) as described above or a pharmaceutically acceptable salt thereof; and / or

[0128] iii) An isoxazoline compound of formula (III) as described above or a pharmaceutically acceptable salt thereof; and / or

[0129] iv) An isoxazoline compound of formula (IV) as described above or a pharmaceutically acceptable salt thereof; and / or

[0130] v) An isoxazoline compound of formula (V) as described above or a pharmaceutically acceptable salt thereof; and / or

[0131] vi) An isoxazoline compound of formula (VI) as described above or a pharmaceutically acceptable salt thereof;

[0132] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0133] c) Optionally, at least one co - solvent, wherein the co - solvent is a polar solvent miscible with water;

[0134] d) Optionally, an antioxidant; and

[0135] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0136] wherein there is no other pharmaceutically acceptable polymer.

[0137] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[0138] a) At least one isoxazoline active agent in an anti - parasite effective amount, which is:

[0139] i) An isoxazoline compound of formula (I) as described above or a pharmaceutically acceptable salt thereof; and / or

[0140] ii) An isoxazoline compound of formula (II) as described above or a pharmaceutically acceptable salt thereof; and / or

[0141] iii) An isoxazoline compound of formula (III) as described above or a pharmaceutically acceptable salt thereof; and / or

[0142] iv) An isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof; and / or

[0143] v) An isoxazoline compound of formula (V) as described above, or a pharmaceutically acceptable salt thereof; and / or

[0144] vi) An isoxazoline compound of formula (VI) as described above, or a pharmaceutically acceptable salt thereof;

[0145] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0146] c) Optionally, at least one co-solvent, wherein the co-solvent is not miscible with water or is only partially soluble in water;

[0147] d) Optionally, an antioxidant; and

[0148] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0149] wherein no other pharmaceutically acceptable polymers are present.

[0150] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0151] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof;

[0152] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0153] c) Optionally, at least one co-solvent;

[0154] d) Optionally, an antioxidant; and

[0155] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0156] wherein no other pharmaceutically acceptable polymers are present.

[0157] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0158] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof;

[0159] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0160] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0161] d) optionally an antioxidant; and

[0162] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0163] wherein there are no other pharmaceutically acceptable polymers.

[0164] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[0165] a) an anti-parasite effective amount of at least one isoxazoline active agent of formula (I) above, or a pharmaceutically acceptable salt thereof;

[0166] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0167] c) optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0168] d) optionally an antioxidant; and

[0169] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0170] wherein there are no other pharmaceutically acceptable polymers.

[0171] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0172] a) an anti-parasite effective amount of an isoxazoline compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0173]

[0174] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0175] c) optionally at least one co-solvent;

[0176] d) optionally an antioxidant; and

[0177] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0178] There are no other pharmaceutically acceptable polymers present.

[0179] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0180] a) An anti - parasite effective amount of at least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof;

[0181] b) At least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0182] c) Optionally, at least one co - solvent, wherein the co - solvent is a polar solvent miscible with water;

[0183] d) Optionally, an antioxidant; and

[0184] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0185] There are no other pharmaceutically acceptable polymers present.

[0186] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0187] a) An anti - parasite effective amount of at least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof;

[0188] b) At least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0189] c) Optionally, at least one co - solvent, wherein the co - solvent is immiscible with water or only partially soluble in water;

[0190] d) Optionally, an antioxidant; and

[0191] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0192] There are no other pharmaceutically acceptable polymers present.

[0193] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0194] a) At least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof, in an amount effective against parasites;

[0195] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0196] c) Optionally, a co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, butyldiglycol, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide (DMI), dimethylacetamide, dimethyl sulfoxide, or glycerol formal, or a combination thereof;

[0197] d) Optionally, an antioxidant; and

[0198] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0199] wherein no other pharmaceutically acceptable polymers are present.

[0200] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0201] a) At least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof, in an amount effective against parasites;

[0202] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0203] c) Optionally, a co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C8-C 10 triglyceride (e.g., 810 and 812), a C8-C triglyceride in combination with linoleic acid (e.g., 10 818), a C8-C triglyceride in combination with succinic acid (e.g., 829), a C8-C 10 triglyceride (e.g., 829), a C8-C 10Propylene glycol diesters of fatty acids (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil, or combinations thereof;

[0204] d) an optional antioxidant; and

[0205] e) an optional surfactant, and an optional at least one other pharmaceutically acceptable additive, excipient, or mixture thereof;

[0206] wherein there are no other pharmaceutically acceptable polymers.

[0207] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0208] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof;

[0209] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0210] c) an optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

[0211] d) an optional antioxidant; and

[0212] e) an optional at least one pharmaceutically acceptable additive, excipient, or mixture thereof;

[0213] wherein there are no other pharmaceutically acceptable polymers.

[0214] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0215] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof;

[0216] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0217] c) an optional co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[0218] d) an optional antioxidant; and

[0219] e) an optional at least one pharmaceutically acceptable additive, excipient, or mixture thereof;

[0220] There are no other pharmaceutically acceptable polymers therein.

[0221] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0222] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof;

[0223] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0224] c) optionally at least one co-solvent, wherein the co-solvent is a C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0225] d) optionally an antioxidant; and

[0226] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0227] There are no other pharmaceutically acceptable polymers therein.

[0228] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0229] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ia) as described above, or a pharmaceutically acceptable salt thereof;

[0230] b) at least one neutral oil, wherein the neutral oil is a C8-C 10 triglyceride;

[0231] c) optionally at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0232] d) optionally an antioxidant; and

[0233] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0234] There are no other pharmaceutically acceptable polymers therein.

[0235] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0236] a) An isoxazoline compound of formula (Ib) or a pharmaceutically acceptable salt thereof in an anti - parasite effective amount:

[0237]

[0238] wherein

[0239] R 2 is independently halogen, C1 - C6 alkyl or C1 - C6 haloalkyl;

[0240] R 4 is H or C1 - C6 alkyl;

[0241] R 5 is C1 - C4 alkyl optionally substituted by one or more R 7 ; and R 7 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 (e.g., - CH2C(O)NHCH2CF3); and

[0242] n is 0, 1 or 2;

[0243] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0244] c) Optionally, at least one co - solvent;

[0245] d) Optionally, an antioxidant; and

[0246] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0247] wherein no other pharmaceutically acceptable polymers are present.

[0248] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0249] a) At least one isoxazoline compound of formula (Ib) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0250] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0251] c) Optionally, at least one co - solvent, wherein the co - solvent is a polar solvent miscible with water;

[0252] d) Optional antioxidant; and

[0253] e) Optionally at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0254] wherein there are no other pharmaceutically acceptable polymers.

[0255] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0256] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0257] b) At least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0258] c) Optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0259] d) Optional antioxidant; and

[0260] e) Optionally at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0261] wherein there are no other pharmaceutically acceptable polymers.

[0262] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0263] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0264] b) At least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0265] c) Optionally a co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including but not limited to diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0266] d) Optional antioxidant; and

[0267] e) Optional at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0268] wherein there are no other pharmaceutically acceptable polymers.

[0269] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0270] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0271] b) At least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0272] c) Optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglyceride (e.g. 810 and 812), C8-C triglyceride in combination with linoleic acid (e.g. 10 818), C8-C triglyceride in combination with succinic acid (e.g. 829), propylene glycol diester of C8-C 10 fatty acid (e.g. 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil or combinations thereof; 10 d) Optional antioxidant; and e) Optional at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0273] wherein there are no other pharmaceutically acceptable polymers.

[0274] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0275] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0276] b) At least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0277] c) Optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C

[0278] d) Optional antioxidant; and

[0279] c) An optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

[0280] d) An optional antioxidant; and

[0281] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0282] wherein there are no other pharmaceutically acceptable polymers.

[0283] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0284] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0285] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0286] c) An optional co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[0287] d) An optional antioxidant; and

[0288] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0289] wherein there are no other pharmaceutically acceptable polymers.

[0290] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0291] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0292] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0293] c) An optional at least one co-solvent, wherein the co-solvent is a C8-C 10 triglyceride, benzyl alcohol, or a combination thereof;

[0294] d) An optional antioxidant; and

[0295] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0296] There are no other pharmaceutically acceptable polymers present.

[0297] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0298] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ib) as described above, or a pharmaceutically acceptable salt thereof;

[0299] b) at least one neutral oil, wherein the neutral oil is a C8-C 10 triglyceride;

[0300] c) optionally at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0301] d) optionally an antioxidant; and

[0302] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0303] There are no other pharmaceutically acceptable polymers present.

[0304] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0305] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (II) as described above, or a pharmaceutically acceptable salt thereof,

[0306] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0307] c) optionally at least one co-solvent;

[0308] d) optionally an antioxidant; and

[0309] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0310] There are no other pharmaceutically acceptable polymers present.

[0311] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0312] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (II) as described above, or a pharmaceutically acceptable salt thereof;

[0313] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0314] c) Optionally, at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0315] d) Optionally, an antioxidant; and

[0316] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0317] wherein there is no other pharmaceutically acceptable polymer.

[0318] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0319] a) An anti-parasitic effective amount of at least one isoxazoline compound of formula (II) as described above, or a pharmaceutically acceptable salt thereof;

[0320] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0321] c) Optionally, at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0322] d) Optionally, an antioxidant; and

[0323] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0324] wherein there is no other pharmaceutically acceptable polymer.

[0325] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0326] a) An anti-parasitic effective amount of at least one isoxazoline compound of formula II-1.001 to II-1.025 or II-2.00 to II-2.018 or a pharmaceutically acceptable salt thereof:

[0327]

[0328] Compounds II-1.001 to II-1.025

[0329]

[0330]

[0331]

[0332] Compounds II-2.001 to II-2.018

[0333]

[0334]

[0335] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0336] c) optionally at least one co-solvent;

[0337] d) optionally an antioxidant; and

[0338] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof.

[0339] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0340] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula II-1.001 to II-1.025 or II-2.00 to II-2.018 as described above, or a pharmaceutically acceptable salt thereof;

[0341] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0342] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0343] d) optionally an antioxidant; and

[0344] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0345] wherein there is no other pharmaceutically acceptable polymer.

[0346] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0347] a) At least one isoxazoline compound of formulae II-1.001 to II-1.025 or II-2.00 to II-2.018 as described above, or a pharmaceutically acceptable salt thereof, in an anti-parasite effective amount;

[0348] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0349] c) Optionally, at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0350] d) Optionally, an antioxidant; and

[0351] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0352] wherein no other pharmaceutically acceptable polymers are present.

[0353] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0354] a) An isoxazoline compound of formula (III) or a pharmaceutically acceptable salt thereof in an anti-parasite effective amount;

[0355]

[0356] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0357] c) Optionally, at least one co-solvent;

[0358] d) Optionally, an antioxidant; and

[0359] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0360] wherein no other pharmaceutically acceptable polymers are present.

[0361] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0362] a) At least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof, in an anti-parasite effective amount;

[0363] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0364] c) Optionally, at least one cosolvent, wherein the cosolvent is a polar solvent miscible with water;

[0365] d) Optionally, an antioxidant; and

[0366] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0367] wherein there are no other pharmaceutically acceptable polymers.

[0368] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0369] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0370] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0371] c) Optionally, at least one cosolvent, wherein the cosolvent is immiscible with water or only partially soluble in water;

[0372] d) Optionally, an antioxidant; and

[0373] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0374] wherein there are no other pharmaceutically acceptable polymers.

[0375] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0376] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0377] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0378] c) An optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0379] d) An optional antioxidant; and

[0380] e) An optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0381] wherein there is no other pharmaceutically acceptable polymer.

[0382] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactically) parasite infections and infestations in or on an animal, comprising:

[0383] a) An anti-parasite effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0384] b) At least one pharmaceutically acceptable polymer, which is a liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0385] c) An optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C8-C 10 triglyceride (e.g. 810 and 812), a C8-C triglyceride in combination with linoleic acid (e.g. 10 818), a C8-C triglyceride in combination with succinic acid (e.g. 829), a propylene glycol diester of a C8-C fatty acid (e.g. 10 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil or a combination thereof; 829), a C8-C 10 propylene glycol diester of a fatty acid (e.g. 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil or a combination thereof;

[0386] d) An optional antioxidant; and

[0387] e) An optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0388] wherein there is no other pharmaceutically acceptable polymer.

[0389] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0390] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0391] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0392] c) optionally, at least one co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol or a combination thereof;

[0393] d) optionally, an antioxidant; and

[0394] e) optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0395] wherein no other pharmaceutically acceptable polymers are present.

[0396] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0397] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0398] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0399] c) optionally, at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0400] d) optionally, an antioxidant; and

[0401] e) optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0402] wherein no other pharmaceutically acceptable polymers are present.

[0403] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0404] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0405] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0406] c) Optionally, at least one co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0407] d) Optionally, an antioxidant; and

[0408] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0409] wherein there is no other pharmaceutically acceptable polymer.

[0410] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0411] a) An anti-parasitic effective amount of at least one isoxazoline compound of formula (III) as described above, or a pharmaceutically acceptable salt thereof;

[0412] b) At least one neutral oil, wherein the neutral oil is C8-C 10 triglyceride;

[0413] c) Optionally, at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0414] d) Optionally, an antioxidant; and

[0415] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0416] wherein there is no other pharmaceutically acceptable polymer.

[0417] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0418] iv) An anti-parasitic effective amount of the isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0419] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0420] c) Optionally, at least one co-solvent;

[0421] d) Optionally, an antioxidant; and

[0422] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0423] wherein there are no other pharmaceutically acceptable polymers.

[0424] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0425] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0426] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0427] c) Optionally, at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0428] d) Optionally, an antioxidant; and

[0429] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0430] wherein there are no other pharmaceutically acceptable polymers.

[0431] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0432] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0433] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0434] c) Optionally, at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0435] d) Optionally, an antioxidant; and

[0436] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0437] wherein there are no other pharmaceutically acceptable polymers.

[0438] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0439] a) An isoxazoline compound of formula (IV) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0440] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0441] c) An optional co - solvent, wherein the co - solvent is a C1 - C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2 - pyrrolidone, N - methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0442] d) An optional antioxidant; and

[0443] e) An optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0444] wherein there is no other pharmaceutically acceptable polymer.

[0445] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0446] a) An isoxazoline compound of formula (IV) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0447] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0448] c) An optional co - solvent, wherein the co - solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C8 - C 10 triglyceride (e.g., 810 and 812), a C8 - C 10 triglyceride in combination with linoleic acid (e.g., 818), a C8 - C 10 triglyceride in combination with succinic acid (e.g., 829), a propylene glycol diester of a C8 - C 10 fatty acid (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil or a combination thereof;

[0449] d) Optional antioxidant; and

[0450] e) Optional at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0451] wherein there are no other pharmaceutically acceptable polymers.

[0452] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0453] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0454] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0455] c) Optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol or a combination thereof;

[0456] d) Optional antioxidant; and

[0457] e) Optional at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0458] wherein there are no other pharmaceutically acceptable polymers.

[0459] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0460] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0461] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0462] c) Optional co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0463] d) Optional antioxidant; and

[0464] e) Optional at least one pharmaceutically acceptable additive, excipient or mixture thereof;

[0465] wherein there are no other pharmaceutically acceptable polymers.

[0466] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0467] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0468] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0469] c) optionally at least one co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0470] d) optionally an antioxidant; and

[0471] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0472] wherein there is no other pharmaceutically acceptable polymer.

[0473] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0474] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (IV) as described above, or a pharmaceutically acceptable salt thereof;

[0475] b) at least one neutral oil, wherein the neutral oil is C8-C 10 triglyceride;

[0476] c) optionally at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0477] d) optionally an antioxidant; and

[0478] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0479] wherein there is no other pharmaceutically acceptable polymer.

[0480] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0481] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (V) as described above, or a pharmaceutically acceptable salt thereof;

[0482] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0483] c) optionally at least one co-solvent;

[0484] d) optionally an antioxidant; and

[0485] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0486] wherein there is no other pharmaceutically acceptable polymer.

[0487] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0488] a) an anti-parasitic effective amount of at least one isoxazoline compound of formula (V) as described above, or a pharmaceutically acceptable salt thereof;

[0489] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0490] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0491] d) optionally an antioxidant; and

[0492] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0493] wherein there is no other pharmaceutically acceptable polymer.

[0494] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0495] a) an anti-parasitic effective amount of at least one isoxazoline compound of formula (V) as described above, or a pharmaceutically acceptable salt thereof;

[0496] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0497] c) optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0498] d) optionally an antioxidant; and

[0499] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0500] There are no other pharmaceutically acceptable polymers present.

[0501] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising

[0502] a) an anti-parasitically effective amount of an isoxazoline compound of formula (Va):

[0503]

[0504] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0505] c) optionally at least one co-solvent;

[0506] d) optionally an antioxidant; and

[0507] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0508] There are no other pharmaceutically acceptable polymers present.

[0509] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0510] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Va) as described above, or a pharmaceutically acceptable salt thereof;

[0511] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0512] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0513] d) optionally an antioxidant; and

[0514] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0515] There are no other pharmaceutically acceptable polymers present.

[0516] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0517] a) At least one isoxazoline compound of formula (Va) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0518] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0519] c) Optionally, at least one co - solvent, wherein the co - solvent is not miscible with water or is only partially soluble in water;

[0520] d) Optionally, an antioxidant; and

[0521] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0522] wherein no other pharmaceutically acceptable polymers are present.

[0523] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0524] a) At least one isoxazoline compound of formula (Va) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0525] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0526] c) Optionally, a co - solvent, wherein the co - solvent is a C1 - C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2 - pyrrolidone, N - methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0527] d) Optionally, an antioxidant; and

[0528] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0529] wherein no other pharmaceutically acceptable polymers are present.

[0530] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0531] a) At least one isoxazoline compound of formula (Va) as described above, or a pharmaceutically acceptable salt thereof, in an anti - parasite effective amount;

[0532] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0533] c) Optionally, a co - solvent, wherein the co - solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8 - C 10 triglycerides (e.g., 810 and 812), C8 - C triglycerides in combination with linoleic acid (e.g., 10 818), C8 - C triglycerides in combination with succinic acid (e.g., 829), propylene glycol diesters of C8 - C fatty acids (e.g., 10 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or combinations thereof; 829), C8 - C 10 fatty acid propylene glycol diesters (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or combinations thereof;

[0534] d) Optionally, an antioxidant; and

[0535] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0536] wherein there are no other pharmaceutically acceptable polymers.

[0537] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (blocking) parasite infections and infestations in or on an animal, comprising:

[0538] a) At least one isoxazoline compound of formula (Va) as described above, or a pharmaceutically acceptable salt thereof, in an anti - parasite effective amount;

[0539] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0540] c) Optionally, a co - solvent, wherein the co - solvent is a C1 - C6 alcohol, benzyl alcohol or a combination thereof;

[0541] d) Optionally, an antioxidant; and

[0542] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0543] wherein there are no other pharmaceutically acceptable polymers.

[0544] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactic) parasite infections and infestations in or on an animal, comprising:

[0545] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (Va) as described above, or a pharmaceutically acceptable salt thereof;

[0546] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0547] c) an optional co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0548] d) an optional antioxidant; and

[0549] e) an optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0550] wherein no other pharmaceutically acceptable polymers are present.

[0551] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactic) parasite infections and infestations in or on an animal, comprising:

[0552] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (Va) as described above, or a pharmaceutically acceptable salt thereof;

[0553] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0554] c) an optional at least one co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0555] d) an optional antioxidant; and

[0556] e) an optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0557] wherein no other pharmaceutically acceptable polymers are present.

[0558] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactic) parasite infections and infestations in or on an animal, comprising:

[0559] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (Va) as described above, or a pharmaceutically acceptable salt thereof;

[0560] b) At least one neutral oil, wherein the neutral oil is a C8-C 10 triglyceride;

[0561] c) Optionally, at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[0562] d) Optionally, an antioxidant; and

[0563] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0564] wherein there are no other pharmaceutically acceptable polymers.

[0565] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising

[0566] a) An anti-parasitically effective amount of at least one compound of formula (VI) as described above, or a pharmaceutically acceptable salt thereof;

[0567] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0568] c) Optionally, at least one co-solvent;

[0569] d) Optionally, an antioxidant; and

[0570] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0571] wherein there are no other pharmaceutically acceptable polymers.

[0572] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0573] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (VI) as described above, or a pharmaceutically acceptable salt thereof;

[0574] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0575] c) Optionally, at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0576] d) Optionally, an antioxidant; and

[0577] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0578] There are no other pharmaceutically acceptable polymers present.

[0579] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0580] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (VI) as described above, or a pharmaceutically acceptable salt thereof;

[0581] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0582] c) optionally at least one co-solvent, wherein the co-solvent is not miscible with water or is only partially soluble in water;

[0583] d) optionally an antioxidant; and

[0584] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0585] There are no other pharmaceutically acceptable polymers present.

[0586] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0587] a) an anti-parasitically effective amount of at least one compound of formula (VIa) or a pharmaceutically acceptable salt thereof;

[0588]

[0589] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0590] c) optionally at least one co-solvent;

[0591] d) optionally an antioxidant; and

[0592] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0593] There are no other pharmaceutically acceptable polymers present.

[0594] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0595] a) An isoxazoline compound of formula (VIa) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0596] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0597] c) Optionally, at least one co - solvent, wherein the co - solvent is a polar solvent miscible with water;

[0598] d) Optionally, an antioxidant; and

[0599] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0600] wherein there are no other pharmaceutically acceptable polymers.

[0601] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0602] a) An isoxazoline compound of formula (VIa) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0603] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0604] c) Optionally, at least one co - solvent, wherein the co - solvent is immiscible with water or only partially soluble in water;

[0605] d) Optionally, an antioxidant; and

[0606] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0607] wherein there are no other pharmaceutically acceptable polymers.

[0608] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0609] a) An isoxazoline compound of formula (VIa) as described above in an anti - parasite effective amount, or a pharmaceutically acceptable salt thereof;

[0610] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0611] c) An optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide, or glycerol formal, or a combination thereof;

[0612] d) An optional antioxidant; and

[0613] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0614] wherein there are no other pharmaceutically acceptable polymers.

[0615] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactically) parasite infections and infestations in or on an animal, comprising:

[0616] a) An anti-parasite effective amount of at least one isoxazoline compound of formula (VIa) as described above, or a pharmaceutically acceptable salt thereof;

[0617] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0618] c) An optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C8-C 10 triglyceride (e.g., 810 and 812), a C8-C 10 triglyceride in combination with linoleic acid (e.g., 818), a C8-C 10 triglyceride in combination with succinic acid (e.g., 829), a propylene glycol diester of a C8-C 10 fatty acid (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil, or a combination thereof;

[0619] d) An optional antioxidant; and

[0620] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0621] wherein there are no other pharmaceutically acceptable polymers.

[0622] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0623] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (VIa) as described above, or a pharmaceutically acceptable salt thereof;

[0624] b) at least one pharmaceutically acceptable polymer which is liquid PEG;

[0625] c) an optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol or a combination thereof;

[0626] d) an optional antioxidant; and

[0627] e) an optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0628] wherein no other pharmaceutically acceptable polymers are present.

[0629] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0630] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (VIa) as described above, or a pharmaceutically acceptable salt thereof;

[0631] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0632] c) an optional at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0633] d) an optional antioxidant; and

[0634] e) an optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0635] wherein no other pharmaceutically acceptable polymers are present.

[0636] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0637] a) an anti-parasite effective amount of at least one isoxazoline compound of formula (VIa) as described above, or a pharmaceutically acceptable salt thereof;

[0638] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0639] c) Optionally, at least one co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0640] d) Optionally, an antioxidant; and

[0641] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0642] wherein there is no other pharmaceutically acceptable polymer.

[0643] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactic) parasite infections and infestations in or on an animal, comprising:

[0644] a) An anti-parasite effective amount of at least one isoxazoline compound of formula (VIa) as described above, or a pharmaceutically acceptable salt thereof;

[0645] b) At least one neutral oil, wherein the neutral oil is C8-C 10 triglyceride;

[0646] c) Optionally, at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0647] d) Optionally, an antioxidant; and

[0648] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0649] wherein there is no other pharmaceutically acceptable polymer.

[0650] In another embodiment, the long-acting injectable composition of the present invention comprises an anti-parasite effective amount of at least one isoxazoline of formula (Ib) having the following formula or a pharmaceutically acceptable salt thereof:

[0651]

[0652] wherein

[0653] R 2 is independently halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0654] R 4 is H or C1-C6 alkyl;

[0655] R 5 is optionally substituted with one or more R 7a substituted C1-C4 alkyl; and R 7 is a C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl (e.g., -CH2C(O)NHCH2CF3); and

[0656] n is 0, 1 or 2.

[0657] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0658] a) an anti-parasitically effective amount of an isoxazoline compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0659]

[0660] wherein

[0661] X 1 , X 2 and X 3 are each independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0662] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0663] c) optionally at least one co-solvent;

[0664] d) optionally an antioxidant; and

[0665] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0666] wherein there are no other pharmaceutically acceptable polymers.

[0667] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0668] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0669] b) at least one pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0670] c) Optionally, at least one cosolvent, wherein the cosolvent is a polar solvent miscible with water;

[0671] d) Optionally, an antioxidant; and

[0672] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0673] wherein there are no other pharmaceutically acceptable polymers.

[0674] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0675] a) An anti-parasitic effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0676] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0677] c) Optionally, at least one cosolvent, wherein the cosolvent is immiscible with water or only partially soluble in water;

[0678] d) Optionally, an antioxidant; and

[0679] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0680] wherein there are no other pharmaceutically acceptable polymers.

[0681] In one embodiment, the long-acting injectable composition of the present invention comprises a compound of formula (Ic), wherein X 1 and X 3 are independently halogen and X 2 is hydrogen.

[0682] In another embodiment, the long-acting injectable composition of the present invention comprises a compound of formula (Ic), wherein X 1 、X 2 and X 3 are each independently halogen.

[0683] In another embodiment of the present invention, the long-acting injectable composition comprises a compound of formula (Ic), wherein X 1 and X 3 are each independently halogen and X 2 is C1-C3 haloalkyl.

[0684] In another embodiment, the present invention provides a long-acting injectable composition comprising a compound of formula (Ic), wherein X 1 and X 2 are independently halogen and X 3 is C1-C3 haloalkyl.

[0685] In another embodiment, the present invention provides a long-acting injectable composition comprising a compound of formula (Ic), wherein X 1 and X 2 are independently halogen and X 3 is CF3.

[0686] In another embodiment, the present invention provides a long-acting injectable composition comprising a compound of formula (Ic), wherein X 1 and X 3 are chlorine and X 2 is hydrogen.

[0687] In another embodiment, the present invention provides a long-acting injectable composition comprising a compound of formula (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3.

[0688] In another embodiment, the present invention provides a long-acting injectable composition comprising a compound of formula (Ic), wherein X 1 and X 3 are chlorine and X 2 is fluorine.

[0689] In another embodiment, the long-acting injectable composition of the present invention comprises an anti-parasitic effective amount of 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-decahydronaphthalenecarboxamide (compound of formula Ia).

[0690] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0691] a) an anti-parasitic effective amount of an isoxazoline compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0692]

[0693] wherein

[0694] X 1 and X3 each independently is a halogen or a C1-C3 haloalkyl; and

[0695] X 2 is a halogen or hydrogen;

[0696] b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0697] c) optionally at least one co-solvent;

[0698] d) optionally an antioxidant; and

[0699] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0700] wherein there are no other pharmaceutically acceptable polymers.

[0701] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0702] a) an anti-parasite effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof,

[0703] wherein

[0704] X 1 and X 3 each independently is a halogen or a C1-C3 haloalkyl; and

[0705] X 2 is a halogen or hydrogen;

[0706] b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0707] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0708] d) optionally an antioxidant; and

[0709] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0710] wherein there are no other pharmaceutically acceptable polymers.

[0711] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0712] a) At least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof, in an anti - parasite effective amount;

[0713] wherein

[0714] X 1 and X 3 are each independently halogen or C1 - C3 haloalkyl; and

[0715] X 2 is halogen or hydrogen;

[0716] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0717] c) Optionally, at least one co - solvent, wherein the co - solvent is immiscible with water or only partially soluble in water;

[0718] d) Optionally, an antioxidant; and

[0719] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0720] wherein no other pharmaceutically acceptable polymers are present.

[0721] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0722] a) An isoxazoline compound of formula (Ic) as shown above or a pharmaceutically acceptable salt thereof, in an anti - parasite effective amount,

[0723] wherein

[0724] X 1 and X 2 are each independently chlorine or fluorine; and

[0725] X 3 is chlorine or CF3;

[0726] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0727] c) Optionally, at least one co - solvent;

[0728] d) Optionally, an antioxidant; and

[0729] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0730] wherein no other pharmaceutically acceptable polymers are present.

[0731] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0732] a) an anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof,

[0733] wherein

[0734] X 1 and X 2 are each independently chlorine or fluorine; and

[0735] X 3 is chlorine or CF3;

[0736] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0737] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0738] d) optionally an antioxidant; and

[0739] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0740] wherein no other pharmaceutically acceptable polymers are present.

[0741] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0742] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0743] wherein

[0744] X 1 and X 2 are each independently chlorine or fluorine; and

[0745] X 3 is chlorine or CF3;

[0746] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0747] c) optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0748] d) optionally an antioxidant; and

[0749] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0750] wherein there are no other pharmaceutically acceptable polymers.

[0751] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0752] a) An anti - parasite effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0753] wherein

[0754] X 1 and X 2 are each independently chlorine or fluorine; and

[0755] X 3 is chlorine or CF3;

[0756] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0757] c) Optionally, a co - solvent, wherein the co - solvent is a C1 - C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2 - pyrrolidone, N - methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0758] d) Optionally, an antioxidant; and

[0759] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0760] wherein there are no other pharmaceutically acceptable polymers.

[0761] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0762] a) An anti - parasite effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0763] wherein

[0764] X1 and X 2 are each independently chlorine or fluorine; and

[0765] X 3 is chlorine or CF3;

[0766] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0767] c) an optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglyceride (e.g. 810 and 812), C8-C triglyceride in combination with linoleic acid (e.g. 10 818), C8-C triglyceride in combination with succinic acid (e.g. 829), propylene glycol diester of C8-C 10 fatty acid (e.g. 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or a combination thereof; 10 d) an optional antioxidant; and

[0768] e) an optional at least one surfactant and / or at least one additional pharmaceutically acceptable additive, excipient or a mixture thereof;

[0769]

[0770] wherein there is no other pharmaceutically acceptable polymer.

[0771]

[0772] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0773] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0774] wherein

[0775] X 1 and X 2 are each independently chlorine or fluorine; and

[0775] X 3 is chlorine or CF3;

[0776] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0777] c) an optional at least one co-solvent, wherein the co-solvent is C8-C 10Triglyceride, benzyl alcohol, or a combination thereof;

[0778] d) An optional antioxidant; and

[0779] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0780] wherein there is no other pharmaceutically acceptable polymer.

[0781] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0782] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0783] wherein

[0784] X 1 and X 2 are each independently chlorine or fluorine; and

[0785] X 3 is chlorine or CF3;

[0786] b) At least one neutral oil, wherein the neutral oil is a C8-C 10 triglyceride;

[0787] c) An optional at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[0788] d) An optional antioxidant; and

[0789] e) An optional at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0790] wherein there is no other pharmaceutically acceptable polymer.

[0791] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0792] a) An anti-parasitically effective amount of the isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof

[0793] wherein

[0794] X 1 and X 3 are each chlorine; and

[0795] X 2 is fluorine or hydrogen;

[0796] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0797] c) Optionally, at least one co-solvent;

[0798] d) Optionally, an antioxidant; and

[0799] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0800] wherein there are no other pharmaceutically acceptable polymers.

[0801] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, which comprises:

[0802] a) An anti-parasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof,

[0803] wherein

[0804] X 1 and X 3 are each chlorine; and

[0805] X 2 is fluorine or hydrogen;

[0806] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0807] c) Optionally, at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0808] d) Optionally, an antioxidant; and

[0809] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0810] wherein there are no other pharmaceutically acceptable polymers.

[0811] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, which comprises:

[0812] a) An anti-parasitic effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0813] wherein

[0814] X1 and X 3 each is chlorine; and

[0815] X 2 is fluorine or hydrogen;

[0816] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0817] c) optionally at least one co-solvent, wherein the co-solvent is not miscible with water or is only partially soluble in water;

[0818] d) optionally an antioxidant; and

[0819] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0820] wherein there are no other pharmaceutically acceptable polymers.

[0821] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0822] a) an anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as shown above or a pharmaceutically acceptable salt thereof,

[0823] wherein

[0824] X 1 is chlorine;

[0825] X 2 is fluorine; and

[0826] X 3 is CF3;

[0827] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0828] c) optionally at least one co-solvent;

[0829] d) optionally an antioxidant; and

[0830] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0831] wherein there are no other pharmaceutically acceptable polymers.

[0832] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0833] a) An isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof, in an anti - parasite effective amount,

[0834] wherein

[0835] X 1 is chlorine;

[0836] X 2 is fluorine; and

[0837] X 3 is CF3;

[0838] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0839] c) Optionally, at least one co - solvent, wherein the co - solvent is a polar solvent miscible with water;

[0840] d) Optionally, an antioxidant; and

[0841] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0842] wherein no other pharmaceutically acceptable polymers are present.

[0843] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0844] a) At least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof, in an anti - parasite effective amount;

[0845] wherein

[0846] X 1 is chlorine;

[0847] X 2 is fluorine; and

[0848] X 3 is CF3;

[0849] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0850] c) Optionally, at least one co - solvent, wherein the co - solvent is immiscible with water or only partially soluble in water;

[0851] d) Optionally, an antioxidant; and

[0852] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0853] There is no other pharmaceutically acceptable polymer therein.

[0854] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0855] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0856] wherein

[0857] X 1 is chlorine;

[0858] X 2 is fluorine; and

[0859] X 3 is CF3;

[0860] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0861] c) an optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0862] d) an optional antioxidant; and

[0863] e) an optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0864] There is no other pharmaceutically acceptable polymer therein.

[0865] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0866] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0867] wherein

[0868] X 1 is chlorine;

[0869] X 2 is fluorine; and

[0870] X 3 is CF3;

[0871] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0872] c) an optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglyceride (such as 810 and 812), C8-C triglyceride combined with linoleic acid (such as 10 818), C8-C triglyceride combined with succinic acid (such as 829), propylene glycol diester of C8-C 10 fatty acid (such as 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or a combination thereof; 10 propyleneglycol diester of C8-C 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or a combination thereof;

[0873] d) an optional antioxidant; and

[0874] e) an optional at least one surfactant and an optional at least one additional pharmaceutically acceptable additive, excipient or a mixture thereof;

[0875] wherein there is no other pharmaceutically acceptable polymer.

[0876] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0877] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0878] wherein

[0879] X 1 is chlorine;

[0880] X 2 is fluorine; and

[0881] X 3 is CF3;

[0882] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0883] c) Optionally, at least one cosolvent, wherein the cosolvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

[0884] d) Optionally, an antioxidant; and

[0885] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0886] wherein there are no other pharmaceutically acceptable polymers.

[0887] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0888] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0889] wherein

[0890] X 1 is chlorine;

[0891] X 2 is fluorine; and

[0892] X 3 is CF3;

[0893] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0894] c) Optionally, at least one cosolvent, wherein the cosolvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[0895] d) Optionally, an antioxidant; and

[0896] e) Optionally, at least one pharmaceutically acceptable additive, excipient, or a mixture thereof;

[0897] wherein there are no other pharmaceutically acceptable polymers.

[0898] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0899] a) An anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0900] wherein

[0901] X 1 is chlorine;

[0902] X 2 is fluorine; and

[0903] X 3 is CF3;

[0904] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[0905] c) optionally at least one co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0906] d) optionally an antioxidant; and

[0907] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0908] wherein there is no other pharmaceutically acceptable polymer.

[0909] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0910] a) an anti-parasitically effective amount of at least one isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0911] wherein

[0912] X 1 is chlorine;

[0913] X 2 is fluorine; and

[0914] X 3 is CF3;

[0915] b) at least one neutral oil, wherein the neutral oil is C8-C 10 triglyceride;

[0916] c) optionally at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0917] d) optionally an antioxidant; and

[0918] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0919] wherein there is no other pharmaceutically acceptable polymer.

[0920] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0921] a) an anti-parasite effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharmaceutically acceptable salt thereof,

[0922] wherein

[0923] X 1 and X 3 are chlorine; and

[0924] X 2 is fluorine;

[0925] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0926] c) optionally at least one co-solvent;

[0927] d) optionally an antioxidant; and

[0928] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0929] wherein there is no other pharmaceutically acceptable polymer.

[0930] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, comprising:

[0931] a) an anti-parasite effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof;

[0932] wherein

[0933] X 1 and X 3 are chlorine; and

[0934] X 2 is fluorine;

[0935] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0936] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[0937] d) optionally an antioxidant; and

[0938] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0939] There are no other pharmaceutically acceptable polymers present.

[0940] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0941] a) an anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[0942] wherein

[0943] X 1 and X 3 are chlorine; and

[0944] X 2 is fluorine;

[0945] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0946] c) optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[0947] d) optionally an antioxidant; and

[0948] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0949] There are no other pharmaceutically acceptable polymers present.

[0950] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0951] a) an anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[0952] wherein

[0953] X 1 and X 3 are chlorine; and

[0954] X 2 is fluorine;

[0955] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0956] c) Optional co-solvent, where the co-solvent is C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, cyclic carbonate (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[0957] d) Optional antioxidant; and

[0958] e) Optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0959] where there is no other pharmaceutically acceptable polymer.

[0960] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) parasite infections and infestations in or on an animal, comprising:

[0961] a) An anti-parasite effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[0962] where

[0963] X 1 and X 3 are chlorine; and

[0964] X 2 is fluorine;

[0965] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0966] c) Optional co-solvent, where the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglyceride (for example 810 and 812), C8-C 10 triglyceride combined with linoleic acid (for example 818), C8-C 10 triglyceride combined with succinic acid (for example 829), propylene glycol diester of C8-C 10 fatty acid (for example 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or a combination thereof;

[0967] d) Optional antioxidant; and

[0968] e) Optionally, at least one surfactant, and optionally at least one additional pharmaceutically acceptable additive, excipient or a mixture thereof;

[0969] Wherein there are no other pharmaceutically acceptable polymers.

[0970] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0971] a) An anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[0972] Wherein

[0973] X 1 and X 3 is chlorine; and

[0974] X 2 is fluorine;

[0975] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[0976] c) Optionally, at least one co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[0977] d) Optionally, an antioxidant; and

[0978] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0979] Wherein there are no other pharmaceutically acceptable polymers.

[0980] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0981] a) An anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[0982] Wherein

[0983] X 1 and X 3 is chlorine; and

[0984] X 2 is fluorine;

[0985] b) At least one neutral oil, wherein the neutral oil is C8-C 10 triglyceride;

[0986] c) An optional at least one cosolvent, wherein the cosolvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[0987] d) An optional antioxidant; and

[0988] e) An optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0989] wherein there is no other pharmaceutically acceptable polymer.

[0990] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[0991] a) An anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as shown above or a pharmaceutically acceptable salt thereof,

[0992] wherein

[0993] X 1 、X 2 and X 3 are each chlorine;

[0994] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[0995] c) An optional at least one cosolvent;

[0996] d) An optional antioxidant; and

[0997] e) An optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[0998] wherein there is no other pharmaceutically acceptable polymer.

[0999] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1000] a) An anti-parasitically effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1001] wherein

[1002] X 1 、X 2 and X 3 are each chlorine;

[1003] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1004] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[1005] d) optionally an antioxidant; and

[1006] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1007] wherein there is no other pharmaceutically acceptable polymer.

[1008] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1009] a) an anti-parasitic effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1010] wherein

[1011] X 1 、X 2 and X 3 are each chlorine;

[1012] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1013] c) optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[1014] d) optionally an antioxidant; and

[1015] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1016] wherein there is no other pharmaceutically acceptable polymer.

[1017] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1018] a) an anti-parasitic effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1019] wherein

[1020] X 1 、X 2 and X 3Each is chlorine;

[1021] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1022] c) an optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[1023] d) an optional antioxidant; and

[1024] e) an optional at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1025] wherein there is no other pharmaceutically acceptable polymer.

[1026] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylactically) parasite infections and infestations in or on an animal, comprising:

[1027] a) an anti-parasite effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1028] wherein

[1029] X 1 , X 2 and X 3 each is chlorine;

[1030] b) at least one pharmaceutically acceptable polymer, which is liquid PEG;

[1031] c) an optional co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C8-C 10 triglyceride (e.g. 810 and 812), a C8-C 10 triglyceride combined with linoleic acid (e.g. 818), a C8-C 10 triglyceride combined with succinic acid (e.g. 829), a propylene glycol diester of a C8-C 10 fatty acid (e.g. 840), castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil, or combinations thereof;

[1032] d) an optional antioxidant; and

[1033] e) an optional at least one surfactant, and an optional at least one additional pharmaceutically acceptable additive, excipient, or mixture thereof;

[1034] wherein there are no other pharmaceutically acceptable polymers.

[1035] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1036] a) an anti-parasitic effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1037] wherein

[1038] X 1 、X 2 and X 3 are each chlorine;

[1039] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or neutral oil;

[1040] c) an optional co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

[1041] d) an optional antioxidant; and

[1042] e) an optional at least one pharmaceutically acceptable additive, excipient, or mixture thereof;

[1043] wherein there are no other pharmaceutically acceptable polymers.

[1044] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1045] a) an anti-parasitic effective amount of an isoxazoline compound of formula (Ic) as shown above or a pharmaceutically acceptable salt thereof,

[1046] wherein

[1047] X 1 、X 2 and X 3 are each independently chlorine or fluorine;

[1048] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1049] c) Optionally, at least one co-solvent;

[1050] d) Optionally, an antioxidant; and

[1051] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1052] wherein there are no other pharmaceutically acceptable polymers.

[1053] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, which comprises:

[1054] a) An anti-parasite effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1055] wherein

[1056] X 1 、X 2 and X 3 are each independently chlorine or fluorine;

[1057] b) At least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1058] c) Optionally, at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[1059] d) Optionally, an antioxidant; and

[1060] e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1061] wherein there are no other pharmaceutically acceptable polymers.

[1062] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing (prophylaxis) of parasite infections and infestations in or on an animal, which comprises:

[1063] a) An anti-parasite effective amount of an isoxazoline compound of formula (Ic) as described above, or a pharmaceutically acceptable salt thereof

[1064] wherein

[1065] X 1 、X 2 and X 3 are each independently chlorine or fluorine;

[1066] b) at least one pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1067] c) optionally at least one co-solvent, wherein the co-solvent is immiscible with water or only partially soluble in water;

[1068] d) optionally an antioxidant; and

[1069] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1070] wherein there are no other pharmaceutically acceptable polymers.

[1071] The compounds of formula (I) to formula (VIa) may exist as stereoisomers, and each individual stereoisomer present is included in the structural formulas described herein. The various stereoisomers include enantiomers, diastereomers and atropisomers. To avoid doubt, when an isoxazoline compound (e.g., any of the isoxazoline active agents described herein) includes two or more stereoisomers (e.g., (S)- and (R)-enantiomers), the formulas described herein that do not explicitly include a stereochemical configuration include each of the possible stereoisomers. Those skilled in the art will understand that one stereoisomer of an active isoxazoline compound may be more active relative to other enantiomers and / or may exhibit beneficial properties. Additionally, those skilled in the art know how to separate, enrich and / or selectively prepare the stereoisomers of the isoxazoline compounds described herein. The isoxazoline compounds described herein contain a chiral quaternary carbon atom in the 5-membered isoxazoline ring (denoted by an asterisk (*) in the following structures); thus, the compounds will contain at least two possible stereoisomers. As an example of a compound of formula (Ia), the two possible stereoisomers arising from the quaternary carbon are shown as formula (S)-Ia and (R)-Ia:

[1072]

[1073] The compound of formula (S)-Ia above has the (S) configuration at the chiral carbon atom, and the compound of formula (R)-Ia has the (R) configuration. The molecular diagrams drawn herein follow the standard convention for depicting stereochemistry. To indicate the stereoconfiguration, a bond rising out of the plane of the drawing and towards the observer is represented by a solid wedge, where the wide end of the wedge is attached to the atom rising out of the plane of the drawing towards the observer. A bond going down from the plane of the drawing and away from the observer is represented by a dashed wedge, where the narrow end of the wedge is attached to the atom further away from the observer. Constant-width lines indicate bonds having an opposite or neutral direction relative to the bonds shown with solid or dashed wedges; constant-width lines also depict bonds in a molecule or a portion of a molecule where it is not intended to specify a particular stereoconfiguration.

[1074] In one embodiment of the present invention, the more biologically active enantiomer is considered to be of formula (S)-Ia. Similarly, the more biologically active enantiomers of the isoxazoline compounds of formula (Ib), (Ic), and (II) to (VIa) are considered to have the (S) configuration at the chiral carbon of the isoxazoline ring. In certain embodiments, the isoxazoline compounds of the present invention or compositions containing said compounds are enriched in the enantiomer (eutomer) that exhibits significant in vitro and in vivo activity, which has a favorable toxicity profile compared to a compound or composition enriched in the other corresponding enantiomer (distomer) that exhibits significantly less in vitro and in vivo activity.

[1075] When enantiomers are enriched, one enantiomer is present in a greater amount than the other, and the degree of enrichment can be defined by the expression enantiomeric excess ("ee"), which is defined as (2x - 1)·100%, where x is the mole fraction of the preponderant enantiomer in the mixture (e.g., 20% ee corresponds to a 60:40 enantiomer ratio). In certain embodiments, the compositions of the present invention contain a compound having an enantiomeric excess of at least 50%. In other embodiments, the compositions of the present invention contain a compound having an enantiomeric excess of at least 75%, at least 90% or at least 94% of the more active isomer. Particular mention is made of the enantiomerically pure embodiments of the more active isomer (eutomer).

[1076] Due to the restricted rotation around the amide bond (e.g., the amide bonded to the naphthyl group in formula (I)) bonded to the aryl or heteroaryl ring, the compounds of the present invention can also exist as one or more conformational isomers. The present invention encompasses mixtures of conformational isomers. Additionally, the present invention includes compounds that are enriched in one conformational isomer relative to other conformational isomers.

[1077] It should be understood that due to the quaternary carbon atoms on the isoxazoline ring, in addition to the compounds of formula (Ia), other isoxazoline compounds of formula (I), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) and formula (VIa) will also have at least two possible enantiomers. Additionally, certain compounds may include other chiral centers in one or more substituents.

[1078] The present invention encompasses racemic mixtures, for example, equimolar amounts of the enantiomers of formula (I) to (VIa). The present invention also includes compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-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 substantially pure enantiomers of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa).

[1079] Thus, in one embodiment, the long-acting injectable composition of the present invention comprises an anti-parasitically effective amount of at least one isoxazoline of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is substantially enriched in one enantiomer, or a pharmaceutically acceptable salt thereof. The term "substantially enriched" means that the compound is enriched in the desired enantiomer at a weight:weight ratio of at least about 1.5 or higher. In another embodiment, the long-acting composition of the present invention comprises at least one isoxazoline compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in one enantiomer at a weight:weight ratio of at least 2:1, at least 5:1 or at least 10:1. In another embodiment, the composition comprises at least one compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in one enantiomer at a weight:weight ratio of at least 15:1 or at least 20:1, or a pharmaceutically acceptable salt thereof. In one embodiment, the isoxazoline compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa) present in the composition of the present invention is a substantially pure enantiomer.

[1080] In another embodiment of the present invention, the composition comprises a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in the (S)-enantiomer at a weight:weight ratio of at least about 1.5:1 or 2:1. In another embodiment, the composition of the present invention comprises a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in the (S)-enantiomer at a weight:weight ratio of at least about 5:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in the (S)-enantiomer at a weight:weight ratio of at least about 10:1, 20:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is substantially pure (S)-enantiomer.

[1081] In one embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in one enantiomer. In another embodiment, the long-acting injectable composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in the (S)-enantiomer. In another embodiment, the long-acting injectable composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in the (R)-enantiomer.

[1082] In another embodiment of the present invention, the composition comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the (S)-enantiomer at a weight:weight ratio of at least about 1.5:1 or 2:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the (S)-enantiomer at a weight:weight ratio of at least about 5:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the (S)-enantiomer at a weight:weight ratio of at least about 10:1, 20:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is substantially pure (S)-enantiomer.

[1083] In another embodiment of the present invention, the composition comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the (R)-enantiomer at a weight:weight ratio of at least about 2:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the (R)-enantiomer at a weight:weight ratio of at least about 5:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the (R)-enantiomer at a weight:weight ratio of at least about 10:1, 20:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (I), (Ia), (Ib) or (Ic) that is substantially pure (R)-enantiomer.

[1084] In another embodiment of the present invention, the composition comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in the (R)-enantiomer at a weight:weight ratio of at least about 2:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in the (R)-enantiomer at a weight:weight ratio of at least about 5:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is enriched in the (R)-enantiomer at a weight:weight ratio of at least about 10:1, 20:1 or greater. In another embodiment, the composition of the present invention comprises a compound of formula (II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula (II-018), formula (III), formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa), which is substantially pure (R)-enantiomer.

[1085] In another embodiment, the long-acting injectable composition of the present invention comprises an anti-parasitically effective amount of at least one isoxazoline disclosed in WO 2007 / 079162, WO 2007 / 075459 and US 2009 / 0133319, WO 2007 / 070606 and US2009 / 0143410, WO 2009 / 003075, WO 2009 / 002809, WO 2009 / 024541, WO 2005 / 085216 and US2007 / 0066617, WO 2008 / 122375, WO 2014 / 439475 A1 and WO2012 120135A1, which are all incorporated herein by reference in their entirety.

[1086] In another embodiment, the long-acting injectable composition of the present invention comprises an anti-parasitically effective amount of at least one isoxazoline compound described in WO 2009 / 02451A2 and WO 2011 / 075591A1, which are incorporated herein by reference in their entirety.

[1087] In another embodiment, the long-acting injectable composition of the present invention comprises an anti-parasitically effective amount of at least one isoxazoline, which is compound 11-1 described in WO 2009 / 02451A2 and has the following structure:

[1088]

[1089] In one embodiment, the composition of the present invention may comprise from about 0.5 to about 50% (w / v) of an isoxazoline active agent of any one of formula (I), (Ia), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof, as a racemic mixture or enriched with the enantiomers as described above. In another embodiment, the composition of the present invention may comprise from about 1 to about 40% (w / v) of an isoxazoline active agent of any one of formula (I), (Ia), (Ib), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present invention may comprise from about 1 to about 30% (w / v), from about 1 to about 20% (w / v) or from about 1 to about 15% (w / v) of an isoxazoline active agent of any one of formula (I), (Ia), (Ib), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present invention may comprise from about 0.5 to about 10% (w / v) or from about 0.5% to about 5% (w / v) of an isoxazoline active agent of any one of formula (I), (Ia), (Ib), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof.

[1090] In another embodiment, the composition of the present invention may comprise from about 5 to about 40% (w / v) or from about 5 to about 30% (w / v) of an isoxazoline active agent, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition may comprise from about 10% to about 40% (w / v) of an isoxazoline active agent, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present invention may comprise from about 15% to about 40% (w / v), from about 15% to about 35% (w / v) or from about 15% to about 30% (w / v) of an isoxazoline compound, or a pharmaceutically acceptable salt thereof.

[1091] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1092] a) About 0.5 - 30% (w / v) of an isoxazoline active agent, for example, any of the isoxazoline compounds provided in the above embodiments (e.g., a compound of any of the above formulas I to VIa), or a pharmaceutically acceptable salt thereof;

[1093] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1094] c) Optionally, about 1% to 40% (w / v) of a co - solvent;

[1095] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1096] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1097] Wherein the only pharmaceutically acceptable polymer present in the long - acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the complement of the composition.

[1098] In another embodiment, the present invention provides a long - acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1099] a) About 0.5 - 20% (w / v) of an isoxazoline active agent, for example, any of the isoxazoline compounds provided in the above embodiments (e.g., a compound of any of the above formulas I to VIa), or a pharmaceutically acceptable salt thereof;

[1100] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1101] c) Optionally, about 1% to 40% (w / v) of a co - solvent;

[1102] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1103] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1104] Wherein the only pharmaceutically acceptable polymer present in the long - acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the complement of the composition.

[1105] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1106] a) from about 5 - 30% (w / v) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., a compound of any one of the above formulas I to VIa), or a pharmaceutically acceptable salt thereof;

[1107] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1108] c) optionally from about 1% to 40% (w / v) of a co-solvent;

[1109] d) optionally from about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1110] e) optionally from about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1111] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1112] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1113] a) from about 0.5 - 30% (w / v) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., a compound of any one of the above formulas I to VIa), or a pharmaceutically acceptable salt thereof;

[1114] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1115] c) optionally from about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[1116] d) optionally from about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1117] e) optionally from about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1118] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1119] In another embodiment, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1120] a) about 0.5 - 20% (w / v) of an isoxazoline active agent, such as any one of the isoxazoline compounds provided in the above embodiments (e.g., a compound of any one of the above formulas I to VIa), or a pharmaceutically acceptable salt thereof;

[1121] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1122] c) optionally about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[1123] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1124] e) optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1125] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1126] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1127] a) about 5 - 30% (w / v) of an isoxazoline active agent, such as any one of the isoxazoline compounds provided in the above embodiments (e.g., a compound of any one of the above formulas I to VIa), or a pharmaceutically acceptable salt thereof;

[1128] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1129] c) optionally about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[1130] d) Optionally, about 0.01% to about 2.0% (w / v) antioxidant; and

[1131] e) Optionally, about 0.01% to about 5.0% (w / v) pharmaceutically acceptable additive, excipient or mixture thereof;

[1132] Wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1133] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1134] a) About 0.5 - 30% (w / v) of an isoxazoline active agent of formula (Ia) (e.g., a compound of formulae I - VIa), for example, a compound of the following formula or a pharmaceutically acceptable salt thereof:

[1135]

[1136] Wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3;

[1137]

[1138] Wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3;

[1139]

[1140] Wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3;

[1141]

[1142]

[1143] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1144] c) Optionally, about 1% to 40% (w / v) of a co-solvent, where the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide, or glycerol formal, or a combination thereof;

[1145] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1146] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1147] where the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and where the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1148] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1149] a) About 0.5 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X 1 、X 2 and X 3 are independently chlorine, fluorine, or CF3; (S)-Ic, where X 1 、X 2 and X 3 are independently chlorine, fluorine, or CF3; (R)-Ic, where X 1 、X 2 and X 3 are independently chlorine, fluorine, or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa), or (S)-VIa as shown above;

[1150] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1151] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[1152] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1153] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1154] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is a liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the complement of the composition.

[1155] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1156] a) About 1-20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3; (R)-Ic, wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above;

[1157] b) A pharmaceutically acceptable polymer, which is a liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1158] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[1159] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1160] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1161] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1162] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1163] a) About 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3; (R)-Ic, wherein X 1 、X 2 and X 3 are independently chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above;

[1164] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1165] c) An optional cosolvent of about 1% to 40% (w / v), wherein the cosolvent is a C1-C6 alcohol, a glycol ether (e.g., including, but not limited to, diethylene glycol monoethyl ether, 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, etc.), glycerol, propylene glycol, a cyclic carbonate (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof;

[1166] d) An optional antioxidant of about 0.01% to about 2.0% (w / v); and

[1167] e) An optional pharmaceutically acceptable additive, excipient or mixture thereof of about 0.01% to about 5.0% (w / v);

[1168] Wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1169] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1170] a) About 0.5-30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above;

[1171] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1172] c) An optional cosolvent of about 1% to 40% (w / v), wherein the cosolvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C8-C 10 triglyceride (e.g. 810 and 812), C8-C in combination with linoleic acid 10 triglyceride (e.g., 818), C8-C in combination with succinic acid 10 triglyceride (e.g., 829), propylene glycol diester of C8-C 10 fatty acid (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil, or a combination thereof;

[1173] d) Optionally from about 0.01% to about 2.0% (w / v) antioxidant; and

[1174] e) Optionally from about 0.01% to about 5.0% (w / v) pharmaceutically acceptable additive, excipient or mixture thereof;

[1175] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1176] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1177] a) About 0.5-20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above;

[1178] b) A pharmaceutically acceptable polymer which is liquid PEG;

[1179] c) Optionally from about 5% to 40% (w / v) of a co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglyceride (e.g., 810 and 812), C8-C in combination with linoleic acid 10 triglycerides (e.g., 818), C8-C in combination with succinic acid 10 triglycerides (e.g., 829), propylene glycol diesters of C8-C 10 fatty acids (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil, or combinations thereof;

[1180] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1181] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

[1182] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1183] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1184] a) About 1-20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va), or (S)-VIa as shown above;

[1185] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1186] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglycerides (e.g., 810 and 812), C8-C in combination with linoleic acid 10 triglycerides (e.g., 818), C8-C in combination with succinic acid 10 triglycerides (e.g., 829), propylene glycol diesters of C8-C 10 fatty acids (e.g., 840), castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil, or combinations thereof;

[1187] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1188] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

[1189] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1190] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1191] a) About 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa), or (S)-VIa as shown above;

[1192] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1193] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C8-C 10 triglycerides (e.g., 810 and 812), C8-C in combination with linoleic acid 10 triglycerides (such as 818), C8-C in combination with succinic acid 10 triglycerides (such as 829), propylene glycol diesters of C8-C 10 fatty acids (such as 840), castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil, or combinations thereof;

[1194] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1195] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

[1196] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition. In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1197] a) About 0.5 - 30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa), or (S)-VIa as shown above;

[1198] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1199] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

[1200] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1201] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

[1202] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1203] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1204] a) about 0.5 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa as shown above;

[1205] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1206] c) optionally about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol or a combination thereof;

[1207] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1208] e) optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1209] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1210] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasitic infections and infestations in or on an animal, comprising:

[1211] a) about 1 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 , X 2 and X 3independently is chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa as shown above;

[1212] or a pharmaceutically acceptable salt thereof,

[1213] b) a pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1214] c) an optional co-solvent of about 1% to 40% (w / v), wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol or a combination thereof;

[1215] d) an optional antioxidant of about 0.01% to about 2.0% (w / v); and

[1216] e) an optional pharmaceutically acceptable additive, excipient or mixture thereof of about 0.01% to about 5.0% (w / v);

[1217] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1218] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1219] a) about 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa as shown above;

[1220] or a pharmaceutically acceptable salt thereof,

[1221] b) a pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1222] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

[1223] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1224] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1225] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1226] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1227] a) About 0.5 - 30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1228] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1229] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1230] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1231] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1232] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1233] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1234] a) About 0.5 - 30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), where X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, where X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1235] b) At least one pharmaceutically acceptable polymer, which is liquid PEG;

[1236] c) Optionally about 1% to 40% (w / v) of a co-solvent, where the co-solvent is C8 - C 10 triglyceride, benzyl alcohol or a combination thereof;

[1237] d) Optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1238] e) Optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1239] where the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and where the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1240] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1241] a) About 0.5 - 30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), where X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, where X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1242] b) At least one neutral oil, where the neutral oil is C8 - C 10 triglyceride;

[1243] c) Optionally about 1% to 40% (w / v) of a co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[1244] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1245] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1246] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1247] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1248] a) About 0.5 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1249] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1250] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1251] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1252] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1253] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1254] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1255] a) About 1 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), where X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, where X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1256] or a pharmaceutically acceptable salt thereof,

[1257] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1258] c) Optionally about 1% to 40% (w / v) of a co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1259] d) Optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1260] e) Optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1261] where the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and where the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1262] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1263] a) About 1 - 15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), where X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, where X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1264] or a pharmaceutically acceptable salt thereof,

[1265] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1266] c) Optionally, about 1% to 40% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1267] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1268] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1269] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1270] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1271] a) About 0.5 - 30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1272] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a neutral oil;

[1273] c) Optionally, about 1% to 20% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1274] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1275] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1276] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1277] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1278] a) About 0.5 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), where X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, where X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1279] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or neutral oil;

[1280] c) Optionally, about 1% to 20% (w / v) of a co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1281] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1282] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1283] where the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and where the liquid PEG and / or neutral oil is present in the total composition in a proportion representing 100% of the composition.

[1284] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1285] a) About 1 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), where X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, where X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1286] or a pharmaceutically acceptable salt thereof,

[1287] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or neutral oil;

[1288] c) Optionally, about 1% to 20% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1289] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1290] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1291] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1292] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1293] a) About 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1294] or a pharmaceutically acceptable salt thereof,

[1295] b) A pharmaceutically acceptable polymer, which is liquid PEG and / or a neutral oil;

[1296] c) Optionally, about 1% to 20% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1297] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1298] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1299] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1300] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1301] a) about 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1302] or a pharmaceutically acceptable salt thereof,

[1303] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1304] c) optionally about 1% to 20% (w / v) of a co-solvent, wherein the co-solvent is C8-C 10 triglyceride, benzyl alcohol or a combination thereof;

[1305] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1306] e) optionally about 0.01% to about 5.0% (w / v) of at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1307] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1308] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1309] a) about 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1310] or a pharmaceutically acceptable salt thereof,

[1311] b) at least one neutral oil, wherein the neutral oil is a C8-C 10 triglyceride;

[1312] c) optionally from about 1% to 20% (w / v) of at least one co-solvent, wherein the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

[1313] d) optionally from about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1314] e) optionally from about 0.01% to about 5.0% (w / v) of at least one pharmaceutically acceptable additive, excipient or a mixture thereof;

[1315] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1316] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1317] a) from about 0.5 - 30% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1318] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1319] c) optionally from about 2% to 15% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1320] d) optionally from about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1321] e) optionally from about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1322] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1323] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1324] a) about 0.5 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1325] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1326] c) optionally about 2% to 15% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1327] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1328] e) optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1329] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1330] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1331] a) about 1 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1332] or a pharmaceutically acceptable salt thereof,

[1333] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1334] c) An optional co-solvent of about 2% to 15% (w / v), wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1335] d) An optional antioxidant of about 0.01% to about 2.0% (w / v); and

[1336] e) An optional pharmaceutically acceptable additive, excipient, or mixture thereof of about 0.01% to about 5.0% (w / v);

[1337] Wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1338] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1339] a) About 1-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (Ia), (S)-Ia, (Ic), wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1340] or a pharmaceutically acceptable salt thereof,

[1341] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1342] c) An optional co-solvent of about 2% to 15% (w / v), wherein the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

[1343] d) An optional antioxidant of about 0.01% to about 2.0% (w / v); and

[1344] e) An optional pharmaceutically acceptable additive, excipient, or mixture thereof of about 0.01% to about 5.0% (w / v);

[1345] Wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1346] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1347] a) about 0.5 - 15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (S)-Ia or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1348] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1349] c) optionally about 2% to 15% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1350] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1351] e) optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1352] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1353] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1354] a) about 5 - 20% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (S)-Ia or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3; as shown above;

[1355] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1356] c) optionally about 2% to 15% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1357] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1358] e) optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1359] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1360] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1361] a) about 5-15% (w / v) of an isoxazoline active agent of the following formula or a pharmaceutically acceptable salt thereof: (S)-Ia or (S)-Ic, wherein X 1 is chlorine, X 2 is fluorine and X 3 is CF3, as shown above;

[1362] or a pharmaceutically acceptable salt thereof,

[1363] b) a pharmaceutically acceptable polymer, which is liquid PEG;

[1364] c) optionally about 2% to 10% (w / v) of a co-solvent, wherein the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

[1365] d) optionally about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1366] e) optionally about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient or a mixture thereof;

[1367] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1368] In certain embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1369] a) about 0.5-30% (w / v) of an isoxazoline active agent, for example, any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulas I to VIa above), for example, compounds of formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X2 and X 3 independently is chlorine, fluorine or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa as shown above;

[1370] or a pharmaceutically acceptable salt thereof,

[1371] b) A pharmaceutically acceptable polymer which is liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1372] c) Optionally a co-solvent selected from ethanol and isopropanol in an amount of about 5% to 40% (w / v);

[1373] d) Optionally an antioxidant in an amount of about 0.01% to about 2.0% (w / v); and

[1374] e) Optionally a pharmaceutically acceptable additive, excipient or a mixture thereof in an amount of about 0.01% to about 5.0% (w / v);

[1375] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or neutral oil is present in the total composition in a proportion representing 100% of the composition.

[1376] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal body, comprising:

[1377] a) About 1-30% (w / v) of an isoxazoline active agent, for example, any of the isoxazoline compounds provided in the above embodiments (for example, a compound of any one of the above formulas I to VIa), for example, a compound of formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 independently is chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa as shown above;

[1378] or a pharmaceutically acceptable salt thereof,

[1379] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a neutral oil;

[1380] c) an optional co-solvent of about 5% to 40% (w / v) selected from ethanol and isopropanol;

[1381] d) an optional antioxidant of about 0.01% to about 2.0% (w / v); and

[1382] e) an optional pharmaceutically acceptable additive, excipient or mixture thereof of about 0.01% to about 5.0% (w / v);

[1383] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1384] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1385] a) about 1-20% (w / v) of an isoxazoline active agent, for example, any one of the isoxazoline compounds provided in the above embodiments (e.g., compounds of formula I-VIa), for example, compounds of formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa as shown above; or a pharmaceutically acceptable salt thereof,

[1386] b) a pharmaceutically acceptable polymer, which is liquid PEG and / or a neutral oil;

[1387] c) an optional co-solvent of about 5% to 40% (w / v) selected from ethanol and isopropanol;

[1388] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1389] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1390] wherein the only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG and / or the neutral oil are present in the total composition in a proportion representing 100% of the composition.

[1391] In other embodiments, the present invention provides a long-acting injectable composition for treating and / or preventing parasite infections and infestations in or on an animal, comprising:

[1392] a) About 5-20% (w / v) or about 5 to about 15% (w / v) of an isoxazoline active agent, for example, any one of the isoxazoline compounds provided in the above embodiments (e.g., compounds of formula I-VIa), for example, compounds of formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (S)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (R)-Ic, wherein X 1 , X 2 and X 3 are independently chlorine, fluorine, or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa), or (S)-VIa as shown above; or a pharmaceutically acceptable salt thereof,

[1393] b) A pharmaceutically acceptable polymer, which is liquid PEG;

[1394] c) Optionally, about 5% to 40% (w / v) of a cosolvent selected from ethanol and isopropanol;

[1395] d) Optionally, about 0.01% to about 2.0% (w / v) of an antioxidant; and

[1396] e) Optionally, about 0.01% to about 5.0% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof;

[1397] The only pharmaceutically acceptable polymer present in the long-acting injectable composition is liquid PEG, and wherein the liquid PEG is present in the total composition in a proportion representing 100% of the composition.

[1398] Another embodiment of the invention is a long-acting injectable composition for the treatment and / or prevention of parasite infections and infestations in or on an animal, which consists essentially of:

[1399] a) an anti-parasite effective amount of at least one isoxazoline active agent, for example, any of the isoxazoline compounds provided in the above embodiments (e.g., compounds of formulae I - VIa), and optionally at least one additional active agent identified in the present application;

[1400] b) liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1401] c) optionally at least one co-solvent, wherein the co-solvent is a polar solvent miscible with water;

[1402] d) optionally an antioxidant; and

[1403] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof.

[1404] Another embodiment of the invention is a long-acting injectable composition for the treatment and / or prevention of parasite infections and infestations in or on an animal, which consists of:

[1405] a) an anti-parasite effective amount of at least one isoxazoline active agent, for example, any of the isoxazoline compounds provided in the above embodiments (e.g., compounds of formulae I - VIa), and optionally at least one additional active agent identified in the present application;

[1406] b) liquid PEG and / or a pharmaceutically acceptable neutral oil;

[1407] c) at least one co-solvent, wherein the co-solvent is immiscible with water;

[1408] d) optionally an antioxidant; and

[1409] e) optionally at least one pharmaceutically acceptable additive, excipient or a mixture thereof.

[1410] In this disclosure and in the claims, terms such as "comprising," "including," "containing," and "having" can have the meanings ascribed to them in United States patent law and can mean "including," "comprising," etc.; "consisting essentially of" or "essentially comprising" likewise have the meanings ascribed to them in United States patent law, and the term is open-ended, thus allowing the presence of other ingredients in addition to the recited components, provided that the basic or novel characteristics of the recited components are not changed by the presence of other ingredients in addition to the recited components, except for prior art embodiments. The term "consisting of" does not include any element, step, or ingredient not specified in the claim.

[1411] Definitions

[1412] The terms used herein have their ordinary meanings in the art, unless otherwise specified. The organic moieties (such as the term halogen) referred to in the definitions of the variables of formula (I) are collective terms for individual listings of individual members. The prefix C n -C m in each case indicates the possible number of carbon atoms in the group.

[1413] The term "animal" is used herein to include all mammals, avians, and fish, and also includes all vertebrates. Animals include, but are not limited to, cats, dogs, cows, chickens, cattle, deer, goats, horses, llamas, pigs, sheep, and yaks. It also includes individual animals at all stages of development, including embryonic and fetal stages. In certain embodiments, the animal is a non-human animal.

[1414] The term "substantially pure" is used herein to indicate that a compound or enantiomer is at least about 90% pure, at least about 95%, at least about 98% pure, or higher.

[1415] The term "alkyl" denotes a saturated straight-chain, branched-chain primary, secondary, or tertiary hydrocarbon, including those having 1-20 atoms. In certain embodiments, alkyl will include C1-C 12 、C1-C 10 、C1-C8、C1-C6 or C1-C4 alkyl. C1-C 10Examples of alkyl groups 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. C1-C4-alkyl refers to, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

[1416] Cyclic alkyl or "cycloalkyl" includes those having a single or multiple fused rings and containing 3-10 carbon atoms. In certain embodiments, cycloalkyl includes C4-C7 or C3-C4 cyclic alkyl. Non-limiting examples of cycloalkyl include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[1417] The alkyl groups described herein may be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, carboxy, acyl, acyloxy, amino, alkyl- or dialkylamino, acylamino, arylamino, alkoxy, aryloxy, nitro, cyano, azido, mercapto, imino, sulfonic acid, sulfate, sulfonyl, thioalkyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acyl halide, acid 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, which is unprotected or protected as necessary, as 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.

[1418] Terms including the term "alkyl" such as "alkylcycloalkyl", "cycloalkylalkyl", "alkylamino", or "dialkylamino" should be understood to include alkyl as defined above attached to other functional groups, where, as understood by those skilled in the art, the group is attached to the compound through the last group listed.

[1419] The term "alkenyl" refers to straight-chain and branched carbon chains having at least one carbon-carbon double bond. In certain embodiments, the alkenyl may include C2-C 20 alkenyl. In other embodiments, the alkenyl includes C2-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C4 alkenyl. In one embodiment of the alkenyl, the number of double bonds is 1-3, and in another embodiment of the alkenyl, the number of double bonds is 1 or 2. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated, depending on the position of the alkenyl moiety on the molecule. "C2-C 10"-enyl" may include more than one double bond in the chain. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-methyl-vinyl, 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, 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.

[1420] "Alkynyl" represents straight-chain and branched-chain carbon chains having at least one carbon-carbon triple bond. In one embodiment of the alkynyl, the number of triple bonds is 1-3; in another embodiment of the alkynyl, the number of triple bonds is 1 or 2. In certain embodiments, the alkynyl includes C2-C 20 alkynyl. In other embodiments, the alkynyl may include C2-C 12 , C2-C10 , C2-C8, C2-C6 or C2-C4 alkynyl. Other ranges of carbon-carbon triple bonds and carbon numbers are also considered, depending on the position of the alkynyl moiety on the molecule. For example, the term "C2-C 10 -alkynyl" as used herein means a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, 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, etc.

[1421] The term "haloalkyl" means an alkyl group as defined herein that is substituted with one or more halogen atoms. For example, C1-C4-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, etc.

[1422] The term "haloalkenyl" means an alkenyl group as defined herein that is substituted with one or more halogen atoms.

[1423] The term "haloalkynyl" means an alkynyl group as defined herein that is substituted with one or more halogen atoms.

[1424] "Alkoxy" means alkyl-O-, where alkyl is as defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "halocycloalkoxy" and "halocycloalkenyloxy" mean the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O- and halocycloalkenyl-O-, respectively, where 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)O-, (CH3)2CH-CH2O-, (CH3)3CO-, n-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, etc.

[1425] The term "alkylthio" means alkyl-S-, where alkyl is as defined above. Similarly, the terms "haloalkylthio", "cycloalkylthio", etc. mean haloalkyl-S- and cycloalkyl-S-, where haloalkyl and cycloalkyl are as defined above.

[1426] The term "alkylsulfinyl" means alkyl-S(O)-, where alkyl is as defined above. Similarly, the term "haloalkylsulfinyl" means haloalkyl-S(O)-, where haloalkyl is as defined above.

[1427] The term "alkylsulfonyl" means alkyl-S(O)2-, where alkyl is as defined above. Similarly, the term "haloalkylsulfonyl" means haloalkyl-S(O)2-, where haloalkyl is as defined above.

[1428] The terms alkylamino and dialkylamino mean alkyl-NH- and (alkyl)2N-, where alkyl is as defined above. Similarly, the term "haloalkylamino" means haloalkyl-NH-, where haloalkyl is as defined above.

[1429] The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" denote alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, where alkyl, alkoxy, alkylamino and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl" and "dihaloalkylaminocarbonyl" denote 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.

[1430] "Aryl" denotes a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple fused rings. In certain embodiments, aryl includes C6-C 10 aryl. Aryl includes, but is not limited to: phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl and indanyl. Aryl may be unsubstituted or substituted with one or more moieties selected from: halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynyloxy, haloalkoxy, haloalkenoxy, haloalkynyloxy, cycloalkoxy, cycloalkenoxy, halocycloalkoxy, halocycloalkenoxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino or trialkylsilyl.

[1431] The term "aralkyl" or "arylalkyl" denotes an aryl bonded to the parent compound through a bivalent alkylene bridge (-CH2-) n where n is 1 - 12, and where "aryl" is as defined above.

[1432] "Heteroaryl" means a monovalent aromatic group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, which has one or more oxygen, nitrogen and sulfur heteroatoms in the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such heteroaryl may have a single ring (e.g., pyridyl or furyl) or multiple fused rings, provided that the point of attachment is through a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuryl and benzothienyl. The heteroaryl ring may be unsubstituted or substituted with one or more of the moieties described above for aryl.

[1433] "Heterocyclic group", "heterocyclic" or "heterocyclo-fused" means a completely saturated or unsaturated cyclic group, e.g., a 3- to 7-membered monocyclic or 4- to 7-membered monocyclic; a 7- to 11-membered bicyclic or 10- to 15-membered tricyclic ring system, which has one or more oxygen, sulfur or nitrogen heteroatoms in the ring, preferably 1 to 4 or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more of the moieties described above for aryl.

[1434] Exemplary 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-oxazepinyl, azepinyl, 4-piperidinonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholine sulfoxide, thiamorpholine sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, etc.

[1435] Exemplary bicyclic heterocyclic groups include, but are not limited to: indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furanopyridyl (such as furano[2,3-c]pyridyl, furano[3,2-b]pyridyl] or furano[2,3-b]pyridyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like.

[1436] Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl (benzidolyl), phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[1437] Halogen means atomic fluorine, chlorine, bromine, and iodine. The designation "halo" (as exemplified, for example, in the term haloalkyl) indicates all degrees of substitution from mono-substitution to perhalo-substitution (e.g., taking methyl as an example, such as chloromethyl (-CH2Cl), dichloromethyl (-CHCl2), trichloromethyl (-CCl3)).

[1438] The term "enriched" means an enantiomer (the preponderant isomer) that exhibits favorably significant in vitro and in vivo activity when the weight:weight ratio is at least about 1.05 or higher.

[1439] Stereoisomers and polymorphic forms

[1440] As noted above, those skilled in the art will understand that certain compounds within the compositions of the present invention can exist in optically active and racemic forms and can be separated. Compounds having one or more chiral centers (including at sulfur atoms) can exist as a single enantiomer or diastereomers or as a mixture 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 a single enantiomer or a racemic mixture. Additionally, the compounds within the compositions of the present invention can include one or more chiral centers, which give rise to the theoretical number of optically active isomers. When the compounds within the compositions of the present invention include n chiral centers, the compounds can contain up to 2 nOptical isomers. The present invention includes compositions that contain a specific enantiomer or diastereomer of each compound, as well as mixtures of different enantiomers and / or diastereomers of the compounds of the present invention having the useful properties described herein. Additionally, the present invention includes compositions that contain one or more conformational isomers (e.g., rotamers) and mixtures of conformational isomers. Conformational isomers of the isoxazoline compounds can be generated by restricted rotation about the amide bond (e.g., the amide bonded to the naphthyl group in formula (I)) that is bonded to the aryl or heteroaryl ring. The optically active forms can be prepared, for example, by resolution of the racemic form 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.

[1441] Additionally, the compounds within the compositions of the present invention can exist as hydrates or solvates, where a specific stoichiometric amount of water or solvent is bound to the molecules in the crystalline form. The compositions of the present invention can include hydrates and solvates of the active agent. In certain embodiments, the compositions of the present invention can include up to 15% (w / w), up to 20% (w / w), or up to 30% (w / w) of a specific solid form.

[1442] Salts

[1443] Also included within the scope of the present invention are the acid or base salts (where appropriate) of the compounds of the present invention provided herein.

[1444] The term "acid salt" includes salts of the compound with all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids, such as hydrohalic acids, such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid, 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 acid, the acid is a straight-chain or branched-chain, saturated or unsaturated C1-C 20 aliphatic carboxylic acid (optionally substituted with halogen or hydroxy) or C6-C 12 aromatic carboxylic acid. 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 4-24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylstearic acid. Other acids include gluconic acid, glycoheptonic acid, and lactobionic acid.

[1445] The term "basic salt" includes salts of the compound with the pharmaceutically acceptable inorganic or organic bases, said bases including hydroxides, carbonates or bicarbonates of alkali or alkaline earth metals. Salts formed with such bases include, for example, alkali and alkaline earth metal salts, including, but not limited to, salts of lithium, sodium, potassium, magnesium or calcium. Salts formed with organic bases include the commonly used hydrocarbon and heterocyclic amine salts, which include, for example, ammonium salts (NH4 + ), alkyl- and dialkylammonium salts and salts of cyclic amines such as morpholine and piperidine salts.

[1446] In another embodiment, the long-acting injectable composition of the invention comprises an effective amount of at least one isoxazoline or a pharmaceutically acceptable salt thereof and at least one other active agent. In one embodiment, the long-acting injectable composition comprises an effective amount of at least one isoxazoline compound of formula (I) to (VI) or a pharmaceutically acceptable salt thereof and at least one other systemically active agent.

[1447] Additional veterinary / pharmaceutical active ingredients can be used with the compositions of the invention. In certain embodiments, the additional active agents can include, but are not limited to, acaricides, anthelmintic agents, antiparasitic agents and insecticides. Antiparasitic agents can include ectoparasiticides and / or endoparasiticides.

[1448] Veterinary pharmaceuticals that can be included in the compositions of the present invention are well known in the art (see, for example, Plumb’s Veterinary Drug Handbook, 5th Edition, edited by Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th Edition, (January 2005)), including, but not limited to: acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, benomyl, albuterol sulfate, alfentanil, allopurinol, alprazolam, allylgestin, amantadine, amikacin sulfate, aminocaproic acid, amylobarbitone hydrogensulfate, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, lipid-based amphotericin B, ampicillin, amprolium, antacids (oral), antivenom, apomorphine, apramycin sulfate, vitamin C, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol chloride, bisacodyl, basic salicylic acid, bleomycin sulfate, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitriol, calcium salts, captopril, carindacillin sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cephalexin, cefazolin sodium, cefixime, closantel, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, cefotriaxone sodium, cefalexin, cephalosporins, cefapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide chlordiazepoxide + / - clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrates, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dichlordiazepoxide Closantel, Cloxacillin, Codeine Phosphate, Colchicine, Corticotrophin (ACTH), Tetracosactide, Cyclophosphamide, Ciclosporin, Cyproheptadine, Cytarabine, Dacarbazine, Actinomycin D / Actinomycin D, Dalteparin Sodium, Danazol, Dantrolene Sodium, Dapsone, Decoquinate, Deferoxamine Mesylate, Deracoxib, Deslorelin Acetate, Desmopressin Acetate, Desoxycorticosterone Pivalate, Detomidine, Dexamethasone, Dexpanthenol, Dexrazoxane, Dextran, Diazepam, Diazoxide (Oral), Dichlorphenamide, Diclofenac Sodium, Dicloxacillin, Diethylcarbamazine Citrate, Diethylstilbestrol (DES), Difloxacin, Digoxin, Dihydrotachysterol (DHT), Diltiazem Dimenhydrinate, Dimercaprol / BAL, Dimethyl Sulfoxide, Dinoprost Tromethamine, Diphenylhydroxylamine, Disopyramide Phosphate, Dobutamine, Dioctyl Sulfosuccinate / DSS, Dolasetron Mesylate, Domperidone, Dopamine, Doramectin, Doxapram, Doxepin, Doxorubicin, Doxycycline, Calcium Disodium Edetate, Calcium Ethylenediaminetetraacetate, Edrophonium Chloride, Enalapril / Enalaprilat, Enoxaparin Sodium, Enrofloxacin, Ephedrine Sulfate, Epinephrine, Epoetin / Erythropoietin, Elinocrotine, Epsiprantel, Erythromycin, Esmolol, Estradiol Cypionate, Etacrynic Acid / Etanidazole Sodium, Ethanol (Ethyl Alcohol), Etidronate Sodium, Etodolac, Etomidate, Euthanasia Agent w / Pentobarbital, Famotidine, Fatty Acids (Essential / ω), Felbamate, Fentanyl, Ferrous Sulfate, Filgrastim, Finasteride, Fipronil, Florfenicol, Fluconazole, Flucytosine, Fludrocortisone Acetate, Flumazenil, Flumethasone, Flunixin Meglumine, Fluorouracil (5-FU), Fluoxetine, Fluticasone Propionate, Fluvoxamine Maleate, Fomepizole (4-MP), Furazolidone, Furosemide, Gabapentin, Gemcitabine, Gentamycin Sulfate, Glimepiride, Glipizide, Glucagon, Glucocorticoid Reagent, Glucosamine / Chondroitin Sulfate, Glutamine, Glibenclamide, Glycerol (Oral), Glycopyrronium Bromide, Gonadorelin, Griseofulvin, Guaifenesin, Halothane, Glutathion-Hb-200 Heparin, Hydroxyethyl Starch, Sodium Hyaluronate, Hydralazine, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydromorphone, Hydroxyurea, Hydroxyzine, Ifosfamide, Imidacloprid, Moxidectin Dipropionate, Imipenem-Cilastatin Sodium, Imipramine, Amrinone Lactate, Insulin, Interferon α-2a (Recombinant Human), Iodide (Sodium / Potassium), Ipecac (Syrup), Iopodate Sodium, Iron Dextran, Isoflurane, Isoproterenol, Isotretinoin, Isoxsuprine, Itraconazole, Ivermectin, Kaolin / Pectin, Ketamine, Ketoconazole, Ketoprofen, Ketorolac Tromethamine, Lactulose, Leuprolide, Levamisole, 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, Megestrol Acetate, Melarsomine, Melatonin, Meloxicam, Melphalan, Meperidine, Mercaptopurine, Meropenem, Metformin, Methadone, Methazolamide, Methenamine Mandelate / Hippurate, Methimazole, Methionine, Methocarbamol, Methohexital Sodium, Methotrexate, Methoxyflurane, Methylene Blue, Methylphenidate, Methylprednisolone, Metoclopramide, Metoprolol, Metronidazole, Mexiletine, Mibolerone, Midazolam, Milbemycin Oxime, Mineral Oil, Minocycline, Misoprostol, Mitotane, Mitoxantrone, Morphine Sulfate, Moxidectin, Naloxone, Nandrolone Decanoate, Naproxen, Narcotic (Opioid) Agonist Analgesics, Neomycin Sulfate, Neostigmine, Niacinamide, Nitazoxanide, Nitenpyram, Nitrofurantoin, Nitroglycerin, Sodium Nitroprusside, Nizatidine, Novobiocin Sodium, Nystatin, Octreotide Acetate, Olsalazine Sodium, Omeprazole, Ondansetron, Opioid Antidiarrheals, Orbifloxacin, Oxacillin Sodium, Oxazepam, Oxybutynin Chloride, Oxymorphone, Oxytetracycline, Oxytocin, Pamidronate Disodium, Pancrelipase, Pancuronium Bromide, Paromomycin Sulfate, Paroxetine, Penicillamine, General Information Penicillins, Penicillin, Penicillin V Potassium, Pentazocine, Pentobarbital Sodium, Sodium Polystyrene Sulfonate, Pentoxifylline, Pergolide Mesylate, Phenobarbital, Phenoxybenzamine, Phenylbutazone, Phenylephrine, Phenylpropanolamine, Phenytoin Sodium, Pheromones, Parenteral Phosphoric Acid, Vitamin K1 / Vitamin K-1, Pimobendan, Piperazine, Pirlimycin, Piroxicam, Polysulfated Glycosaminoglycans, Ponazuril, Potassium Chloride, Pralidoxime Chloride, Prazosin, Prednisolone / Prednisone, Primidone, Procainamide, Procarbazine, Prochlorperazine, Propantheline Bromide, Propionibacterium acnesInjections for acne, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide, mepyramine maleate, pyrimethamine, mepacrine, quinidine, ranitidine, rifampicin, s-adenosyl-methionine (SAMe), saline / hyperosmotic laxatives, selamectin, selegiline / l-deprenyl, sertraline, sevelamer, sevoflurane, silymarin / silybum, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, pituitary growth hormone, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, dimercaptosuccinic acid, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachloropyridazine sodium, sulfadiazine / trimethroprim, sulfamethoxazole / trimethoprim, sulfadimethoxine, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxalin, terbinafine, terbutaline sulfate, testosterone, tetracycline, sodium arsanilate, vitamin B1, thioguanine, thiopental sodium, thiotepa, thyrotropin, thiram, ticarcillin disodium, tiletamine / zolazepam, tilmicosin, tiopronin, tobramycin sulfate, tocainide, tolazoline, tolfenamic acid, topiramate, tramadol, triamcinolone acetonide, trientine, trilostane, alimemazine tartrate w / prednisolone, tripelennamine, tylosin, ursodeoxycholic acid, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zileuton, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide and mixtures thereof.

[1449] In one embodiment of the present invention, arylpyrazole compounds known in the art such as phenylpyrazoles can be combined with isoxazoline compounds in the long-acting injectable compositions of the present invention. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. Patent Nos. 6,001,384, 6,010,710, 6,083,519, 6,096,329, 6,174,540, 6,685,954 and 6,998,131 (which are all incorporated herein by reference and are each assigned to Merial, Ltd., Duluth, GA).

[1450] In another embodiment of the present invention, one or more macrolides or lactams can be added to the compositions of the present invention, which act as acaricides, antihelmintics and / or insecticides.

[1451] The macrolides include, but are not limited to, avermectins such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, and ML-1,694,554, and milbemycins such as milbemycin, milbemycin D, milbemycin oxime, moxidectin, and nemadectin. Also included are 5-oxo and 5-oxime derivatives of the avermectins and milbemycins. Examples of combinations of arylpyrazole compounds with macrolides 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 (each incorporated herein by reference and assigned to Merial, Ltd., Duluth, GA).

[1452] Macrolide compounds are known in the art and can be readily obtained commercially or by synthetic techniques known in the art. Reference may be made to the widely available technical and commercial literature. For avermectins, ivermectin, and abamectin, reference may be made, for example, to the work of M.H. Fischer and H. Mrozik, William C. Campbell's “Ivermectin and Abamectin”, 1989 (published by Springer Verlag), or Albers- et al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin, reference may be made to “Veterinary Parasitology”, Vol. 49, No. 1, July 1993, 5-15. For milbemycins, among others, reference may be made to Davies H.G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Patent No. 4,134,973, and EP 0 677 054.

[1453] Macrolides are natural products or their semi-synthetic derivatives. The structures of avermectins and milbemycins are closely related, for example, by sharing a complex 16-membered macrocyclic lactone ring. The natural product avermectins are disclosed in U.S. Patent No. 4,310,519, and the 22,23-dihydroavermectin compounds are disclosed in U.S. Patent No. 4,199,569. Among others, U.S. Patent Nos. 4,468,390, 5,824,653, EP 0 007 812 A1, British Patent Specification 1 390 336, EP 0 002 916, and New Zealand Patent No. 237 086 are also mentioned. The naturally occurring milbemycins are described in U.S. Patent No. 3,950,360 and in various references cited in “The Merck Index,” 12th Edition, S. Budavari, ed., Merck & Co., Inc., Whitehouse Station, New Jersey (1996). Latidectin is described in “International Nonproprietary Names for Pharmaceutical Substances (INN),” WHODrug Information, Vol. 17, No. 4, pp. 263-286, (2003). The semi-synthetic derivatives of these compound classes are well known in the art and are described, for example, in U.S. Patent Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148, and EP 0 667 054.

[1454] In another embodiment of the invention, the invention encompasses a long-acting injectable composition comprising an isoxazoline compound and a systemically acting compound from the class of acaricides or insecticides known as insect growth regulators (IGRs). Compounds belonging to this group are well known to practitioners 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 U.S. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022, or U.K. 2 140 010, and in U.S. Patent Nos. 6,096,329 and 6,685,954 (both incorporated herein by reference).

[1455] In one embodiment, the IGR is a compound mimicking juvenile hormone. Examples of juvenile hormone mimics include azadirachtin, ethofenprox, fenoxycarb, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-3(2H)-one.

[1456] In one embodiment, the long-acting injectable composition of the present invention comprises an effective amount of at least one isoxazoline of formula (I) to (VIa) or a pharmaceutically acceptable salt thereof, and methoprene or pyriproxyfen.

[1457] In another embodiment, the IGR compound is a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorfluazuron, cyromazine, diflubenzuron, flonicamid, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, tebufenozide, novaluron, triflumuron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea, 1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)phenyl)urea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[1458] In another embodiment of the present invention, an adulticide, an insecticide, and an acaricide can also be added to the long-acting composition 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, cloethocarb, carbaryl, carbofuran, methiocarb, metolcarb, pirimicarb, propoxur, aldicarb, butocarboxim, oxamyl, and thiodicarb). In one embodiment, the composition can include permethrin and an isoxazoline active ingredient.

[1459] In certain embodiments, the long-acting injectable composition of the present invention can include one or more antinematodal agents, including, but not limited to, active ingredients in benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organophosphates. In certain embodiments, benzimidazoles may be included in the composition, including, but not limited to, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cydibenzoline, febantel, thiabendazole, and its o,o-dimethyl analogue.

[1460] In other embodiments, the long-acting injectable compositions of the invention can include imidazothiazole compounds, including but not limited to tetramisole, levamisole, and butamisole. In other embodiments, the long-acting compositions of the invention can include tetrahydropyrimidine active agents, including but not limited to pyrantel, oxantel, and morantel. Suitable organophosphate active agents include but are not limited to coumaphos, malathion, haloxon, naphthalophos, and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and trichlorphon.

[1461] In other embodiments, the long-acting injectable compositions of the invention can include anti-nematode compounds phenothiazine and piperazine (as the neutral compound or in various salt forms), diethylcarbamazine, phenols such as dichlorophen, arsenicals such as arsenamide, ethanolamines such as bephenium, thiabendazole ammonium chlorobenzenesulfonate, and methyridine; cyanine dyes including pyrvinium pamoate, pyrvinium embonate, and iodothyranine; isothiocyanates including disophenol, suramin sodium, phthalylsulfathiazole, and various natural products, including but not limited to hygromycin B, α-santonin, and kainic acid.

[1462] In other embodiments, the long-acting injectable compositions of the invention can include anti-trematodal agents. Suitable anti-trematodal agents include but are not limited to miracils such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivative, oltipraz, anthralin, hycanthone, oxamniquine, nitriformin, niridazole, nitroxynil, various bisphenol compounds known in the art (including fungicidin, bithionol, bithionol sulfoxide, and dichlorophen); various salicylanilide compounds, including tribromsalan, oxyclozanide, diloxanide, rafoxanide, brotianide, broxalan, and closantel; triclabendazole, diphenan, clorsulon, trichloropiperazine, and emetine.

[1463] Anticestodal compounds can also be advantageously used in the long-acting compositions of the invention, including but not limited to arecoline, dibutyltin dilaurate, niclosamide, nitriferon, paromomycin, and paromomycin II in various salt forms.

[1464] In other embodiments, the long-acting injectable compositions of the present invention may include other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to: bromfenvinfos, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, ethion, trithion, chlorfenvinphos, chlorpyrifos, crotoxyphos, coumaphos, diazinon, dichlorenthion, diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion, chlorpyrifos-methyl, iodofenphos, malathion, tribromfon, phosalone, phosmet, phoxim, propetamphos, ronnel, sulprofos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanoacetate, methoprene, sulfluramid, piperonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, IR3535, and the compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofuran carbaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)-dione (MGK-264), dipropyl 2,5-pyridinedicarboxylate (MGK-326), and 2-(octylthio)ethanol (MGK-874).

[1465] The antiparasitic agent that can be used in combination with the isoxazoline compound in the long-acting composition of the present invention can be a bioactive peptide or protein, including, but not limited to, a peptidomimetic, which acts on the neuromuscular junction by stimulating a presynaptic receptor belonging to the secretin receptor family, thereby causing paralysis and death of the parasite. In one embodiment of the peptidomimetic, the peptidomimetic is emodepside (see Willson et al., Parasitology, January 2003, 126(Pt 1):79-86). In another embodiment, the peptidomimetic is PF1022A or a derivative thereof.

[1466] In another embodiment, the long-acting injectable composition of the present invention may contain an active agent from the neonicotinoid insecticides. The neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that can be combined with the isoxazoline compound to form the long-acting injectable composition of the present invention is imidacloprid. Imidacloprid is a well-known neonicotinoid active agent and is a topical antiparasitic product sold by Bayer Animal Health II, K9 and K9 II and the oral soft chewable composition Advantus from Piedmont Animal Health TM The key active ingredients in. Such agents are described, for example, in U.S. Patent No. 4,742,060 or EP 0 892 060.

[1467] In another embodiment, the long-acting injectable composition of the present invention may comprise nitenpyram, another active agent of the neonicotinoid insecticides. Nitenpyram has the following chemical structure and is the active ingredient in the oral product CAPSTAR sold by Novartis Animal Health TM tablets.

[1468]

[1469] Nitenpyram is active against adult fleas when administered orally as a tablet daily. Nitenpyram acts by interfering with normal neurotransmission and causes the death of insects. Nitenpyram acts very rapidly on fleas. For example, CAPSTAR TM tablets begin to act on fleas as early as 30 minutes after administration and are indicated for use as frequently as once a day. However, like CAPSTAR TM tablets, nitenpyram is only known to be effective when administered orally as a systemic parasiticide.

[1470] In another embodiment, the present invention provides a long-acting composition 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-decahydronaphthalenecarboxamide (the compound of formula Ia) and nitenpyram.

[1471] In another embodiment, the present invention provides a long-acting composition 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-decahydronaphthalenecarboxamide (the compound of formula Ia) and imidacloprid.

[1472] In certain embodiments, the insecticides that can be combined with the long-acting composition of the present invention are semicarbazones, such as metaflumizone.

[1473] In another embodiment, the long-acting injectable composition of the present invention may advantageously comprise a combination of isoxazoline compounds known in the art. These active agents are described in WO 2007 / 079162, WO 2007 / 075459 and US2009 / 0133319, WO 2007 / 070606 and US2009 / 0143410, WO 2009 / 003075, WO 2009 / 002809, WO 2009 / 024541, WO 2005 / 085216 and US2007 / 0066617 and WO 2008 / 122375, all of which are hereby incorporated by reference in their entirety.

[1474] In another embodiment of the present invention, spheric acid and its derivatives (a class of known acaricides, antihelminthics, antiparasitics and insecticides) may be added to the long-acting composition of the present invention. These compounds are used for the treatment or prevention of 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 hereby incorporated by reference in their entirety. The composition may comprise one or more spheric acid derivatives known in the art, including all stereoisomers, such as those described in the patents cited above.

[1475] In another embodiment, antihelminthic compounds of the aminoacetonitrile class (AAD) such as morantel (ZOLVIX) etc. may be added to the long-acting composition of the present invention. These compounds are described in, for example, 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.

[1476] The composition of the present invention may also comprise arylbenzimidazol-2-yl cyanoethylamino compounds, such as those described in U.S. Patent No. 8,088,801 to Soll et al. (which is incorporated herein in its entirety), and thioamide derivatives of these compounds, as described in U.S. Patent No. 7,964,621 (which is incorporated herein by reference).

[1477] The long-acting injectable compositions of the present invention can also be combined with paraherquamide compounds and derivatives of these compounds, including dequalinium (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). Compounds of the paraherquamide family are a class of known compounds that include a spirodioxepinoindole nucleus that is active against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). Additionally, compounds of the structurally related marcfortine family, such as marcfortine A-C, are also known and can be combined with the compositions of the present invention (see J. Chem. Soc.-Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). For other references regarding paraherquamide derivatives, see, for example, WO 91 / 09961, WO 92 / 22555, WO 97 / 03988, WO 01 / 076370, WO 09 / 004432, U.S. Patent 5,703,078, and U.S. Patent 5,750,695, all of which are hereby incorporated by reference in their entirety.

[1478] Generally, an additional active agent is included in the long-acting compositions of the present invention in an amount from about 0.1 μg to about 1000 mg. More typically, the additional active agent can be included in an amount from about 10 μg to about 500 mg, from about 1 mg to about 300 mg, from about 10 mg to about 200 mg, or from about 10 mg to about 100 mg.

[1479] In other embodiments of the present invention, an additional active agent can be included in the composition to deliver a dose of about 5 μg / kg to about 50 mg / kg of animal body weight. In other embodiments, the additional active agent can be present in an amount sufficient to deliver a dose of about 0.01 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of animal body weight. In other embodiments, the additional active agent can be present in a dose of about 5 μg / kg to about 200 μg / kg or about 0.1 mg / kg to about 1 mg / kg of animal body weight. In another embodiment of the present invention, the additional active agent is included in a dose of about 0.5 mg / kg to about 50 mg / kg.

[1480] It has surprisingly been found that the long-acting compositions of the present invention, which comprise at least one isoxazoline active agent, at least one liquid PEG and / or neutral oil and an optional co-solvent, are stable and effective against a broad spectrum of ectoparasites and, if another active agent is included, may also be effective against endoparasites, for a continuously extended period of time; for example, a period of three (3) to six (6) months, while exhibiting favorable properties with respect to the injection site.

[1481] The liquid PEGs provided herein are those polyethylene glycols that are liquid at room temperature (20 - 30 °C). Polyethylene glycol has the following structural formula:

[1482] H-(O-CH2-CH2) n -OH.

[1483] Non-limiting examples of n in the above formula are those compounds in which n ranges from 1 to about 10,000 (e.g., about 4 to about 25). The liquid PEGs include combinations of different polyethylene glycols. Non-limiting examples of liquid PEGs include PEG 200, PEG300, PEG 400, PEG 600, and PEG 1000 or combinations thereof.

[1484] Pharmaceutically acceptable polymers other than PEG are specifically excluded from the long-acting compositions of the present invention. Examples of pharmaceutically acceptable polymers specifically excluded from the long-acting compositions of the present invention include polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyestersamides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures thereof, including copolymers of polylactide, polycaprolactone, polyglycolide (e.g., poly(lactide-co-glycolide)).

[1485] In certain embodiments, poloxamer may be included in the composition. For the purposes of the compositions described herein, poloxamer is not considered a pharmaceutically acceptable polymer, but rather a solvent or surfactant. Poloxamer is a family of synthetic block copolymers of ethylene oxide and propylene oxide. Poloxamer can be liquid, an emulsified white paste, or a powder, and is represented by the following structure:

[1486]

[1487] Wherein a is an integer between 2 and 130, and b is an integer between 15 and 67 (see, US 3,740,421, incorporated herein by reference). Poloxamers are available from commercial sources such as BASF and Croda. An example of a poloxamer that can be used in the compositions of the present invention is P-124, which is a solid at room temperature. The viscosity of the long-acting injectable composition is an important parameter in terms of ease of administering the composition to an animal. Generally, a viscosity of less than about 150 centipoise (cPs) is acceptable. Thus, in one embodiment, the composition of the present invention has a viscosity at 25 °C of less than about 150 cPs. In other embodiments, the composition of the present invention has a viscosity at 25 °C of less than about 140 cPs, less than about 130 cPs or less than about 120 cPs. In other embodiments, the composition of the present invention has a viscosity at 25 °C of less than about 110 cPs or less than about 100 cPs.

[1488] The co-solvent used in the long-acting injectable composition can be a single co-solvent or a blend of co-solvents. A co-solvent can be used in the compositions of the present invention to increase the solubility of the isoxazoline active agent and / or to reduce the viscosity of the composition. In one embodiment, the co-solvent used in the long-acting injectable composition of the present invention comprises a polar solvent that is miscible in water. Non-limiting examples of such co-solvents include ethanol, isopropyl alcohol, glycol ethers (e.g., including, but not limited to, diethylene glycol monoethyl ether (DGME, )), 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, etc.), propylene glycol, glycerol, carbonates (e.g., propylene carbonate or ethylene carbonate), 2-pyrrolidone, substituted 2-pyrrolidones (including N-methylpyrrolidone, 1-ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, l-(secondary- or tertiary- or n-butyl)pyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone, 1-(2-hydroxyethyl)-pyrrolidone, 1-(3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl)-pyrrolidone, 1-(3-methoxypropyl)pyrrolidone and 1-benzylpyrrolidone), dimethyl isosorbide (DMI), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), glycerol formal or a mixture of at least two of these solvents.

[1489] In one embodiment, the long-acting composition of the present invention comprises a polar protic solvent, including but not limited to, alcohols such as C1-C6 alcohols, including but not limited to, ethanol, isopropanol. In another embodiment, the polar protic solvent is a diol, such as glycerol or propylene glycol, or a glycol ether such as diethylene glycol monoethyl ether (Transcutol) or other commonly used ethanol ethers such as those described above.

[1490] In another embodiment, the long-acting injectable composition of the present invention comprises a polar aprotic solvent, including but not limited to, N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, dimethyl sulfoxide, or propylene carbonate.

[1491] In another embodiment of the present invention, the composition of the present invention comprises a water-immiscible co-solvent or a solvent that is only partially soluble in water. Water-immiscible solvents include esters of aliphatic carboxylic acids (including fatty acids) and glycerol (glycerides) or esters of aliphatic carboxylic acids (including fatty acids) and propylene glycol. Water-immiscible solvents also include oils acceptable for injectable compositions. Non-limiting examples of these co-solvents include benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, triglycerides (including medium-chain triglycerides such as C8-C 10 triglycerides such as caprylic / capric triglyceride), propylene glycol derivatives (e.g., propylene glycol monolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol) (a nonionic water-dispersible surfactant), isopropyl myristate, or a mixture of at least two of these co-solvents.

[1492] In one embodiment, the composition of the present invention may comprise a pharmaceutically acceptable neutral oil as the main component of the composition or as a co-solvent with the liquid PEG. When a neutral oil is used in combination with liquid PEG, a bridging solvent or surfactant may be necessary to ensure miscibility. Some neutral oils are fractionated triglycerides of plant fatty acids having a chain length of C8 to C 10 and include caprylic / capric triglyceride. Two commercially available products are called 810 and 812. In another embodiment, the neutral oil is a fractionated triglyceride of plant fatty acids having a chain length of C8 and C 10 combined with linoleic acid (about 4-5%). A commercially available product is called 818. In another embodiment, the neutral oil is a fractionated triglyceride of plant fatty acids having a chain length of C8 and C 10Glycerides of plant fatty acids with a chain length of. A commercially available product is called 829. In another embodiment, the neutral oil can be a propylene glycol diester of saturated plant fatty acids having a chain length of C8 and C 10 of. A commercially available product is called 840 (propylene glycol dicaprylate / dicaprate). In another embodiment, the co-solvent can be a mixture of two or more neutral oils. Other oils acceptable for inclusion in the long-acting injectable compositions of the present invention include, but are not limited to, castor oil, cottonseed oil, sesame oil, soybean oil, and safflower oil.

[1493] In one embodiment, the composition of the present invention can comprise from about 0.5% to about 70% (w / v) of a co-solvent. In another embodiment, the composition of the present invention can comprise from about 0.5% to about 60% (w / v) or from about 1% to about 50% (w / v) of a co-solvent. In another embodiment, the composition can comprise from about 1% to about 40% (w / v), from about 5% to about 50% (w / v), from about 5% to about 40% (w / v), or from about 5% to about 35% (w / v) of a co-solvent. In other embodiments, the composition of the present invention can comprise from about 1% to about 20% (w / v), from about 2% to about 15% (w / v), or from about 2% to about 10% (w / v) of a co-solvent.

[1494] The long-acting injectable compositions of the present invention can include pharmaceutically acceptable additives or excipients. Pharmaceutically acceptable additives and excipients include, but are not limited to, surfactants, antioxidants, preservatives, pH stabilizers (such as buffers), and other inert excipients. In another embodiment, the composition of the present invention can comprise from about 0.01% to about 20% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof. In other embodiments, the composition can comprise from about 0.01% to about 5% (w / v), from about 0.1% to about 10% (w / v), or from about 0.1% to about 5% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof. In other embodiments, the composition can comprise from about 5 to about 15% (w / v) or from about 5 to about 10% (w / v) of a pharmaceutically acceptable additive, excipient, or a mixture thereof. In another embodiment, the composition can comprise from about 7 to about 10% of a pharmaceutically acceptable additive, excipient, or a mixture thereof.

[1495] Surfactants can be present in the compositions of the present invention at a concentration of about 0.1% to about 10% (w / w), about 1% to about 10% (w / w), or about 5% to about 10% (w / w). More typically, surfactants can be present at a concentration of about 0.1% to about 5% (w / w) or about 1 to about 5% (w / w). Examples of surfactants that can be used in the compositions include, but are not limited to: glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters (including sorbitan monooleate ( 20)), polyvinyl alcohol, polysorbates (including polysorbate 20 and polysorbate 80), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, copolymers of ethylene oxide and propylene oxide (e.g., poloxamers such as F87, etc.), polyethylene glycol castor oil derivatives (including polyoxyethylene 35 castor oil ( EL), polyoxyethylene 40 hydrogenated castor oil ( RH 40), polyoxyethylene 60 hydrogenated castor oil ( RH60)); propylene glycol monolaurate glycerides, including glycerol caprylate / caprate ( MCM), polyethylene glycolated glycerides PEG300 caprylic / capric glyceride ( 767), PEG 400 caprylic / capric glyceride PEG300 oleic glyceride ( M-1944CS), PEG 300 linoleic glyceride ( M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates, including polyoxyethylene 8 stearate (PEG 400 monostearate), polyoxyethylene 40 stearate (PEG 1750 monostearate, etc.). Polyethylene glycol stearate (synonyms include polyethylene glycol (macrogol) stearate, polyoxyethylene stearate, polyoxyethylene stearate, ethoxylated stearate; CAS No. 9004-99-3, 9005-08-7) is a mixture of mono- and distearates of mixed polyethylene glycol polymers. Polyethylene glycol hydroxystearate is a mixture of mono- and di-esters of hydroxystearic acid with polyethylene glycol. One polyethylene glycol hydroxystearate that can be used in the compositions is polyethylene glycol 12-hydroxystearate. In another embodiment, the compositions of the present invention can include the surfactant polyethylene glycol 15 12-hydroxystearate (from BASF's HS15), which is a mixture of mono- and di-esters of 12-hydroxy stearic acid with 15 moles of ethylene oxide. Additionally, these compounds and their amounts are well known in the art. In another embodiment of the present invention, the composition of the present invention may include polyoxyethylene 35 castor oil ( EL) as a surfactant. In other embodiments, the composition of the present invention may include polyoxyethylene 40 hydrogenated castor oil ( RH 40) or polyoxyethylene 60 hydrogenated castor oil as a surfactant. The composition of the present invention may also include a combination of surfactants.

[1496] The composition of the present invention may contain other inert ingredients such as antioxidants, preservatives or pH stabilizers. These compounds are well known in the field of compositions. Antioxidants such as vitamin E, α-tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfite, sodium bisulfite, propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol, tert-butylhydroquinone (TBHQ), etc. may be added to the present composition. Based on the total weight (w / w) of the composition, usually about 0.01% to about 3%, or about 0.01 to about 2% (w / v) of antioxidant is included in the composition of the present invention. In another embodiment, the composition contains about 0.05 to about 1.0% (w / w) of an antioxidant or a mixture of antioxidants.

[1497] Preservatives, such as parabens (methylparaben and / or propylparaben), are suitably used in the composition in an amount in the range of about 0.01 to about 2.0%, with about 0.05 to about 1.0% being particularly preferred. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, etc. The preferred range of these compounds includes about 0.01 to about 5%.

[1498] Compounds for stabilizing the pH of the composition are also contemplated. Additionally, such compounds and how to use these compounds are well known to those skilled in the art. Buffer systems include, for example, systems selected from the following: acetic acid / acetic acid salts, malic acid / malates, citric acid / citrates, tartaric acid / tartrates, lactic acid / lactates, phosphoric acid / phosphates, glycine / glycinates, tris, glutamic acid / glutamates, and sodium carbonate.

[1499] The dosage form may 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 the active agent in the compositions of the present invention will be from about 1 mg to about 3 g. In another embodiment, the amount of the active agent in the composition will be from about 20 mg to about 3 g. In another embodiment, the amount of the active agent present in the composition will be from about 20 mg to about 2 g, from about 20 mg to about 1.5 g, or from about 20 mg to about 1 g. In other embodiments, the amount of the active agent in the composition will be from about 20 mg to about 500 mg, from about 30 mg to about 200 mg, or from about 50 mg to about 200 mg. In another embodiment, the amount of the active agent present in the composition will be from about 50 mg to about 2 g, from about 50 mg to about 1 g, or from about 50 mg to about 500 mg. In another embodiment of the present invention, the amount of the active agent present will be from about 100 mg to about 2 g, from about 100 mg to about 1 g, or from about 100 mg to about 500 mg.

[1500] In another embodiment, the amount of the active agent present in the compositions of the present invention is from about 1 mg to about 500 mg of active agent, from about 1 mg to about 100 mg or from about 1 mg to about 25 mg. In other embodiments, the amount of the active agent present in the composition is about 10 mg, about 50 mg, or from about 10 mg to about 100 mg. In other embodiments, the amount of the active agent present in the composition is from about 50 mg to about 200 mg, from about 100 mg to about 300 mg, from about 100 mg to about 400 mg, from about 200 mg to about 500 mg, from about 300 mg to about 600 mg, from about 400 mg to about 800 mg, or from about 500 mg to about 1000 mg.

[1501] The composition of the present invention is prepared as follows: Mix appropriate amounts of an active agent, liquid PEG and / or neutral oil, a co-solvent (if present), and optionally an antioxidant, a pharmaceutically acceptable additive and / or excipient to form the composition of the present invention. In certain embodiments, the composition of the present invention can be obtained by following the methods for preparing these forms, the descriptions of which are referred to general composition textbooks known to those skilled in the art, such as 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).

[1502] Methods of treatment

[1503] In another aspect of the present invention, there is provided a method for preventing or treating parasite infestation / infection in an animal, the method comprising administering to the animal a long-acting injectable composition comprising an effective amount of at least one isoxazoline compound, liquid PEG and / or neutral oil, an optional co-solvent, and an optional antioxidant, a pharmaceutically acceptable additive and / or excipient. The compositions of the present invention have a long-lasting efficacy against ectoparasites (such as fleas and ticks), and in certain embodiments, they can also be active against endoparasites that harm the animal.

[1504] In one embodiment of the present invention, there is provided a method for treating or preventing parasite infestation or infection in a domestic animal, the method comprising administering to the animal a long-acting injectable composition, the long-acting injectable composition comprising an effective amount of at least one isoxazoline active agent. The ectoparasites against which the methods and compositions of the present invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies and lice. In certain embodiments in which the composition of the present invention comprises one or more additional active agents that are active against endoparasites, the compositions and methods of the present invention can also be effective against endoparasites, which include, but are not limited to, tapeworms, nematodes, hookworms and roundworms in the digestive tract of animals and humans.

[1505] In an alternative embodiment of the present invention, there is provided a method for treating or preventing parasite infestation or infection in domestic animals, the method comprising administering to the animal a long-acting injectable composition comprising an effective amount of at least one isoxazoline active agent. Ectoparasites against which the methods and compositions of the present invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, and lice. In certain embodiments in which the compositions of the present invention include one or more additional active agents that are active against endoparasites, the compositions and methods of the present invention may also be effective against endoparasites, including, but not limited to, tapeworms, nematodes, hookworms, and roundworms of the digestive tract of animals and humans.

[1506] In one embodiment of the treatment against ectoparasites, the ectoparasites are 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.

[1507] In another embodiment of the treatment against ectoparasites, the ectoparasites are from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, and / or Boophilus. Ectoparasites to be treated 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., etc.), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., etc.), and mites (Demodex sp., Sarcoptes sp., Otodectes sp., etc.), lice (Trichodectes sp., Cheyletiella sp., Linognathus sp., etc.), mosquitoes (Aedes sp., Culex sp., Anopheles sp., etc.), and flies (Haematobia sp. including Haematobia irritans, Musca sp., Stomoxys sp. including Stomoxys calcitrans, Hypoderma sp., Cochliomyia sp., etc.).

[1508] Other examples of ectoparasites include, but are not limited to, ticks of the genus Boophilus, in particular the following species: Boophilus microplus (cattle tick), Boophilus decoloratus, those of Boophilus annulatus; myiasis such as Dermatobia hominis (referred to as Berne in Brazil) and Cochliomyia hominivorax (green blowfly); sheep myiasis such as Lucilia sericata, Lucilia cuprina (referred to as blowfly strike in Australia, New Zealand and South Africa). Flies, suitable ones, i.e., those whose adults constitute parasites, such as Haematobia irritans (horn fly) and Stomoxys calcitrans (stable fly); lice such as 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, migratory dipterous larvae.

[1509] In certain embodiments of the invention, the composition can also be used to treat endoparasites such as those worms selected from the genera Anaplocephala, Ancylostoma, Necator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostomum, Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris and Trichostrongylus and others.

[1510] In one embodiment, the invention provides a method for treating and preventing parasite infections and infestations in or on animals (wild or domestic), including livestock and companion animals such as cats, dogs, horses, poultry (including chickens), sheep, goats, pigs, deer, turkeys and cattle, with the aim of ridding these hosts of parasites commonly encountered by such animals.

[1511] In one embodiment, the present invention provides methods and compositions for treating or preventing parasite infections and infestations in livestock animals (e.g., sheep and cattle) or companion animals (including, but not limited to, cats and dogs). The methods and compositions are particularly effective for preventing or treating parasite infestations of fleas and ticks in cattle and sheep.

[1512] In another embodiment, the methods and compositions of the present invention are used for treating or preventing parasite infections and infestations in cattle or sheep. When treating livestock animals such as cattle or sheep, the methods and compositions are particularly effective against Rhipicephalus microplus (Boophilus microplus), Haematobia irritans (horn fly), Stomoxys calcitrans (stable fly), and sheep flystrike such as Lucilia sericata, Lucilia cuprina (referred to as blowfly strike in Australia, New Zealand, and South Africa).

[1513] The term “treating” (“treating” or “treat” or “treatment”) is intended to mean administering the long-acting compositions of the present invention to an animal having a parasite infestation to eradicate the parasites infesting the treated animal or to reduce the number of parasites. It should be noted that the compositions of the present invention can be used to prevent such parasite infestations.

[1514] The term “preventing” (“prevent” or “prevention”) or “prophylaxis” is intended to mean administering the long-acting compositions of the present invention to an animal before a parasite infection or infestation has occurred in order to prevent the infection or infestation from occurring. By killing new parasites attacking the animal before they can reproduce to establish an infestation or infection, administering the long-acting compositions at recommended regular intervals will effectively prevent new parasite infestations or infections in the animal.

[1515] The compositions of the present invention are administered in a parasitically effective amount suitable for controlling the target parasites to the desired degree as described below. In each aspect of the present invention, the compounds and compositions of the present invention can be administered against a single pest or a combination thereof.

[1516] "An antiparasitically effective amount" means an amount of the composition of the invention sufficient to eradicate parasites infesting an animal or reduce the number of parasites infesting an animal. In certain embodiments, an effective amount of the active agent achieves at least 70% efficacy against a target parasite. In other embodiments, an effective amount of the active agent achieves at least 80% or at least 90% efficacy against a target pest. Preferably, an effective amount of the active agent will achieve at least 95%, at least 98% or 100% efficacy against a target parasite.

[1517] Typically, a dose of about 0.001 to about 100 mg / kg body weight administered as a single dose or divided doses over a period of 1 - 5 days will be satisfactory, but of course there may be instances indicating higher or lower dose ranges and this is within the scope of the present invention. Determining a particular dosage regimen for a particular host and parasite is entirely within the routine skill of the practitioner.

[1518] In certain embodiments, for companion animals, the dose of the isoxazoline active agent administered from the topical composition of the invention is between about 0.1 and about 50 mg / kg body weight. More typically, the dose of the isoxazoline active agent administered is about 0.5 to about 30 mg / kg or about 0.5 to about 30 mg / kg body weight. In another embodiment, the dose of the isoxazoline active agent will be about 0.5 to about 20 mg / kg, about 0.5 to about 10 mg / kg or about 0.5 to about 5 mg / kg body weight. In another embodiment, the dose will be about 0.5 to about 2.5 mg / kg body weight. In another embodiment, the dose of the isoxazoline active agent administered is about 10 to about 30 mg / kg, about 15 to about 30 mg / kg or about 20 to about 30 mg / kg body weight.

[1519] In other embodiments, the dose administered can be lower, depending on the animal and the isoxazoline administered. For example, if the composition contains a more active enantiomer of the isoxazoline compound, a lower dose can be administered. In certain embodiments, the dose is about 0.1 to about 30 mg / kg body weight. In another embodiment, the dose can be about 0.1 to about 20 mg / kg or about 0.1 to about 10 mg / kg body weight. In another embodiment, a dose of about 0.1 to about 5 mg / kg, about 0.1 to about 2.5 mg / kg body weight will be used. In other embodiments, the dose can be about 1 to about 20 mg / kg body weight or about 1 to about 10 mg / kg. In another embodiment, the dose can be about 5 to about 20 mg / kg or about 10 to about 20 mg / kg body weight.

[1520] The volume of the dose of the long-acting injectable composition is generally less than about 10 mL / 50 kg of the body weight of the animal being treated. In other embodiments, the injection volume is about 7 mL / 50 kg of body weight. In other embodiments, the injection volume is less than about 5 mL / 50 kg, less than about 3 mL / 50 kg of body weight, or less than about 2 mL / 50 kg of body weight. In other embodiments, the injection volume is from about 0.1 to about 2 mL / 50 kg of animal body weight. In other embodiments, the injection volume is from about 0.05 to about 1 mL / 50 kg of animal body weight.

[1521] In other embodiments for treating livestock animals such as cattle or sheep, the dose of the isoxazoline active agent administered can be from about 0.1 to about 40 mg / kg of body weight. More typically, the dose administered will be from about 1 to about 30 mg / kg, from about 1 to about 20 mg / kg, or from about 1 to about 10 mg / kg of body weight. In another embodiment, the dose can be from about 10 to about 25 mg / kg, from about 15 to about 30 mg / kg of body weight, or from about 20 - 30 mg / kg of body weight.

[1522] In one embodiment of the method for use in livestock animals (e.g., cattle or sheep), the long-acting composition of the present invention comprising an isoxazoline compound has at least about 90.0% or higher efficacy against ectoparasites (including, but not limited to, fleas, ticks, mites) and parasitic flies for about 3 months or longer. In another embodiment, the long-acting composition of the present invention provides at least 95.0% or higher efficacy against ectoparasites for about 3 months or longer.

[1523] In another embodiment, the long-acting composition of the present invention provides at least about 80% efficacy against ectoparasites in livestock animals (e.g., cattle or sheep) for 2 months or longer. In another embodiment, the long-acting composition of the present invention provides about 90% efficacy against ectoparasites in livestock animals (e.g., cattle or sheep) for at least about 2 months. In another embodiment, the composition provides about 95% efficacy for about 2 months or longer. In another embodiment, the long-acting composition of the present invention provides about 90% efficacy against ectoparasites in livestock animals (e.g., cattle or sheep) for about 3 months or longer. In another embodiment, the composition provides about 95% efficacy for about 3 months or longer.

[1524] In another embodiment, the long-acting composition of the present invention has at least about 80% efficacy against external parasites for about 3 months or longer. In another embodiment, the long-acting composition of the present invention provides at least about 90% efficacy against external parasites for 3 months or longer. In another embodiment, the long-acting composition of the present invention provides at least about 95% efficacy against external parasites for 3 months or longer. In another embodiment, the long-acting composition of the present invention provides at least 80% or at least 90% efficacy against external parasites in livestock animals (e.g., cattle or sheep) for about 3 months to about 6 months or longer.

[1525] In other embodiments, the long-acting composition of the present invention has at least about 90% efficacy against external parasites (including, but not limited to, fleas, ticks, mites, and botflies) for about 7 months or longer, about 8 months or longer, or about 9 months or longer. In other embodiments, the long-acting composition of the present invention has at least about 90% efficacy against external parasites (including, but not limited to, fleas, ticks, mites, and botflies) for about 10 months or longer, about 11 months (118 months) or longer, or even about 12 months or longer.

[1526] In another aspect of the present invention, there is provided a kit for treating or preventing parasite infestations in animals, which comprises the long-acting composition of the present invention and a syringe.

[1527] Anti-parasitic compounds

[1528] In a second aspect of the present invention, there are provided novel and inventive isoxazoline compounds of formula (Id) which are insecticidal and parasiticidal:

[1529]

[1530] wherein X 1 is bromine, chlorine, iodine or fluorine; and X 2 is chlorine, fluorine or CF3;

[1531] Y is group Y-1, Y-2, Y-3, Y-4 (where Z is N or CH), Y-5 or Y-6

[1532]

[1533] Q is OH, -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, -C(O)NHCH2CH2SCH3 or (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3.

[1534] The second aspect of the present invention includes at least the following features:

[1535] (a) In one embodiment, the present invention provides novel compounds of formula (Id) or pharmaceutically or agriculturally acceptable salts thereof, which are active against arthropod pests and parasites harmful to animals and plants;

[1536] (b) Veterinary and pesticidal compositions for combating and controlling pests and parasites, which comprise an insecticidal or parasitocidal effective amount of a compound of formula (Id) or a pharmaceutically or agriculturally acceptable salt thereof and a pharmaceutically or agriculturally acceptable carrier or diluent;

[1537] (c) Plant propagation material (such as seeds), which comprises at least one compound of formula (Id) or an agriculturally acceptable salt thereof.

[1538] (d) Veterinary and pesticidal compositions for combating arthropod pests and parasites, which comprise an insecticidal or parasitocidal effective amount of a compound of the present invention or a pharmaceutically or agriculturally acceptable salt thereof and at least one additional active agent and a pharmaceutically or agriculturally acceptable carrier or diluent;

[1539] (e) A method for treating a parasite infestation / infection in or on an animal, which method comprises administering to an animal in need thereof a parasitocidal effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof;

[1540] (f) A method for preventing a parasite infestation / infection in an animal, which method comprises administering to an animal in need thereof a parasitocidal effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof;

[1541] (g) A method for combating or controlling pests that are harmful to crops, plants, plant propagation material or materials containing or derived from wood, which method comprises bringing the crop, plant, plant propagation material or materials containing or derived from wood into contact with an insecticidal effective amount of a compound of formula (Id) or an agriculturally acceptable salt thereof or a composition comprising said compound;

[1542] (h) A method for combating or controlling pests in a premises, which method comprises applying to the premises an insecticidal or parasitocidal effective amount of a compound of formula (Id) or a pharmaceutically or agriculturally acceptable salt thereof;

[1543] (i) Use of a compound of formula (Id) or a pharmaceutically or agriculturally acceptable salt thereof for controlling pests (including parasites) in or on an animal or on the surface of a crop, plant, plant propagation material or materials containing or derived from wood; and

[1544] (j) Use of a compound of formula (Id) or a pharmaceutically acceptable salt thereof in the preparation of a veterinary medicament for controlling pests (including parasites).

[1545] An important aspect of the present invention is to provide such isoxazoline active agents that exhibit surprisingly and unexpectedly rapid-acting and long-lasting efficacy against parasites, especially ticks, compared to isoxazoline active compounds having different substitution patterns on the phenyl ring attached to the quaternary carbon of the isoxazoline ring. Thus, it has been found that compared to known isoxazoline compounds (where Y is Y-2 and Q is -C(O)NHCH2C(O)NHCH2CF3, but having different substitution patterns on the phenyl ring), the compounds of formula (Id) (where Y is Y-2, Q is -C(O)NHCH2C(O)NHCH2CF3, X 1 is fluorine and X 2 is chlorine, which are not specifically described in WO2007 / 079162A1 or WO 2009 / 002890 A2) have surprisingly improved active durations against Rhipicephalus microplus (formerly Boophilus microplus) on the surface of cattle.

[1546] In addition, it has also been found that compared to known isoxazoline compounds (where Y is Y-2 and Q is Y is Y-2, Q is -C(O)NHCH2C(O)NHCH2CF3, but having different substitution patterns on the phenyl ring), the compounds of formula (Id) (where Y is Y-2, Q is -C(O)NHCH2C(O)NHCH2CF3, X 1 is fluorine and X 2 is chlorine) have surprisingly improved rapid-acting efficacy against Rhipicephalus microplus on the surface of cattle.

[1547] In one embodiment, the present invention provides compounds of formula (Id) wherein the group Y is Y-1. In another embodiment, Y is Y-2. In another embodiment, Y is Y-3. In another embodiment, Y is Y-4. In another embodiment, Y is Y-5. In another embodiment, Y is Y-6.

[1548] In one embodiment, the present invention provides compounds of formula (Id) wherein Y is Y-1, X 1 is fluorine, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X 1 is fluorine, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-3, X 1is fluorine and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of Y-3. In another embodiment, Y is Y-4, X 1 is fluorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X 1 is fluorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-6, X 1 is fluorine and Q is OH.

[1549] In another embodiment, the present invention provides a compound of formula (Id), where Y is Y-1, X 1 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X 1 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-3, X 1 is chlorine and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of Y-3. In another embodiment, Y is Y-4, X 1 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X 1 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-6, X 1 is chlorine and Q is OH.

[1550] In one embodiment, Y is Y-1, X 1 is fluorine, X 2 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is fluorine, X2 is fluorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is fluorine, X 2 is CF3 and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

[1551] In another embodiment, Y is Y-1, X 1 is chlorine, X 2 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is chlorine, X 2 is fluorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is chlorine, X 2 is CF3 and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

[1552] In one embodiment, Y is Y-1, X 1 is bromine, X 2 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is bromine, X 2 is fluorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is bromine, X 2 is CF3 and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

[1553] In one embodiment, Y is Y-1, X 1 is iodine, X 2is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is iodine, X 2 is fluorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X 1 is iodine, X 2 is CF3 and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

[1554] In one embodiment, Y is Y-2, X 1 is fluorine, X 2 is chlorine and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NH...

Claims

1. A long-acting injectable composition for treating or preventing parasitic infections or infestations in animals, comprising: a) An effective amount of at least one antiparasitic isoxazoline active agent, which is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: Wherein: X 1 is Cl; X 2 is F; and X 3 is -CF3; b) a neutral oil selected from triglycerides of fractionated vegetable fatty acids having a chain length of C8 to C 10 ; c) Optionally, at least one co-solvent; d) Optionally, an antioxidant; and e) Optionally, at least one pharmaceutically acceptable additive, excipient or a mixture thereof, wherein no other pharmaceutically acceptable polymers are present.

2. The long-acting injectable composition according to claim 1, wherein the isoxazoline active agent is an enriched enantiomer.

3. The long-acting injectable composition according to claim 2, wherein the isoxazoline active agent is a compound of formula (S)-Ic or a pharmaceutically acceptable salt thereof: where X 1 is Cl; X 2 is F; and X 3 is -CF3.

4. The long-acting injectable composition according to any one of claims 1-3, wherein the composition comprises a co-solvent, and wherein the co-solvent is a C1-C6 alcohol, a glycol ether, a cyclic carbonate, 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, dimethyl sulfoxide or glycerol formal or a combination thereof.

5. The long-acting injectable composition according to any one of claims 1-3, wherein the composition comprises a co-solvent, and wherein the co-solvent is glycerol, propylene glycol or a combination thereof.

6. The long-acting injectable composition according to any one of claims 1-3, wherein the composition comprises a co-solvent, and wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, castor oil, cottonseed oil, sesame oil, soybean oil or safflower oil or a combination thereof.

7. The long-acting injectable composition according to any one of claims 1-3, wherein the composition comprises a co-solvent, and wherein the co-solvent is C8-C 10 triglycerides, C8-C in combination with linoleic acid 10 triglycerides, C8-C in combination with succinic acid 10 triglycerides, C8-C 10 propylene glycol diesters of fatty acids or combinations thereof.

8. The long-acting injectable composition according to any one of claims 1-3, wherein the composition comprises a co-solvent, and wherein the co-solvent is ethanol, isopropanol or benzyl alcohol or a mixture thereof.

9. The long-acting injectable composition according to any one of claims 1-3, wherein the composition comprises a pharmaceutically acceptable excipient, and wherein the excipient is a surfactant.

10. The long-acting injectable composition according to claim 9, wherein the surfactant is selected from glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan monooleate, polyvinyl alcohol, polysorbate 20, polysorbate 80, d-α-tocopheryl polyethylene glycol 1000 succinate, sodium lauryl sulfate, a copolymer of ethylene oxide and propylene oxide, a polyethylene glycol castor oil derivative, propylene glycol monolaurate, glycerol caprylate / caprate, a polyethylene glycolated glyceride, PEG 300 caprylic / capric glyceride, PEG 400 caprylic / capric glyceride, PEG 300 oleic glyceride, PEG 300 linoleic glyceride, polyethylene glycol stearate and polyethylene glycol hydroxystearate or a combination thereof.

11. The long-acting injectable composition according to claim 1, comprising: a) About 0.5 to about 30% w / v of an isoxazoline compound of formula (Ic) or a pharmaceutically acceptable salt thereof: Wherein: X 1 is Cl; X 2 is F; and X 3 is -CF3; b) neutral oil, said neutral oil being selected from triglycerides of fractionated plant fatty acids having a chain length of C8 to C 10 ; c) An optional co-solvent of about 5% to 40% w / v, wherein the co-solvent is selected from ethanol and isopropanol; d) An optional antioxidant of about 0.01% to about 2% w / v; and e) An optional pharmaceutically acceptable additive, excipient or mixture thereof of about 0.01% to about 5% w / v, wherein the neutral oil is present in the total composition in a proportion representing 100% of the composition.

12. The long-acting injectable composition according to any one of claims 1-3 and 10-11, further comprising an effective amount of at least one additional active agent.

13. The long-acting injectable composition according to claim 12, wherein the additional pharmaceutically active agent is a macrolide, a neonicotinoid active agent, a 1-N-arylpyrazole active agent, a cyclic lipopeptide, a benzimidazole, an imidazothiazole, a tetrahydropyrimidine active agent, an organophosphate active agent, levamisole, a diamidazine active agent, a moxidectin active agent, praziquantel, closantel, pyrantel, morantel, clorsulon, a spinosad active agent, a spinosyn active agent, an aminoacetonitrile active agent, an arylpyrazol-2-yl cyanoethyl active agent or an insect growth regulator.

14. The long-acting injectable composition according to claim 13, wherein the macrolide is abamectin, demaectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554, milbemycin, milbemycin D, moxidectin or nemadectin.

15. Use of the long-acting injectable composition according to any one of claims 1-14 in the preparation of a medicament for the treatment or prevention of parasites in non-human animals, wherein the medicament is administered for 3-6 months.

16. The use according to claim 15, wherein the animal is a dog, a cat, a sheep or a cow.

17. The use according to claim 15, wherein the parasites are treated or prevented for about 5-6 months.

18. The use according to claim 15, wherein the parasites are fleas and / or ticks.

19. An insecticidal and parasiticidal isoxazoline compound of formula (Ie) or a pharmaceutically or agriculturally acceptable salt thereof:

20. An insecticidal and parasiticidal (S)-Ie isoxazoline compound or a pharmaceutically or agriculturally acceptable salt thereof:

21. A veterinary parasiticidal composition comprising an effective amount of the isoxazoline compound of formula (Ie) defined in claim 19, or the (S)-(Ie) isoxazoline compound defined in claim 20 and a pharmaceutically acceptable carrier.

22. An insecticidal composition for controlling pests damaging plants or materials derived from wood, comprising an effective amount of the isoxazoline compound of formula (Ie) defined in claim 19, or the (S)-(Ie) isoxazoline compound defined in claim 20 and an agriculturally acceptable carrier.

23. An insecticidal composition for controlling pests damaging plant propagation materials or crops, which comprises an effective amount of an isoxazoline compound of formula (Ie) as defined in claim 19, or an isoxazoline compound of formula (S)-(Ie) as defined in claim 20, and an agriculturally acceptable carrier.

24. An isoxazoline compound of formula (Ie) as defined in claim 19, or an isoxazoline compound of formula (S)-(Ie) as defined in claim 20, for treating or preventing parasite infestations in animals.

25. A method for controlling pests damaging plants or materials derived from wood, the method comprising applying to the plants, the soil in which the plants grow, or the materials derived from wood, an effective amount of an isoxazoline compound of formula (Ie) as defined in claim 19, or an isoxazoline compound of formula (S)-(Ie) as defined in claim 20.

26. A method for controlling pests damaging plant propagation materials or crops, the method comprising applying to the plant propagation materials or crops an effective amount of an isoxazoline compound of formula (Ie) as defined in claim 19, or an isoxazoline compound of formula (S)-(Ie) as defined in claim 20.

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