Parasiticidal collars containing isoxazoline compounds

Abstract

Provided herein is a long-acting antiparasitic device comprising a parasiticidal isoxazoline active agent for external use on the body of an animal to treat and / or prevent ectoparasitic infestations and, in some embodiments, also parasitic infections. The present disclosure also describes methods and uses of the antiparasitic external device for treating and / or preventing parasitic infestations and / or infections in animals.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 128,362, filed December 21, 2020, which is incorporated by reference in its entirety. The present disclosure relates to antiparasitic external devices comprising an antiparasitic isoxazoline active agent. In one embodiment, the present disclosure relates to antiparasitic collars for pets, particularly cats and dogs. The antiparasitic collars of the present invention are active against ectoparasites of these animals, particularly fleas and ticks. The present disclosure also relates to the use of isoxazoline compounds to manufacture such collars or external devices, and to the treatment methods related thereto. [Background technology]

[0002] Animals, such as mammals and birds, are often susceptible to parasitic infestations / infections. These parasites can be ectoparasites, such as fleas, ticks and parasitic flies, and endoparasites, such as nematodes and other helminths. Domestic animals, such as cats and dogs, are often infested with one or more of the following ectoparasites: fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis), - ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., etc.), - mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., etc.), - lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.), Mosquitoes (such as Aedes spp., Culex spp., Anopheles spp.), and - Flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.).

[0003] Fleas are a particular problem because they not only have a negative effect on the health of animals or humans, but also cause a great deal of psychological stress. Moreover, fleas can also transmit disease agents to animals and humans, such as tapeworms (Dipylidium caninum). Similarly, ticks are also 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 both humans and animals. The major diseases that can be transmitted by ticks include borreliosis (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. Sometimes these toxins are fatal to the host.

[0004] Similarly, livestock are also susceptible to infestation by parasites. For example, cattle and other bovine species are affected by many parasites. Parasites widespread among cattle in some areas are ticks of the genus Rhipicephalus, especially the species microplus (cattle tick), decoloratus and annulatus. Ticks such as Rhipicephalus microplus (formerly Boophilus microplus) are difficult to control because they lay their eggs in the pastures where livestock graze. This species of tick is considered a single-host tick, spending its developmental and adult stages on one animal before the female becomes engorged, sheds from the host and lays eggs in the environment. The tick life cycle is approximately 3-4 weeks. In addition to cattle, Ixodes sanguineus microplus infests buffalo, horses, donkeys, goats, sheep, deer, pigs, and dogs. Heavy tick burdens on animals can reduce production, damage the hide, and transmit diseases such as babesiosis ("bovine fever") and anaplasmosis.

[0005] Animals and humans are also plagued by internal parasitic infections including, for example, helminthiasis caused by parasites classified as Cestoda (tapeworms), Nematoda (roundworms) and Trematoda (flatworms or flukes). These parasites adversely affect animal nutrition, causing severe economic losses in pigs, sheep, horses and cattle, as well as affecting companion animals and poultry. Other parasites occurring in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, and parasites found in the blood or other tissues and organs, such as heartworms and extraintestinal stages of Strongyloides, Toxocara, and Trichinella.

[0006] Certain isoxazoline compounds have been demonstrated to be effective against parasites that harm animals. For example, US 7,964,204 (DuPont, the entirety of which is incorporated herein by reference) discloses isoxazoline compounds according to the following formula (I), which are active against ectoparasites and / or endoparasites:

[0007] [ka] (I)

[0008] In addition, published patent application numbers US2010 / 0254960, WO2007 / 070606, WO2007 / 123855, WO2010 / 003923, US2010 / 0137372, US2010 / 0179194, US2011 / 0086886, US2011 / 0059988, US2010 / 0179195, and WO2007 / 075459, as well as U.S. Pat. Nos. 7,951,828 and 7,662,972, all of which are incorporated herein by reference, describe various other parasiticidal isoxazoline compounds. Other published patent applications that describe various other parasiticidal isoxazoline compounds and compositions, including parasiticidal isoxazoline compounds and compositions, include WO2007 / 079162, WO2008 / 154528, WO2009 / 002809, WO2011 / 149749, WO2014 / 439475, U.S. Patent No. 8,466,115, WO2012 / 120399, WO2014 / 039484, WO2014 / 189837 (Zoetis), and WO2012 / 120135 (Novartis). WO2012 / 089623 describes topical isoxazoline compositions that contain glycofurol. WO2013 / 039948 provides topical veterinary compositions comprising at least one isoxazoline active agent, and WO2013 / 119442 provides oral veterinary compositions, such as soft chewable tablets, comprising at least one isoxazoline active agent. In addition to topical and oral dosage forms, solid antiparasitic external devices for external use can be used, where the device comprises a matrix, usually a biologically acceptable polymer matrix capable of incorporating an effective amount of active agent and releasing it over time. Isoxazoline compounds are believed to show low or weak insecticidal activity via contact exposure.Existing cat and dog products containing isoxazoline active agents are in the form of oral dosage forms or transdermal spot-on solutions (e.g., NexGard® (afoxolaner) canine chewables, Bravecto® (fluralaner) chewable tablets, Bravecto® (fluralaner topical solution), Simparica™ (sarolaner) chewables, and Credilio™ (lotilaner) chewable tablets). See, for example, Williams et al. "Fluralaner activity against life stages of ticks using Rhipicephalus sanguineus and Ornithodoros moubat IN in vitro contact and feeding assays," Parasites & vectors, 8(1), p.90. Thus, the availability of potent ectoparasiticidal activity from externally worn devices, such as parasiticidal collars containing isoxazoline active agents, is unexpected. Summary of the Invention

[0009] Despite the existence of highly active isoxazoline active agents and compositions comprising isoxazoline active agents alone or in combination with other active agents described in the literature, there is a need for additional veterinary compositions and methods that provide pet owners with greater flexibility and longer duration of effectiveness for protecting their pets from ectoparasites and, optionally, endoparasites. More specifically, there is a need to develop long-acting external device compositions comprising isoxazoline compounds that are effective against parasites (e.g., fleas and ticks) for extended periods of time (e.g., 3-6 months or longer).

[0010] In a first aspect, the present disclosure provides a novel and unique long acting antiparasitic device for external use, such as an antiparasitic collar comprising an antiparasitic effective amount of at least one isoxazoline active agent for treating and / or preventing parasitic infection and / or infestation in an animal.

[0011] In a second aspect, the present disclosure provides a novel and unique long-acting antiparasitic device for external use, such as an antiparasitic collar comprising an antiparasitic effective amount of Tigoraner for treating parasitic infections and / or infestations in animals. Tigoraner is listed in the BCPC Compendium of Pesticide Common Names (www.bcpc.org) and has acaricidal and insecticidal activity and a mechanism of action similar to isoxazoline compounds. In one embodiment, a solid antiparasitic external device according to the present disclosure contains an effective amount of Tigoraner or Tigoraner derivatives, salts, and analogs for treating and / or preventing parasitic infections and / or infestations in animals.

[0012] A solid anti-parasitic external device according to the present disclosure is, for example, a neck collar, a pendant (medallion) for a neck collar, an ear tag, a collar for attachment to a limb or body part, hi some embodiments, the anti-parasitic external device is a medallion, an ear tag, and, in particular, a neck collar. In some embodiments, the antiparasitic external device according to the present disclosure comprises a polymer matrix containing one or more isoxazoline active agents, optionally in combination with other parasiticidal active agents and, where appropriate, additional auxiliary substances and additives, such that any additional auxiliary substances and additives included in the device are of a different material than the polymer in the polymer matrix of the device.

[0013] The present disclosure further provides methods for treating and / or preventing parasitic infestations, and in some embodiments, parasitic infections, in an animal, comprising applying to the animal an antiparasitic external device of the present invention that allows an active ingredient to be delivered to the animal in effective concentrations over an extended period of time. The provided methods allow for the delivery of effective concentrations of an active ingredient (i.e., active agent) over an extended period of time. In accordance with the first and second aspects of the present disclosure, the long-acting antiparasitic external device compositions of the present invention comprising an isoxazoline active agent, or tigolaner or tigolaner derivatives, salts, and analogs (hereinafter "tigolaner compounds") exhibit long-term efficacy. In addition, a single administration of the antiparasitic external device compositions of the present invention generally provides potent activity against one or more parasites (e.g., ectoparasites) while also providing a long-term activity. The present disclosure encompasses the use or veterinary use of antiparasitic external devices comprising the isoxazoline compounds or tigolaner compounds described herein to treat and / or prevent parasitic infections and / or infestations in or on animals (either wild or domesticated) including livestock and companion animals, such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle, with the goal of ridding these hosts of parasites commonly encountered by such animals.

[0014] The present disclosure also provides methods for administering an isoxazoline active agent or a tigolaner compound to an animal by applying to the animal an antiparasitic external device comprising an effective amount of an isoxazoline active agent or a tigolaner compound, thereby treating or preventing parasitic infection and / or infestation in an animal. Surprisingly, it has been found that the isoxazoline-containing antiparasitic external device compositions (e.g., antiparasitic collars) described herein exhibit superior broad spectrum effectiveness against harmful parasites (e.g., ectoparasites, such as fleas and ticks) over an extended period of time as compared to other compositions containing isoxazoline active agents known in the art or other known antiparasitic external device compositions. The disclosure also provides for the use of an isoxazoline active agent or a tigolaner compound in the preparation of a long-acting antiparasitic external device composition for treating and / or preventing parasitic infestation and / or infection in an animal.

[0015] In one embodiment, the present disclosure provides a method for the preparation of a composition comprising administering to a subject an antiparasitic effective amount of at least one isoxazoline of formula (I) as shown below, or a pharma- ceutical or veterinarily acceptable salt thereof, in an acceptable polymer matrix (Variable 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 defined herein.

[0016] [ka] (I) In another embodiment, the present invention provides a method for the preparation of a parasitically effective amount of an isoxazoline active agent of formula (Ia):

[0017] [ka] (Ia) or a pharma- ceutically acceptable salt thereof in combination with an acceptable polymer matrix. The compound of formula (Ia) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (INN afoxolaner). In another embodiment, the present disclosure provides an isoxazoline compound of formula (Ic):

[0018] [ka] or a pharma- ceutically acceptable salt thereof (wherein, X 1 , X 2 and X3 are each independently H, halogen, or C 1 -C 3 Alkyl or C 1 -C 3 In another embodiment, the present invention provides a long-acting antiparasitic external device comprising a compound of formula (Ic), wherein X is a cyclic alkyl group, and X is a cyclic alkyl group. In another embodiment, the present invention provides a long-acting antiparasitic external device comprising a compound of formula (Ic), wherein X is a cyclic alkyl group, and X is a cyclic alkyl group. 1 is chloro and X 2 is fluoro and X 3 CF 3 The present invention provides an antiparasitic external device comprising: In another embodiment, the present invention provides a method for the preparation of a parasitically effective amount of an isoxazoline active agent of formula (Id):

[0019] [ka] (Id) or a pharma- ceutically or veterinarily acceptable salt thereof in combination with an acceptable polymer matrix.

[0020] In another embodiment, the present invention provides a long-acting antiparasitic external device comprising a parasitically effective amount of an isoxazoline active agent of formula (Ib), (II), (III), (IV), (V), (Va), (VI) or (VIa) as described herein, or a pharma- ceutically acceptable salt thereof, in combination with a suitable polymer matrix. In other embodiments, the long-acting antiparasitic external device composition of the present invention can further comprise one or more additional active agents. In one embodiment, the long-acting antiparasitic external device composition can comprise at least one macrocyclic lactone active agent, including but not limited to avermectin or milbemycin. In some embodiments, the avermectin or milbemycin active agent is eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin. The isoxazoline compounds used in the long-acting antiparasitic external device compositions of the present invention are highly active against arthropod pests and parasites and are useful for protecting animals, including livestock and companion animals, such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle, from parasites that infest or infect such animals.

[0021] It is the object of this disclosure not to encompass within this disclosure, and applicant therefore reserves its rights and hereby discloses a disclaimer of any previously known products, processes, or methods of making a product, or using a product. It is further noted that this disclosure does not intend to encompass within its scope, and applicant therefore reserves its rights and hereby discloses a disclaimer of any previously described products, processes, or methods of making a product, or using a product, that do not meet the written description and enablement requirements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (EPC, Article 83). [Brief description of the drawings]

[0022] [Figure 1] "Confirmation of (S)-Ia in PVC Matrix After Extrusion and Processing" which shows overlaid Fourier transform infrared spectroscopy ("FTIR") spectra of 1) PVC80 matrix, 2) compound (S)-Ia, and 3) PVC80 matrix containing 11% (w / w) compound (S)-Ia after extrusion and processing. [Diagram 2] "Confirmation of (S)-Id in PVC matrix after extrusion and processing" shows overlaid FTIR spectra of 1) PVC80 matrix, 2) compound (S)-Id, and 3) PVC80 matrix containing 11% (w / w) compound (S)-Id after extrusion and processing. [Diagram 3]"Confirmation of (Ia) in PVC matrix after extrusion and processing" shows overlaid FTIR spectra of 1) PVC80 matrix, 2) compound (Ia), and 3) PVC80 matrix containing 11% (w / w) compound (Ia) after extrusion and processing. [Figure 4] 1 shows differential scanning calorimetry ("DSC") curves of Compound (S)-Ia, a PVC matrix, and a PVC collar having Compound (S)-Ia. [Diagram 5] 1 shows drug plasma concentrations for dogs wearing PVC-based isoxazoline collars containing compounds (Ia), (S)-Ia, and (S)-Id. [Figure 6] 1 shows drug concentrations in hair from different parts of a dog after wearing a collar containing Compound (S)-Id for 166 days (comparing drug concentrations in the mid-thorax, lower back or caudal regions, right thorax, left thorax, and upper neck / base of the skull). [Figure 7] 1 shows the DSC curves of an EVA collar with Compound (S)-Ia, an EVA matrix, and Compound (S)-Ia. [Figure 8] 1 shows the DSC curves of a PBSA collar with Compound (S)-Ia, a PBSA matrix, and Compound (S)-Ia. [Figure 9] FIG. 1 shows pharmacokinetic ("PK") data in dogs following wearing collars with various non-PVC polymers containing isoxazoline compound (S)-Ia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present disclosure provides long-acting antiparasitic external devices and device compositions comprising an antiparasitic effective amount of at least one isoxazoline compound and an acceptable polymer matrix for the treatment and / or prevention of parasitic infections and infestations in or on an animal. In a first aspect, the present disclosure provides a novel and inventive long-acting antiparasitic external device composition for treating or preventing a parasitic infection or infestation in an animal comprising an antiparasitic effective amount of at least one isoxazoline compound and one or more excipients and / or an acceptable polymer matrix present as defined herein.

[0024] In one embodiment, the present disclosure provides a novel and original long acting antiparasitic external device for treating or preventing parasitic infection and / or infestation in an animal comprising an antiparasitic effective amount of at least one isoxazoline compound in combination with an antiparasitic effective amount of one or more additional active agents, one or more excipients and / or an acceptable polymer matrix present as defined herein. Also provided are methods and uses for the treatment and / or prevention of parasitic infection and / or infestation in or on an animal in need thereof, comprising administering to an animal in need thereof an antiparasitic external device comprising an antiparasitic effective amount of at least one isoxazoline compound and one or more excipients and an acceptable polymer matrix.

[0025] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one isoxazoline active agent; i) An isoxazoline compound of formula (I):

[0026] [ka] (I) [In the formula, A 1 , A 2 , A 3 , A 4 , A 5 and A 6 Independently, CR 3and N, where A 1 , A 2 , A 3 , A 4 , A 5 and A 6 up to three of them shall be N, B 1 , B 2 and B. 3 Independently, CR 2 and N, W is O or S; R 1 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 6 and Each R 2 are independently H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C6 Alkylamino, C 2 -C 6 Dialkylamino, C 2 -C 4 Alkoxycarbonyl, -CN, -SF 5 OR -NO 2 and Each R 3 are independently H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Halocycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, -CN, -SF 5 OR -NO 2 and R 4 , H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl, C 4 -C 7Cycloalkylalkyl, C 2 -C 7 Alkylcarbonyl or C 2 -C 7 is an alkoxycarbonyl; R 5 H, OR 10 , N.R. 11 R 12 Or Q 1 or C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 7 or R 4 and R 5 together with the nitrogen to which they are attached form a ring containing 2 to 6 carbon atoms and, optionally, one additional atom selected from the group consisting of N, S and O, said ring being 1 -C 2 Alkyl, halogen, -CN, -NO 2 and C 1 -C 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy; Each R 6 are independently halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Alkylsulfonyl, -CN or -NO 2 and Each R 7 are independently halogen or C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 8 Dialkylamino, C 3 -C 6 Cycloalkylamino, C 2 -C 7 Alkyl carbonyl, C 2 -C 7 Alkoxycarbonyl, C 2 -C 7 Alkylaminocarbonyl, C 3 -C 9 Dialkylaminocarbonyl, C 2 -C 7 Haloalkylcarbonyl, C 2 -C 7 Haloalkoxycarbonyl, C 2 -C 7 Haloalkylaminocarbonyl, C 3 -C 9 Dihaloalkylaminocarbonyl, hydroxy, -NH 2 , -CN or -NO 2 or Q 2 and Each R 8 are independently halogen, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, C 2 -C 4 Alkoxycarbonyl, -CN or -NO 2 and Each R 9 are independently halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Halocycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, -CN, -SF 5 , -NO 2 , phenyl or pyridinyl; R 10 is H or C 1 -C 6 Alkyl, C 2 -C 6Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is optionally substituted with one of further halogens; R 11 , H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl, C 4 -C 7 Cycloalkylalkyl, C 2 -C 7 Alkylcarbonyl or C 2 -C 7 is an alkoxycarbonyl; R 12 is either H or Q 3 or C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 7 or R 11 and R 12 together with the nitrogen to which they are attached form a ring containing 2 to 6 carbon atoms and, optionally, one additional atom selected from the group consisting of N, S and O, said ring being1 -C 2 Alkyl, halogen, -CN, -NO 2 and C 1 -C 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy; Q 1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-, or 10-membered fused bicyclic ring system optionally containing 1 to 3 heteroatoms selected from up to 1 O, up to 1 S, and up to 3 N, each ring or ring system being selected from R 8 and Each Q 2 are independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring being 9 and Q 3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring being 9 and n is 0, 1, 2 or 3] or a pharma- ceutically acceptable salt thereof, and / or ii) An isoxazoline compound of formula (II):

[0027] [ka] [In the formula, R 1 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, or cycloalkylalkyl, each of which is unsubstituted or substituted with halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)-, R 7 S(O)2 -, R 7 C(O)-, R 7 R 8 NC(O)-, R 7 OC(O)-, R 7 C(O)O-, R 7 C(O)NR 8 -, -CN or -NO 2 and is substituted with one or more of X is aryl or heteroaryl, which aryl or heteroaryl may be unsubstituted or substituted with halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)-, R 7 S(O) 2 -, R 7 C(O)-, R 7 R 8 NC(O)-, R 7 OC(O)-, R 7 C(O)O-, R 7 C(O)NR 8 -, -CN or -NO 2 may be substituted with one or more of A 1 is oxygen, A 2 is oxygen, NR 2 or CR 7 R 8 and G is G-1 or G-2

[0028] [ka] and B 1 , B 2 , B 3 , B 4 and B. 5 are independently N or CR 9 and Y is hydrogen, halogen, -CN, or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl, each of which is unsubstituted or selected from halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)-, R 7 S(O) 2 -, R 7 C(O)-, R 7 R 8 NC(O)-, R 7 OC(O)-, R 7 C(O)O-, R 7 C(O)NR 8 -, -CN or -NO 2 or Y is substituted with one or more of 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.

[0029] [ka] and R 2 , R 3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, 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)-, R 4, R 5 and R 6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl, or heteroaryl; R 7 and R 8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, or haloalkynyl; R 9 is hydrogen, halogen, -CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, or cycloalkylalkyl, each of which is unsubstituted or selected from halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)-, R 7 S(O) 2 -, R 7 C(O)-, R 7 R 8 NC(O)-, R 7 OC(O)-, R 7 C(O)O-, R 7 C(O)NR 8 -, -CN or -NO 2 and is substituted with one or more of R 10 , R 11 , R 12 and R 13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, or haloalkynyl; R 10 is R 11Together with =O, =S or =NR 2 or R 12 is R 13 Together with =O, =S or =NR 2 Forming W is O, S or NR 2 and n is 1 to 4; m is 0, 1 or 2] or a pharma- ceutically acceptable salt thereof, and / or iii) an isoxazoline compound of formula (III)

[0030] [ka] (III) (INN Fluralaner) or a pharma- ceutically acceptable salt thereof, and / or iv) an isoxazoline compound of formula (IV)

[0031] [ka] (IV) or a pharma- ceutically acceptable salt thereof, and / or v) an isoxazoline compound of formula (V):

[0032] [ka] (V) [In the formula, R 1 , R 2 and R 3 are independently H, Cl, F or CF 3 and Y is a diradical group

[0033] [ka] and T is C 1 -C 6 -alkyl group, 1 -C6 The alkyl group is unsubstituted or substituted with halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 -Alkoxy, C 1 -C 6 -Haloalkoxy, C 1 -C 6 -Alkylthio, C 1 -C 6 -alkylthio, carboxy, carbamoyl or C 2 -C 6 -substituted with an alkanoyl group (which may be unsubstituted or substituted in the alkyl portion with halogen) or a pharma- ceutically acceptable salt thereof, and / or vi) An isoxazoline compound of formula (VI):

[0034] [ka] (VI) wherein Y is hydrogen, fluoro, chloro or bromo; R 1 is phenyl substituted by 2 to 4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or trifluoroethoxy; R 2 is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl, R 3a and R 3b is independently selected from hydrogen, methyl, ethyl, or fluoromethyl, or R 3a and R 3b taken together with the carbons to which they are attached form a cyclopentyl or cyclohexyl ring, or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0035] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ia)

[0036] [ka] (Ia) (INN Afoxolaner) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0037] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ib)

[0038] [ka] (Ib) or a pharma- ceutically acceptable salt thereof [In the formula, R 2 are independently halogen, C 1 -C 6 Alkyl or C 1 -C 6 is haloalkyl, R 4 is H or C 1 -C 6 is alkyl, R 5 is one or more R 7 C which may be substituted with 1 -C 4 is alkyl, R7 is C 2 -C 7 Alkyl carbonyl, C 2 -C 7 Alkoxycarbonyl, C 2 -C 7 Alkylaminocarbonyl, C 3 -C 9 Dialkylaminocarbonyl, C 2 -C 7 Haloalkylcarbonyl, C 2 -C 7 Haloalkoxycarbonyl, C 2 -C 7 Haloalkylaminocarbonyl, C 3 -C 9 Dihaloalkylaminocarbonyl (e.g., -CH 2 C(O)NHCH 2 CF 3 ) where n is 0, 1 or 2; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0039] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic)

[0040] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, X 1 , X 2 and X 3 are each independently H, halogen, or C 1 -C 3 Alkyl or C 1 -C 3 haloalkyl], b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0041] In one embodiment, the long-acting antiparasitic external device of the present disclosure comprises a compound of formula (Ic), 1 and X 3 are independently halogen; X 2 is hydrogen). In another embodiment, the long-acting antiparasitic external device of the present disclosure comprises a compound of formula (Ic), 1 , X 2 and X 3 are each independently a halogen. In another embodiment of the present disclosure, the long-acting antiparasitic external device comprises a compound of formula (Ic), 1 and X 3 are each independently a halogen; X 2 is C 1 -C 3 haloalkyl). In yet another embodiment, the present disclosure provides a compound of formula (Ic), 1 and X 2 are independently halogens, and X 3 is C 1 -C 3 The present invention provides a long-acting antiparasitic external device comprising a compound comprising:

[0042] In another embodiment, the present disclosure provides a compound of formula (Ic), 1 and X 2 are independently halogens, and X 3 CF 3 The present invention provides a long-acting antiparasitic external device comprising: In another embodiment, the present disclosure provides a compound of formula (Ic), 1 and X 3 is chloro and X 2is hydrogen). In yet another embodiment, the present disclosure provides a compound of formula (Ic), 1 is chloro and X 2 is fluoro and X 3 CF 3 The present invention provides a long-acting antiparasitic external device comprising: In another embodiment, the present disclosure provides a compound of formula (Ic), 1 and X 3 is chloro and X 2 is fluoro). In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic)

[0043] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, X 1 and X 3 are each independently a halogen or C 1 -C 3 is haloalkyl, X 2 is a halogen or hydrogen; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0044] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infections and infestations in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above; or a pharma- ceutically acceptable salt thereof (In the formula, X 1 and X 2 are each independently chloro or fluoro; X 3 is chloro or CF 3 ) and b) an acceptable polymer matrix; c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0045] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharma- ceutically acceptable salt thereof; (In the formula, X 1 and X 3 are chloro, X 2 is fluoro or hydrogen; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0046] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above; or a pharma- ceutically acceptable salt thereof (In the formula, X 1 is chloro, X 2 is fluoro, X 3 CF 3 ) and b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0047] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above, or a pharma- ceutically acceptable salt thereof; (In the formula, X 1 and X 3 is chloro, X 2 is fluoro) and b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0048] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above; or a pharma- ceutically acceptable salt thereof (In the formula, X 1 , X 2 and X 3 are chloro), and b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Ic) as shown above; or a pharma- ceutically acceptable salt thereof (In the formula, X 1 , X 2 and X 3 are each independently chloro or fluoro; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0049] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula (Id)

[0050] [ka] (Id) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0051] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula (II) as described above, or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of the formulae II-1.001 to II-1.025 or II-2.001 to II-2.018

[0052] [ka]

[0053] [Table 1]

[0054] [ka]

[0055] [Table 2] or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0056] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula II-1.001 to II-1.025 or II-2.001 to II-2.018 as defined above, or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally with a pharma- ceutically acceptable additive, excipient or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0057] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (III)

[0058] [ka] (III) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (IV)

[0059] [ka] (IV) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one isoxazoline compound of formula (V);

[0060] [ka] (V) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of an isoxazoline compound of formula (Va)

[0061] [ka] (Va) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one compound of formula (VI)

[0062] [ka] (VI) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one compound of formula (VIa)

[0063] [ka] or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0064] In another embodiment, the present disclosure provides a long-acting antiparasitic external device for the treatment and / or prevention (prophylaxis) of parasitic infection and / or infestation in or on an animal, comprising: a) an antiparasitic effective amount of at least one compound of formula (VII)

[0065] [ka] (VII) (INN: Chigoranel) or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, at least one pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0066] stereoisomer The compounds of formula (I) through formula (VIa) shown above can exist as stereoisomers, and each individual stereoisomer that exists is encompassed by the structural formula shown herein. When a compound within the composition of the present disclosure contains n chiral centers, the compound is a chiral compound having 2 n The present disclosure encompasses compositions that include a mixture of different enantiomers and / or diastereomers of the disclosed compounds that possess the specific enantiomers or diastereomers of each compound, as well as the useful properties described herein. In addition, the present disclosure encompasses compositions that include one or more conformational isomers (e.g., rotamers) as well as mixtures of conformational isomers. Conformational isomers of isoxazoline compounds can be generated, for example, by restricting rotation around an amide bond attached to an aryl or heteroaryl ring (e.g., the amide attached to the naphthyl group in formula (I)). For the avoidance of 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 formulae depicted herein, without expressly including the stereochemical configuration, encompass each of the possible stereoisomers. Those skilled in the art understand that one stereoisomer of an active isoxazoline compound may be more active and / or exhibit beneficial properties compared to the other enantiomer. In addition, 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 five-membered isoxazoline ring (indicated by an asterisk (*) in the structure below). Thus, the compound contains at least two possible stereoisomers. As an example for a compound of formula (Ia), the two possible stereoisomers generated from the quaternary carbon are represented by formulas (S)-Ia and (R)-Ia:

[0067] [ka] is shown as:

[0068] The compounds of formula (S)-Ia above have an (S) configuration at the chiral carbon atom, and the compounds of formula (R)-Ia have an (R) configuration. The depictions of molecules depicted herein follow standard conventions for depicting stereochemistry. To indicate configuration, bonds that extend out of the plane of the drawing toward the viewer are represented by solid wedges, with the wider end of the wedge attached to an atom that extends out of the plane of the drawing toward the viewer. Bonds that run away from the viewer, down the plane of the drawing, are represented by dashed wedges, with the narrower end of the wedge attached to an atom further away from the viewer. Lines of constant width indicate bonds that have an opposite or intermediate orientation compared to the bonds shown as solid or dashed wedges. Lines of constant width also represent bonds in molecules or portions of molecules, where no particular configuration is intended to be specified. Optically active forms of the isoxazoline compounds can be prepared by methods known in the art, for example, by resolution of racemates by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using chiral stationary phases, or by enzymatic resolution.

[0069] In addition to the compound of formula (Ia), it is recognized that other isoxazoline compounds of formula (I), (Ib), (Ic), (Id), (II), (II-1.1001) to (II-1.025), (II-2.001) to (II-2.018), (III), (IV), (V), (Va), (VI) and (VIa) also have at least two possible enantiomers as a result of the quaternary carbon atom on the isoxazoline ring. In addition, a compound may contain other chiral centers in one or more substituents, resulting in diastereomers. In one embodiment of the disclosure, the more biologically active enantiomer is believed to be of formula (S)-Ia (this is based on previous studies of the parasiticidal efficacy of the enantiomers of the compound of formula (Ia) in other product types, e.g., oral, injectable, and spot-on compositions, and is understood to be so). In one embodiment of the disclosure, the more biologically active enantiomer is of formula (S)-Ia. Similarly, the more biologically active enantiomers of the isoxazoline compounds of formulae (Ib), (Ic), (Id), and (II)-(VIa) are believed to have the (S) configuration at the chiral carbon of the isoxazoline ring. In certain embodiments, the isoxazoline compounds of the disclosure, or compositions comprising the compounds, are enantiomer-enriched (eutomers) that exhibit significant in vitro and in vivo activity with a favorable toxicity profile compared to other corresponding enantiomer-enriched compounds or compositions (distomers) that exhibit significantly lower in vitro and in vivo activity.

[0070] When an enantiomer is enriched, one enantiomer is present in greater amount than the other, and the extent of enrichment can be defined in terms of enantiomeric excess ("ee"), which is defined as (2x-1)·100%, where x is the molar fraction of the predominant enantiomer in the mixture (e.g., 20% ee corresponds to a 60:40 ratio of enantiomers). In some embodiments, the compositions of the present disclosure include compounds having an enantiomeric excess of at least 50%. In other embodiments, the compositions of the present disclosure include compounds having an enantiomeric excess of at least 75%, an enantiomeric excess of at least 90%, or an enantiomeric excess of at least 94% of the more active isomer. Of special note are enantiomerically pure embodiments of the more active isomer (eutomers).

[0071] The present disclosure includes racemic mixtures, e.g., isoxazoline compounds of formulas (I)-(VIa) in equal amounts of the enantiomers. The present disclosure also includes compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001)-(II-1.025), (II-2.001)-(II-2.018), (III), (IV), (V), (Va), (VI) or (VIa) that are enriched in one enantiomer as compared to the racemic mixture. Also included are essentially pure enantiomers of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) to (II-1.025), (II-2.001) to (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa).

[0072] Thus, in one embodiment, the long-acting antiparasitic external device of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa) that is substantially enriched in one enantiomer, or a pharma- ceutically acceptable salt thereof. The term "substantially enriched" means that the compound is enriched in the desired enantiomer in a weight:weight ratio of at least about 1.5 or higher. In another embodiment, the long acting compositions of the present disclosure comprise at least one isoxazoline compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa) enriched in one enantiomer in 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), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa), or a pharma- ceutically acceptable salt thereof, enriched in one enantiomer in a weight:weight ratio of at least 15:1 or at least 20:1. In one embodiment, the isoxazoline compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa) present in the composition of the present disclosure is an essentially pure enantiomer.

[0073] In another embodiment of the disclosure, a composition comprises a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa), wherein the compound is enriched in the (S)-enantiomer in a weight:weight ratio of at least about 1.5:1 or 2:1. In yet another embodiment, the compositions of the present disclosure comprise a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI), or (VIa), which is enriched in the (S)-enantiomer in a weight:weight ratio of at least about 5:1 or greater. In yet another embodiment, the compositions of the present disclosure comprise a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa), which is enriched in the (S)-enantiomer in a mass:mass ratio of at least about 10:1, 20:1, or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II-1.1001) through (II-1.025), (II-2.001) through (II-2.018), (III), (IV), (V), (Va), (VI) or (VIa), which is an essentially pure (S)-enantiomer.

[0074] In one embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) that is substantially enriched in the enantiomer. In another embodiment, the long-acting antiparasitic external device of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) that is substantially enriched in the (S)-enantiomer. In another embodiment, the long-acting solid antiparasitic external device of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) that is substantially enriched in the (R)-enantiomer.

[0075] In another embodiment of the present disclosure, the composition comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) enriched in the (S)-enantiomer at a mass:mass ratio of at least about 1.5:1 or 2:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) enriched in the (S)-enantiomer at a mass:mass ratio of at least about 5:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) enriched in the (S)-enantiomer at a mass:mass ratio of at least about 10:1, 20:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) that is essentially the pure (S)-enantiomer.

[0076] In another embodiment of the present disclosure, the composition comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) enriched in the (R)-enantiomer at a mass:mass ratio of at least about 2:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) enriched in the (R)-enantiomer at a mass:mass ratio of at least about 5:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) enriched in the (R)-enantiomer at a mass:mass ratio of at least about 10:1, 20:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) that is essentially the pure (R)-enantiomer.

[0077] In another embodiment of the present disclosure, the composition comprises a compound of formula (II), (II-1.1001) to (II-1.025), (II-2.001) to (II-2.018), (III), (IV), (V), (Va), (VI), or (VIa), which is enriched in the (R)-enantiomer in a mass:mass ratio of at least about 2:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (II), (II-1.1001) to (II-1.025), (II-2.001) to (II-2.018), (III), (IV), (V), (Va), (VI), or (VIa), which is enriched in the (R)-enantiomer in a mass:mass ratio of at least about 5:1 or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (II), (II-1.1001) to (II-1.025), (II-2.001) to (II-2.018), (III), (IV), (V), (Va), (VI), or (VIa), which is enriched in the (R)-enantiomer at a mass:mass ratio of at least about 10:1, 20:1, or greater. In yet another embodiment, the composition of the present disclosure comprises a compound of formula (II), (II-1.1001) to (II-1.025), (II-2.001) to (II-2.018), (III), (IV), (V), (Va), (VI), or (VIa), which is essentially the pure (R)-enantiomer.

[0078] In another embodiment, the long-acting antiparasitic external device of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline disclosed in WO2007 / 079162, WO2007 / 075459 and US2009 / 0133319, WO2007 / 070606 and US2009 / 0143410, WO2009 / 003075, WO2009 / 002809, WO2009 / 024541, WO2005 / 085216 and US2007 / 0066617, WO2008 / 122375, WO2014 / 439475 and WO2012120135, all of which are incorporated by reference in their entirety herein.

[0079] In yet another embodiment, the long-acting antiparasitic external device of the present disclosure comprises an antiparasitic effective amount of at least one isoxazoline compound described in WO2009 / 02451 and WO2011 / 075591, both of which are incorporated herein by reference in their entireties.

[0080] In one embodiment, the compositions of the present disclosure can comprise from about 0.5 to about 50% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI), or (VIa), or a pharma- ceutically acceptable salt thereof, as a racemic mixture or enantiomerically enriched as described above. In another embodiment, the compositions of the present disclosure can comprise from about 1 to about 40% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI), or (VIa), or a pharma- ceutically acceptable salt thereof. In yet another embodiment, the compositions of the present disclosure can comprise about 1 to about 30% (w / w), about 1 to about 20% (w / w), or about 1 to about 15% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI), or (VIa), or a pharma- ceutically acceptable salt thereof. In another embodiment, the compositions of the present disclosure can comprise about 0.5 to about 10% (w / w), or about 0.5% to about 5% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI), or (VIa), or a pharma- ceutically acceptable salt thereof.

[0081] In another embodiment, the composition of the present disclosure can comprise about 5 to about 40% (w / w) or about 5 to about 30% (w / w) of an isoxazoline active agent described herein, or a pharma- ceutically acceptable salt thereof. In another embodiment, the composition can comprise about 10% to about 40% (w / w) of an isoxazoline active agent described herein, or a pharma- ceutically acceptable salt thereof. In yet another embodiment, the composition of the present disclosure can comprise about 15% to about 40% (w / w), about 15% to about 35% (w / w), or about 15% to about 30% (w / w) of an isoxazoline compound, or a pharma- ceutically acceptable salt thereof. In embodiments, the long-acting solid antiparasitic external device of the present disclosure comprises one or more of the compounds and compositions described above.

[0082] In certain embodiments, the present disclosure provides a long-acting, solid, anti-parasitic external device for treating and / or preventing parasitic infection and infestation in or on an animal, comprising: a) about 0.5-50% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting solid anti-parasitic external device comprising:

[0083] In another embodiment, the present disclosure provides: a) about 0.5-40% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0084] In another embodiment, the present disclosure provides: a) about 0.5-30% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0085] In another embodiment, the present disclosure provides: a) about 0.5-20% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device for treating and / or preventing parasitic infection and infestation in or on an animal, comprising: In certain embodiments, the present disclosure provides: a) about 5-40% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device for treating and / or preventing parasitic infection and infestation in or on an animal, comprising:

[0086] In another embodiment, the present disclosure provides: a) about 5-30% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0087] In another embodiment, the present disclosure provides: a) about 10-40% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0088] In another embodiment, the present disclosure provides: a) about 15-40% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0089] In another embodiment, the present disclosure provides: a) about 15-30% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising:

[0090] In another embodiment, the present disclosure provides: a) about 20-50% (w / w) of an isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., any of the compounds of formulae I-VIa described above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device comprising: In certain embodiments, the present disclosure provides: a) about 5 to about 50% (w / w) of an isoxazoline activator of formula (Ia) (e.g., a compound of formula I-VIa), such as a compound of the formula:

[0091] [ka] (In the formula, X 1 , X 2 and X 3 are independently chloro, fluoro or CF 3 is)

[0092] [ka] (In the formula, X 1 , X 2 and X 3 are independently chloro, fluoro or CF 3 is)

[0093] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0094] In certain embodiments, the present disclosure provides: a) about 1 to 40% (w / w) of an isoxazoline activator of formula (Ia), (S)-Ia, (Ic), (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof, b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0095] In another embodiment, the present disclosure provides: a) about 1 to 30% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3(Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0096] In another embodiment, the present disclosure provides: a) about 1 to 20% (w / w) of a compound of formula (Ia), (S)-Ia, (Ic), (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0097] In another embodiment, the present disclosure provides: a) about 1 to 15% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein 1 is chloro and X 2 is fluoro and X 3 CF 3(S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0098] In another embodiment, the present disclosure provides: a) about 5 to 15% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0099] In certain embodiments, the present disclosure provides: a) about 5 to 20% (w / w) of formula (S)-Ia or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0100] In another embodiment, the present disclosure provides: a) about 10 to 30% (w / w) of formula (S)-Ia or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0101] In another embodiment, the present disclosure provides: a) about 10 to 40% (w / w) of formula (S)-Ia or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0102] In other embodiments, the present disclosure provides: a) about 0.5 to about 50% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharma- ceutically acceptable salt thereof, as a racemic mixture or enantiomerically enriched as described above; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0103] In another embodiment, the present disclosure provides: a) about 1% to about 40% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising: In yet another embodiment, the present disclosure provides: a) about 1 to about 30% (w / w), about 1 to about 20% (w / w), or about 1 to about 15% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0104] In another embodiment, the present disclosure provides: a) about 0.5% to about 10% (w / w) or about 0.5% to about 5% (w / w) of an isoxazoline active agent of any of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0105] In another embodiment, the present disclosure provides: a) about 5 to about 40% (w / w), or about 5 to about 30% (w / w) of an isoxazoline active agent, or a pharma- ceutically acceptable salt thereof, as described herein; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0106] In another embodiment, the present disclosure provides: a) about 10% to about 40% (w / w) of an isoxazoline active agent described herein, or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0107] In yet another embodiment, the present disclosure provides: a) about 15% to about 40% (w / w), about 15% to about 35% (w / w), or about 15% to about 30% (w / w) of an isoxazoline compound, or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, comprising:

[0108] Another embodiment of the present disclosure is a) an antiparasitic effective amount of at least one isoxazoline active agent, such as 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 specified in this application; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting anti-parasitic external device for treating and / or preventing parasitic infection and infestation in or on an animal, the device consisting essentially of:

[0109] In another embodiment, the present disclosure provides: a) about 1 to 40% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0110] In another embodiment, the present disclosure provides: a) about 1 to 30% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0111] In another embodiment, the present disclosure provides: a) about 1 to 20% (w / w) of a compound of formula (Ia), (S)-Ia, (Ic), (wherein 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0112] In another embodiment, the present disclosure provides: a) about 1 to 15% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein 1 is chloro and X 2 is fluoro and X 3 CF 3 (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0113] In another embodiment, the present disclosure provides: a) about 5 to 15% (w / w) of a compound of formula (Ia), (S)-Ia, or (Ic) (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3(Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; a) an acceptable polymer matrix; b) c) optionally from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0114] In certain embodiments, the present disclosure provides: a) about 5 to 20% (w / w) of formula (S)-Ia or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Id (as shown above) an isoxazoline active agent, or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0115] In another embodiment, the present disclosure provides: a) about 10 to 30% (w / w) of formula (S)-Ia or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of: In another embodiment, the present disclosure provides: a) about 10 to 40% (w / w) of formula (S)-Ia or (S)-Ic (wherein X 1 is chloro and X 2 is fluoro and X 3 CF 3 or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 5% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0116] Another embodiment of the present disclosure is a) an antiparasitic effective amount of at least one isoxazoline active agent, such as any of the isoxazoline compounds provided in the above embodiments (e.g., compounds of formulae I-VIa), and optionally at least one further active agent specified in this application; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; and / or a long-acting antiparasitic external device for treating and / or preventing parasitic infection and infestation in or on an animal, comprising:

[0117] In another embodiment, the present disclosure provides: a) about 1-40% (w / w) of an isoxazoline active agent of formula (Ia), (S)-Ia, (Ic) (wherein X1 is chloro, X2 is fluoro and X3 is CF3); or (S)-Ic (wherein X1 is chloro, X2 is fluoro and X3 is CF3) (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0118] In another embodiment, the present disclosure provides: a) about 1-30% (w / w) of an isoxazoline active agent of formula (Ia), (S)-Ia, (Ic) (wherein X1 is chloro, X2 is fluoro and X3 is CF3); or (S)-Ic (wherein X1 is chloro, X2 is fluoro and X3 is CF3), (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0119] In another embodiment, the present disclosure provides: a) about 1-20% (w / w) of an isoxazoline active agent of formula (Ia), (S)-Ia, (Ic) (wherein X1 is chloro, X2 is fluoro and X3 is CF3); or (S)-Ic (wherein X1 is chloro, X2 is fluoro and X3 is CF3); (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0120] In another embodiment, the present disclosure provides: a) about 1-15% (w / w) of an isoxazoline active agent of formula (Ia), (S)-Ia, (Ic), (wherein X1 is chloro, X2 is fluoro and X3 is CF3); (S)-Ic (wherein X1 is chloro, X2 is fluoro and X3 is CF3); (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0121] In another embodiment, the present disclosure provides: a) about 5-15% (w / w) of an isoxazoline active agent of formula (Ia), (S)-Ia, (Ic), (wherein X1 is chloro, X2 is fluoro and X3 is CF3); (S)-Ic (wherein X1 is chloro, X2 is fluoro and X3 is CF3); (Id) or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0122] In certain embodiments, the present disclosure provides: a) about 5-20% (w / w) of an isoxazoline active agent of formula (S)-Ia, (S)-Ic (wherein X1 is chloro, X2 is fluoro, and X3 is CF3); or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0123] In another embodiment, the present disclosure provides: a) about 10-30% (w / w) of an isoxazoline active agent of formula (S)-Ia, (S)-Ic (wherein X1 is chloro, X2 is fluoro, and X3 is CF3); or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of: In another embodiment, the present disclosure provides: a) about 10-40% (w / w) of an isoxazoline active agent of formula (S)-Ia, (S)-Ic (wherein X1 is chloro, X2 is fluoro, and X3 is CF3); or (S)-Id (as shown above), or a pharma- ceutically acceptable salt thereof; b) an acceptable polymer matrix; and c) optionally, from about 1% to about 50% (w / w) of one or more plasticizers; d) optionally, from about 0.01% to about 5.0% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof; The present invention provides a long-acting antiparasitic external device for the treatment and / or prevention of parasitic infections and infestations in or on an animal, consisting essentially of:

[0124] In this disclosure and in the claims, terms such as "comprises," "comprising," "containing," and "having" may have the meaning ascribed to them under U.S. Patent Law and may mean "includes," "including," and the like. "Consisting essentially of" or "consisting essentially of" likewise have the meaning ascribed to them under U.S. Patent Law, where the term is open ended and allows for the presence of more than what is recited, so long as the basic or novel characteristics recited are not altered by the presence of more than what is recited, but excludes prior art embodiments. The term "consisting of" excludes any element, step, or ingredient not specified in the claim.

[0125] definition Terms used herein have their conventional meaning in the art unless otherwise specified. In the definitions of the variables of formula (I), the organic moieties described are generic to the individual enumerations of the members of the individual groups, such as the term halogen. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group. The term "animal" is used herein to include all mammals, birds, and fish, and to include all vertebrate animals. Animals include, but are not limited to, cats, dogs, cows, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. Animals also include individual animals in all stages of development, including fetal and fetal stages. In some embodiments, the animal is a non-human animal.

[0126] The term "effective amount" as used herein means a concentration of active agent in a composition sufficient to induce a desired biological response against a target parasite, as measured by methods known in the art and / or described in the Examples herein, following administration of the composition to an animal. In some embodiments, an "effective amount" of an active agent in a composition results in at least 70% efficacy against a target parasite compared to an untreated control. In other embodiments, an "effective amount" of an active agent results in at least 80% or at least 85% efficacy compared to an untreated control. More typically, an "effective amount" of an active agent results in at least 90%, at least 93%, at least 95% or at least 97% efficacy against a target parasite. In certain embodiments, the term "effective amount" can result in up to 100% efficacy.

[0127] In certain embodiments, the term "effective amount" includes providing a peak mean plasma concentration (Cmax) of the active agent. In certain embodiments, the disclosed invention provides a Cmax of the active agent of at least 50 ng / mL. In other embodiments, the disclosed invention provides a Cmax of the active agent of at least 10 or at least 20 ng / mL. In other embodiments, the disclosed invention provides a Cmax of the active agent of at least 15, at least 25, at least 30, at least 35, at least 40, or at least 45 ng / mL. The terms "treating" or "treat" or "treatment" are intended to mean administering a long-acting antiparasitic external device of the present disclosure to an animal having a parasitic infestation, in order to eradicate the parasites or reduce the number of parasites infesting the animal being treated. It is noted that the antiparasitic external device of the present disclosure can be used to prevent such parasitic infestations.

[0128] The terms "prevent", "prevention" or "prophylaxis" are intended to mean administering a long-acting antiparasitic external device of the present disclosure to an animal before a parasitic infection or infestation occurs to avoid said infection or infestation from occurring. Prevention can also mean effectively killing a parasite before it can reproduce, thereby effecting long-term control of said parasite. Administration of a long-acting antiparasitic external device at recommended regular intervals effectively prevents new parasitic infestations or infections in the animal by killing new parasites that attack the animal before they can multiply and establish an infestation or infection.

[0129] The term "external device" refers to a solid composition comprising at least one polymeric matrix suitable for external attachment to an animal, for example, around the neck of the animal, as a collar, or as an ear tag. An "antiparasitic external device" contains one or more antiparasitic active agents within the device. In some embodiments, the polymeric matrix can optionally contain other excipients, including, but not limited to, one or more plasticizers, one or more stabilizers, one or more antioxidants, one or more lubricants, one or more fillers, one or more colorants, and the like. An external device can also contain a mixture of different polymeric matrices. The term "acceptable polymer matrix" refers to a matrix of polymers or mix of polymers that is safe for use on companion animals as an externally worn device. An acceptable polymer matrix is ​​suitably flexible to allow attachment to a companion animal. Antiparasitic collars are well known in the art, and an acceptable polymer matrix can utilize known polymers used in commercially available antiparasitic collars. In other embodiments, an acceptable polymer matrix can contain a polymer or mixture of polymers that are not typically used in commercially available antiparasitic collars, but are safe for administration to companion animals. The term "essentially 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% or more pure.

[0130] The term "alkyl" refers to a saturated straight chain, branched, primary, secondary, or tertiary hydrocarbon, including those having 1 to 20 carbon atoms. In some embodiments, an alkyl group is a C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 Or C 1 -C 4 Contains alkyl groups. 1 -C10 Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl, and decyl and their isomers. 1 -C 4 -Alkyl means for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[0131] Cyclic alkyl groups or "cycloalkyl" include those having 3 to 10 carbon atoms with a single fused ring or multiple fused rings. In some embodiments, the cycloalkyl group includes C 4 -C 7 Or C 3 -C 4 Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0132] The alkyl groups described herein may be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoric acid, phosphate, phosphonate, or any other available functional group that does not interfere with the biological activity of the compounds of the present disclosure, either unprotected or optionally protected, known to those of skill in the art, e.g., as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, incorporated herein by reference.

[0133] Terms containing the term "alkyl," such as "alkylcycloalkyl," "cycloalkylalkyl," "alkylamino," or "dialkylamino," are considered to include an alkyl group, as defined above, bound to another functional group, which is bound to a compound via the last group listed, as would be understood by one of skill in the art.

[0134] The term "alkenyl" refers to both straight and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group includes C 2 -C 20 In another embodiment, the alkenyl group is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6Or C 2 -C 4 Alkenyl groups include those having 1 to 3 double bonds in one embodiment of alkenyl, and 1 or 2 double bonds in another embodiment of alkenyl. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated, depending on the location of the alkenyl moiety on the molecule. 2 -C 10"-alkenyl" groups can contain more than one double bond in the chain. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl;1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl- 2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl dimethyl-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;

[0135] "Alkynyl" refers to both straight and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3. In another embodiment of alkynyl, the number of triple bonds is 1 or 2. In some embodiments, an alkynyl group is a C 2 -C 20 In another embodiment, the alkynyl group is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 Or C 2 -C 4 Depending on the location of the alkenyl moiety on the molecule, other ranges of carbon-carbon triple bonds and carbon numbers are also envisioned. For example, "C 2 -C 10The term "alkynyl" as used herein means a straight-chain or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as, for example, 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.

[0136] The term "haloalkyl" refers to an alkyl group (as defined herein) that is substituted with one or more halogen atoms. For example, C 1 -C 4-Haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and the like.

[0137] The term "haloalkenyl" refers to an alkenyl group, as defined herein, substituted with one or more halogen atoms. The term "haloalkynyl" refers to an alkynyl group, as defined herein, substituted with one or more halogen atoms.

[0138] "Alkoxy" refers to alkyl-O-, where alkyl is as defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "halocycloalkoxy" and "halocycloalkenyloxy" refer to 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. 1 -C 6 Examples of -alkoxy include, but are not limited to, methoxy, ethoxy, C 2 H 5 -CH 2 O-, (CH 3 ) 2CHO-, n-butoxy, C 2 H 5 -CH(CH 3 )O-, (CH 3 ) 2 CH-CH 2 O- 、 (CH 3 ) 3 CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, and the like.

[0139] The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above. Similarly, the terms "haloalkylthio", "cycloalkylthio", and the like refer to haloalkyl-S- and cycloalkyl-S-, where haloalkyl and cycloalkyl are as defined above. The term "alkylsulfinyl" refers to alkyl-S(O)-, where alkyl is as defined above. Similarly, the term "haloalkylsulfinyl" refers to haloalkyl-S(O)-, where haloalkyl is as defined above. The term "alkylsulfonyl" refers to alkyl-S(O) 2 -, where alkyl is as defined above. Similarly, the term "haloalkylsulfonyl" refers to haloalkyl-S(O) 2 -, where haloalkyl is as defined above. The terms alkylamino and dialkylamino include alkyl-NH- and (alkyl) 2N-, where alkyl is as defined above. Similarly, the term "haloalkylamino" refers to haloalkyl-NH-, where haloalkyl is as defined above.

[0140] The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, where alkyl, alkoxy, alkylamino and dialkylamino are defined above. Similarly, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl" and "dihaloalkylaminocarbonyl" refer to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)-, where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are defined above.

[0141] "Aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple condensed rings. In some embodiments, an aryl group includes C 6 -C 10Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphtyl, phenylcyclopropyl, and indanyl. Aryl groups can be unsubstituted or substituted with halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkenyl. and optionally substituted with one or more moieties selected from alkylthio, 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.

[0142] The term "aralkyl" or "arylalkyl" refers to an aryl group (-CH) attached through an alkylene bridge to a parent diradical. 2 -) n wherein n is 1 to 12, and "aryl" is defined above.

[0143] "Heteroaryl" refers to a monovalent aromatic group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and 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 be oxidized. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed 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, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolylbenzofuranyl, and benzothiophenyl. Heteroaryl rings can be unsubstituted or substituted with one or more moieties as described for aryl above.

[0144] "Heterocyclyl", "heterocycle" or "heterocyclo" refers to a fully 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 a 10- to 15-membered tricyclic ring system, which has one or more oxygen, sulfur or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, in the ring. The nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more moieties as described above for the aryl group.

[0145] 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-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like. Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (e.g., furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0146] Halogen refers to fluorine, chlorine, bromine, and iodine atoms. The designation "halo" (e.g., as exemplified by the term haloalkyl) refers to all degrees of substitution from single to perhalo substitution (e.g., methyl is used to give chloromethyl (-CH 2Cl), dichloromethyl (-CHCl 2 ), trichloromethyl (-CCl 3 ) as exemplified in The term "enriched" means that the mass:mass ratio is at least about 1.05 or higher in favor of the enantiomer, which exhibits significant in vitro and in vivo activity (eutomer).

[0147] salt Where appropriate, the acid or base salts of the disclosed compounds provided herein are also contemplated within the scope of the disclosure. The term "acid salt" contemplates salts of compounds with any pharma- ceutically acceptable inorganic or organic acid. Inorganic acids include mineral acids, such as hydrohalic acids, e.g., hydrobromic and hydrochloric acids, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include any pharma-ceutically acceptable aliphatic, alicyclic, and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, and fatty acids. In one embodiment of the acid, the acid is a linear or branched, saturated or unsaturated C 1 -C 20 Aliphatic carboxylic acids (optionally substituted with halogen or hydroxyl groups) or C 6 -C 12 Aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-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 pharma- ceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid, and lactobionic acid.

[0148] The term "base salt" contemplates salts of the compound with any pharma- ceutically acceptable inorganic or organic base, including alkali metal or alkaline earth metal hydroxides, carbonates, or bicarbonates. Salts formed with such bases include, for example, alkali metal and alkaline earth metal salts, including, but not limited to, for example, lithium, sodium, potassium, magnesium, or calcium salts. Salts formed with organic bases include common hydrocarbon and heterocyclic amine salts, including, for example, ammonium salts (NH4 + ), alkyl- and dialkylammonium salts, and salts of cyclic amines such as morpholine and piperidine salts. In another embodiment, the long-acting antiparasitic external device of the present disclosure comprises an effective amount of at least one isoxazoline or pharma- ceutically acceptable salt thereof in combination with at least one other active agent. In one embodiment, the long-acting antiparasitic external device comprises an effective amount of at least one isoxazoline compound of Formulas (I)-(VI), or a pharma- ceutically acceptable salt thereof, in combination with at least one other active agent.

[0149] Additional veterinary / pharmaceutical active ingredients Additional veterinary / pharmaceutical active ingredients can be used with the compositions of the present disclosure. In some embodiments, the additional active agents can include, but are not limited to, acaricides, anthelmintics, antiparasitic agents, and insecticides. Antiparasitic agents can include both agents with ectoparasiticidal and / or endoparasiticidal activity.

[0150] Veterinary drugs that can be included in the compositions of the present disclosure are well known in the art (e.g., Plumb's Veterinary Drug Handbook, 5 th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 thEdition, (January 2005)), including, but not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline / thene Ofiline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, amphotericin B lipid-based ampicillin, amprolium, antacids (oral), antitoxins, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate , auranofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin salmon, calcitriol, calcium Salt, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftriaxone sodium, cephalexin, cephalosporin, cephapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide + / - clidinium bromide, chlorothiazide, , chlorpheniramine maleate,Chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine Phosphorus, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, 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, diphenylhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium, calcium EDTA, edrophonium chloride, enalapril / E Naraprilat, Enoxaparin Sodium, Enrofloxacin, Ephedrine Sulfate, Epinephrine, Epoetin / Erythropoietin, Eprinomectin, Epsiplantel, Erythromycin, Esmolol, Estradiol Cypionate, Ethacrynic Acid / Ethacrynic Acid Sodium, Ethanol (Alcohol), Etidronate Sodium, Etodolac, Etomidate, Euthanasia Agents with Pentobarbital, Famotidine, Fatty Acids (Essential / Omega), Felbamate, Fentanyl, Ferrous Sulfate, Filgrastim, Finasteride, Fipronil,Florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine / chondroitin sulfate, glutamine, glyburide, Glycerin (oral), glycopyrrolate, gonadorelin, griseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin, hetastarch, sodium hyaluronate, hydrazarin, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate dipropinate), imipenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alpha-2a (human recombinant), iodide (sodium / potassium), ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin / pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, 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 / methenamine hippurate, methimazole, methionine, methocarbamol,Methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxol, mexiletine, mibolerulone, midazolam milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen, opiate agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opioid antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride chloride), oxymorphone, oxytretracycline, oxytocin, disodium pamidronate, pancrelipase, pancuronium bromide, paromomycin sulfate, parosetin, pencilamine, penicillin by general information, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, feibutazone, phenanthroline ... Nylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphates, phytomenadione / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycans, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, propionibacterium acnes acne) injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic mucilage, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline / osmotic laxative, selamectin, selegiline / L-deprenyl,Sertraline, Sevelamer, Sevoflurane, Silymarin / Milk thistle, Sodium bicarbonate, Sodium polystyrene sulfonate, Sodium stibogluconate, Sodium sulfate, Sodium thiosulfate (sodum thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadimentoxin, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxalin, terbinafline, terbutaline sulfate, testosterone, tetracycline, thiacetalamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, tiamulin, ticarcillin disodium disodium), tiletamine / zolazepam, tilmoxin, tiopronin, tobramycin sulfate, tocainide, tolazoline, terfenamic acid, topiramate, tramadol, trimcinolone acetonide, trientine, trilostane, trimepraxine tartrate with prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide and mixtures thereof.

[0151] In one embodiment of the present disclosure, arylpyrazole compounds known in the art, such as phenylpyrazoles, can be used in combination with isoxazoline compounds in the long-acting antiparasitic external device of the present disclosure.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 (all of which are incorporated herein by reference, each assigned to Merial, Ltd., Duluth, GA).In certain embodiments, the antiparasitic external device can include fipronil.

[0152] In another embodiment of the present disclosure, one or more macrocyclic lactones or lactams that act as acaricides, anthelmintic agents and / or insecticides can be added to the antiparasitic external device compositions of the present disclosure.

[0153] Macrocyclic lactones 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 milbemectin, 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 macrocyclic lactones include, but are not limited to, those described in U.S. Patent Nos. 6,426,333; 6,482,425; 6,962,713, and 6,998,131 (all of which are incorporated herein by reference - each assigned to Merial, Ltd., Duluth, GA).

[0154] Macrocyclic lactone compounds are known in the art and can be easily obtained commercially or through synthesis techniques known in the art. Widely available technical and commercial literature is used as a reference. For avermectins, ivermectins and abamectins, reference can be made, for example, to the study "Ivermectin and Abamectin", 1989, by MH Fischer and H.Mrozik, William C.Campbell, published by Springer Verlag. or Albers-Schonberg et al. (1981), "Avermectins Structure Determination", J. Am. Chem. Soc., 103, 4216-4221. For doramectins, reference can be made to "Veterinary Parasitology", vol.49, No.1, July 1993, 5-15. For the milbemycins, see, inter alia, Davies H. Get 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. Pat. No. 4,134,973; and EP 0 677 054.

[0155] Macrocyclic lactones may be either natural products or their semisynthetic derivatives. The structures of the 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. Pat. No. 4,310,519, and the 22,23-dihydroavermectin compounds are disclosed in U.S. Pat. No. 4,199,569. They are also described in U.S. Pat. Nos. 4,468,390, 5,824,653, EP 0007812, UK Patent Specification 1390336, EP 0002916, and New Zealand Patent No. 237086, among others. The naturally occurring milbemycins are described in U.S. Pat. No. 3,950,360, as well as in "The Merck Index" 12 th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, vol.17, no.4, pp. 263- 286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Pat. 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.

[0156] In another embodiment, the present disclosure includes a long-acting antiparasitic external device composition comprising an isoxazoline compound in combination with a compound from a class of acaricides or insecticides known as insect growth regulators (IGRs). Compounds belonging to this group are well known to physicians and represent a wide range of different chemical classes. All of these compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Pat. Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0179022 or UK 2140010, and U.S. Pat. Nos. 6,096,329 and 6,685,954, all of which are incorporated herein by reference.

[0157] In one embodiment, the IGR is a compound that mimics juvenile hormone. Examples of juvenile hormone mimetics include azadirachtin, diofenolan, fenoxybucarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-3(2H)-one. In one embodiment, the long-acting antiparasitic external device of the present disclosure comprises an effective amount of at least one isoxazoline of Formula (I)-(VIa), or a pharma-ceutically acceptable salt thereof, in combination with methoprene or pyriproxyfen.

[0158] In another embodiment, the IGR compound is a chitin synthesis inhibitor, including chlorfluazuron, cilamadine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, triflumuron, novaluron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0159] In yet another embodiment of the present disclosure, adult control insecticides and acaricides can also be added to the long-acting antiparasitic external device of the present disclosure. These include pyrethrins (including cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II, and mixtures thereof) and pyrethroids, as well as carbamates, including but not limited to benomyl, carbanolate, carbaryl, carbofuran, methiocarb, metolcarb, promacyl, propoxur, aldicarb, butoxycarboxim, oxamyl, thiocarboxim, and thiofanox. In one embodiment, the composition can include permethrin in combination with an isoxazoline active agent. In one embodiment, the composition can include flumethrin in combination with an isoxazoline active agent. In one embodiment, the composition can include deltamethrin in combination with an isoxazoline active agent.

[0160] In some embodiments, the long-acting antiparasitic external device of the present disclosure may include one or more anti-nematode agents, including but not limited to benzimidazoles, imidazothiazoles, active agents in the tetrahydropyrimidines, and organophosphorus classes of compounds. In some embodiments, benzimidazoles, including but not limited to thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, pyrantel, thiophanate, and its o,o-dimethyl analogs, may be included in the composition. In other embodiments, the long-acting antiparasitic external device of the present disclosure can include an imidazothiazole compound, including but not limited to tetramisole, levamisole, and butamisole. In yet other embodiments, the long-acting composition of the present disclosure can include a tetrahydropyrimidine active agent, including but not limited to pyrantel, oxantel, and morantel. Suitable organophosphorus active agents include but are not limited to coumaphos, trichlorfon, haloxon, naphthalophos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

[0161] In other embodiments, the long-acting antiparasitic external device of the present disclosure can include anti-nematode compounds phenothiazine and piperazine (as intermediate compounds or in the form of various salts), diethylcarbamazine, phenols such as disophenol, arsenic compounds such as arsenamides, ethanolamines such as bephenium, crosylate, and methyluridine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate, and dithiazanine iodide; isothiocyanates including bitoscanate, sodium suramin, fusarofin, and various natural products including, but not limited to, hygromycin B, α-santonin, and kainic acid.

[0162] In other embodiments, the long-acting antiparasitic external device of the present disclosure can include an anti-fluke agent.Suitable anti-fluke agents include, but are not limited to, miracil, such as miracil D and mirasan; various bisphenol compounds known in the art, including praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, hexachlorophene, bithionol, bithionol sulfoxide and meniclofolan; various salicylanilide compounds, including tribulonsalan, oxyclozanide, diloxanide, lafoxanide, brothianide, bromoxanide and closantel; triclabendazole, diamphenetide, clorsulon, hetrin and emetine.

[0163] Anti-tasteworm compounds may also be advantageously used in the long-acting compositions of the present disclosure, including, but not limited to, praziquantel, arecoline in its various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin, and paromomycin II.

[0164] In yet other embodiments, the long-acting antiparasitic external device of the present disclosure can include other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, dichlorodiphenyltrichloroethane, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorolethion, diemthoate, dioxathion, ethion, fanfen, fenitrothion, fenthion, fospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stylophos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, fenothrin, pyrethrins, resmethrin, anthraquinone, thiazolin ... Examples of suitable antibacterial agents include benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanatoacetate, methoprene, monosulfiram, piperonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate, and the compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326), and 2-(octylthio)ethanol (MGK-874).

[0165] The anthelmintic agent that can be combined with the isoxazoline compound in the long-acting antiparasitic external device of the present disclosure can be a depsipeptide, which acts on the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of the parasite. In one embodiment, the depsipeptide is a 24-membered cyclic depsipeptide isolated by Sasaki et al. from the fungus Mycelia sterilia (see J. Antibiotics 45: 692-697 (1992)), which has been found to exhibit broad anthelmintic activity against a variety of endoparasites in vivo with low toxicity. These compounds are described, for example, in U.S. Patent Nos. 5,514,773; 5,747,448; 5,646,244; and 5,874,530, among others, which are incorporated herein by reference. In one depsipeptide embodiment, the depsipeptide is emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86). In another embodiment, the depsipeptide is PF1022A or a derivative thereof. In other embodiments, the cyclic depsipeptide active agent is a compound described in U.S. Pat. Nos. 10,081,656 and 10,344,056, both of which are incorporated herein by reference in their entirety.

[0166] In another embodiment, the long-acting antiparasitic external device of the present disclosure can include an active agent from the neonicotinoid class of pesticides. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide agent that can be combined with an isoxazoline compound to form the long-acting antiparasitic external device of the present disclosure is imidacloprid. Imidacloprid is a well-known neonicotinoid active agent and is the main active ingredient in the topical parasiticide products Advantage®, Advantage® II, K9 Advantix®, and K9 Advantix® II (sold by Bayer Animal Health) and the oral soft chew composition Advantus™ (manufactured by Piedmont Animal Health). Agents of this class are described, for example, in U.S. Pat. No. 4,742,060 or EP 0892060. In another embodiment, the neonicotinoid active agent can be acetamiprid. In another embodiment, the solid antiparasitic external device of the present invention can include the active agent nitenpyram, which is the active ingredient in the oral product CAPSTAR™ Tablets (sold by Novartis Animal Health).

[0167] In yet another embodiment, the disclosure provides a long-acting composition of the disclosure 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-naphthalenecarboxamide (compound of formula Ia), in combination with nitenpyram. In yet another embodiment, the disclosure provides a long-acting composition of the disclosure 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-naphthalenecarboxamide (compound of formula Ia), in combination with imidacloprid.

[0168] In certain embodiments, insecticidal agents that can be combined with the long-acting compositions of the present disclosure are semicarbazones, such as metaflumizone. In another embodiment, the long-acting antiparasitic external device of the present disclosure can advantageously comprise a combination of isoxazoline compounds known in the art, such as those described in WO2007 / 079162, WO2007 / 075459 and US2009 / 0133319, WO2007 / 070606 and US2009 / 0143410, WO2009 / 003075, WO2009 / 002809, WO2009 / 024541, WO2005 / 085216 and US2007 / 0066617 and WO2008 / 122375, all of which are incorporated by reference herein in their entirety.

[0169] In another embodiment of the present disclosure, nodulisporic acid and its derivatives (a class of drugs with known acaricidal properties, anthelmintic, antiparasitic and insecticidal properties) can be added to the long-acting antiparasitic external device of the present disclosure. These compounds are used to treat or prevent infectious diseases in humans and animals, and are described, for example, in U.S. Patent Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are incorporated herein by reference in their entirety. The antiparasitic external device can include one or more of the nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the patents cited above.

[0170] In another embodiment, anthelmintic compounds of the aminoacetonitrile class (AAD), such as monetel (ZOLVIX), can be added to the long-acting antiparasitic external device of the present disclosure. These compounds are described, for example, in WO2004 / 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, 13 March 2008, 176-181. The antiparasitic external devices of the present disclosure can also include aryl azol-2-yl cyanoethylamino compounds, such as those described in U.S. Pat. No. 8,088,801 to Soll et al., which is incorporated herein in its entirety, and thioamide derivatives of these compounds described in U.S. Pat. No. 7,964,621, which is incorporated herein by reference.

[0171] The long-acting antiparasitic external device of the present disclosure may also be combined with paraherquamide compounds and derivatives of these compounds, including delcantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds containing a spirodioxepinoindole core that has activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). In addition, the structurally related marcfortine family of compounds, such as marcfortines A-C, are also known and may be combined with the compositions of the present disclosure (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to paraherquamide derivatives can be found, for example, in WO91 / 09961, WO92 / 22555, WO97 / 03988, WO01 / 076370, WO09 / 004432, U.S. Patent No. 5,703,078, and U.S. Patent No. 5,750,695, all of which are incorporated herein by reference in their entirety.

[0172] Typically, the additional active agent is included in the long-acting antiparasitic external device of the present disclosure in an amount between about 0.1 μg and about 1000 mg. More typically, the additional active agent may be included in an amount of about 10 μg to about 500 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 100 mg. In other embodiments of the present disclosure, the additional active agent may be included in the antiparasitic external device 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 may 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 may 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 yet another embodiment of the present disclosure, the additional active agent is included in a dose between about 0.5 mg / kg to about 50 mg / kg.

[0173] composition The antiparasitic external device of the present invention comprises at least one polymer suitable for binding to the outer part of an animal. The polymer matrix must possess sufficient strength and flexibility to ensure that they do not tear or become fragile during manufacture and use. They must be durable enough to resist normal wear and tear. In addition, the polymer matrix must allow suitable migration of active compound to the surface of the device for delivery to an animal. Within the scope of the present disclosure, matrices that are commonly used to produce antiparasitic collars can be used. For example, elastomers (particularly thermoplastic elastomers) and thermoplastics, including flexible thermoplastic polyolefins, are suitable for use as carrier materials or bases for antiparasitic external devices. Thermoplastic elastomers and thermoplastics are most suitable for use as polymer matrices for the antiparasitic external devices of the present invention described herein.

[0174] As those skilled in the art will appreciate, thermoplastic elastomers and thermoplastics are polymers that can be thermally processed, for example, by extrusion or injection molding. These polymers can include, for example, polyvinyl resins, such as polyvinyl chloride (PVC) and vinyl chloride copolymers, polyethylene (for example, HDPE or LLDPE) and polypropylene, polyesters, including EPDM (ethylene-propylene-diene terpolymer), polyvinyl acetate (PVAc), ethylene-vinyl acetate copolymer (EVA), polystyrene (PS) and copolymers, polyvinyl resins, and acrylic polymers, which are fully compatible with the active compounds described above. In another embodiment, the external device composition of the present invention includes polyesters, such as polybutylene succinate (PBS), polybutylene succinate adipate (PBSA), polylactic acid (PLA), polylactic acid-glycolide (PLGA), polycaprolactone (PCL), polyhydroxyalkanoate (PHA), and polybutylene adipate terephthalate (PBAT).

[0175] In one embodiment, PVC (polyvinyl chloride) and other vinyl polymers, such as those described in U.S. Patent Nos. 3,318,769, 3,852,416, 4,150,109, and 5,437,869 (all of which are incorporated herein by reference), can be used to prepare the antiparasitic external device of the present invention. Polyvinyl resins include polyvinyl halides, such as polyvinyl chloride, polyvinyl chloride-vinyl acetate, and polyvinyl fluoride; polyvinyl benzene, such as polystyrene and polyvinyl toluene. In some embodiments, polyvinyl chloride, polypropylene, polyethylene, and EPDM can be utilized. Other plastics (i.e., polymers) suitable for use as a matrix for the antiparasitic external device according to the present disclosure are thermoplastic elastomers. These are materials that contain an elastomeric phase that is physically incorporated or chemically bonded to a thermoplastically processable polymer. They are distinguished from polymer blends, in which the elastomeric phase is a constituent of the polymer backbone. As a result of the composition of the thermoplastic elastomer, hard and soft regions exist alongside each other. In this context, the hard domains form a crystalline network or continuous phase whose interstices are filled with elastomeric segments. Due to this configuration, these materials have rubber-like properties. In this context, reference can be made to thermoplastic polyolefins (TPO) and styrene block copolymers (see, for example, EP 542078).

[0176] Polymer matrices that can be used in the present invention include, but are not limited to, the following: 1. Vinyl polymers: including, but not limited to, polyvinyl chloride (PVC); polyvinylidene chloride (PVDC); polyvinylidene fluoride (PVDF); polyethylene (PE); polypropylene (PP); chlorinated polyethylene (CPE); chlorinated polypropylene (CPP); ethylene-propylene copolymers; polyvinyl acetate (PVAc); ethylene-vinyl acetate copolymers (EVA); polyvinyl chloride-vinyl acetate; polyvinyl fluoride; polystyrene and polystyrene copolymers; polyisobutylene (PIB); styrene-butadiene rubber (SBR); styrene-isoprene rubber (SIS); 2. Polyesters: polyethylene terephthalate (PET) and copolymers; polylactic acid (PLA) and copolymers, polylactic acid-co-glycolide (PLGA); polycaprolactone (PCL) and copolymers; polyhydroxyalkanoates (PHAs); polybutylene succinate (PBS); polybutylene succinate-co-adipate (PBSA); and polybutylene adipate terephthalate (PBAT); 3. Nylon: including but not limited to Nylon6; Nylon66; Nylon12; 4. Polyacrylates, polymethacrylates, and methacrylate and acrylate copolymers, including but not limited to polymethyl methacrylate (PMMA); polymethyl acrylate (PMA); polyethyl methacrylate (PEMA); polybutyl methacrylate (PBMA); and copolymers thereof; 5. Biopolymers: Cellulosic polymers, such as cellulose acetate (CA); ethyl cellulose (EC), etc.; 6. Polymer Blends: Any combination of polymer blends containing one or more of any of the individual polymers listed above.

[0177] In certain embodiments, the antiparasitic external device according to the present disclosure comprises a polymer matrix that contains at least one polymer that is a vinyl polymer, a polyester, a nylon, a polyacrylate (or polymethacrylcate), a cellulosis polymer, or a thermoplastic polyurethane. In some embodiments of the anti-parasitic device according to the present disclosure, the vinyl polymer comprises polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polyvinylidene fluoride (PVDF), polyethylene (PE), polypropylene (PP), chlorinated polyethylene (CPE), chlorinated polypropylene (CPP), ethylene-propylene copolymer, polyvinyl acetate (PVAc), ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride-vinyl acetate, polyvinyl fluoride, polystyrene, polyisobutylene (PIB), styrene-butadiene rubber (SBR), styrene-isoprene rubber (SIS), or combinations thereof.

[0178] In some embodiments of the antiparasitic device according to the present disclosure, the polyester comprises polyethylene terephthalate (PET), PET copolymer, polylactic acid (PLA), PL copolymer, polylactic acid-co-glycolide (PLGA), polycaprolactone (PCL), PCL copolymer, polyhydroxyalkanoate (PHA), polybutylene succinate (PBS), polybutylene succinate-co-adipate (PBSA), polybutylene adipate terephthalate (PBAT), or combinations thereof. In some embodiments of the antiparasitic device according to the present disclosure, the polymer matrix comprises a biodegradable polyester selected from polybutylene succinate (PBS); polybutylene succinate-co-adipate (PBSA); polylactic acid (PLA) and / or copolymers; polylactic acid-co-glycolide (PLGA); polycaprolactone (PCL), PCL copolymers, polyhydroxyalkanoates (PHA), polybutylene adipate terephthalate (PBAT), or combinations thereof. In some embodiments, the polymer matrix preferably comprises a biodegradable polyester. In certain embodiments, the biodegradable polyester is polybutylene succinate-co-adipate (PBSA), and / or polybutylene succinate (PBS), and / or polybutylene adipate terephthalate (PBAT).

[0179] In some embodiments of the antiparasitic device according to the present disclosure, the polymer matrix comprises a nylon selected from the group consisting of Nylon6, Nylon66, and Nylon12. In some embodiments of the antiparasitic device according to the present disclosure, the polymer matrix comprises at least one polyacrylate or polymethacrylate selected from the group consisting of polymethyl methacrylate (PMMA), polymethyl acrylate (PMA), polyethyl methacrylate (PEMA), polybutyl methacrylate (PBMA), and copolymers thereof. In some embodiments of the antiparasitic device according to the present disclosure, the polymer matrix comprises a cellulosic polymer that is cellulose acetate (CA) and / or ethyl cellulose (EC).

[0180] In certain embodiments of the antiparasitic device according to the present disclosure, the polymer matrix comprises any one of polyvinyl acetate (PVAc), ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride-vinyl acetate, or mixtures thereof. In certain embodiments, the polymer matrix preferably comprises any one of polyvinyl acetate (PVAc), ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride-vinyl acetate, or mixtures thereof. In yet another embodiment, the polymer matrix preferably comprises or consists of ethylene-vinyl acetate copolymer (EVA).

[0181] In embodiments, plasticizers can be used to soften pharmaceutically acceptable polymers. For example, plasticizers can be used to soften solid vinyl resins to produce antiparasitic external devices based on polyolefins, especially polyvinyl resins. The plasticizer to be used depends on the compatibility of the resin and the plasticizer. Examples of suitable plasticizers are adipates, phthalates, phosphates and citrates, such as phosphates and adipates, such as diiso- and n-butyl adipate. It is also possible to use other esters, such as esters of azelaic acid, maleic acid, ricinoleic acid, myristic acid, palmitic acid, oleic acid, sebacic acid, stearic acid and trimellitic acid, as well as complex linear polyesters, polymeric plasticizers and epoxidized soybean oil.

[0182] In an embodiment, one or more plasticizers are preferably added to the PVC-based matrix, these plasticizers being in particular chosen from the following compounds: diethyl phthalate, bis-(2-ethylhexyl) phthalate (DEHP), dioctyl sebacate, dioctyl adipate, diisodecyl phthalate, acetyl tributyl citrate, diethylhexyl phthalate, di-n-butyl phthalate, benzyl butyl phthalate, acetyl tributyl citrate, tricresyl phosphate, and 2-ethylhexyl diphenyl phosphate. In other embodiments, a PVC base matrix is ​​used in the presence of a primary remanant plasticizer and a secondary plasticizer, such as acetyltriethyl citrate, triethyl citrate, triacetin, diethylene glycol monoethyl ether, and triphenyl phosphate.

[0183] In embodiments, the plasticizer is utilized in an amount of about 5-50% by weight. In some embodiments, the plasticizer is utilized in an amount of about 1-50% by weight. In other embodiments, the plasticizer is utilized in an amount of about 15-45% by weight of the total composition. In still other embodiments, the plasticizer is utilized in an amount of about 5-45% by weight of the total composition. In still other embodiments, the plasticizer may be included in a concentration of about 5-30%, about 5-25%, or about 5-20% by weight. In still other embodiments, the plasticizer may be included in a concentration of about 5-15% or about 5-10% by weight. In other embodiments, the plasticizer may be included in a concentration of about 20-40% or about 25-35% by weight of the composition. In other embodiments, the antiparasitic external device also comprises at least one additional component selected from stabilizers, lubricants, mold release agents, fillers, and coloring materials.Suitable stabilizers are antioxidants and agents that protect the external device from undesirable degradation during UV light and processing, such as extrusion.Some stabilizers, such as epoxidized soybean oil, also function as secondary plasticizers.Examples of lubricants that can be used are stearates (e.g. zinc stearate), stearic acid, and low molecular weight polyethylene. In embodiments, the additional component comprises up to about 10% by weight of the total composition. In one embodiment, the amount of additional component may comprise from about 1 to about 10% or from about 2 to about 8% by weight of the composition. In yet another embodiment, the concentration of additional component may comprise from about 1 to about 5% or from about 2 to about 6% by weight.

[0184] In embodiments, an antiparasitic collar or other antiparasitic external device may comprise two or more polymeric matrices, each of which may differ in concentration and / or composition. By using a collar or other external device according to the present disclosure that comprises two or more polymeric matrices, delivery of two or more active agents can be achieved, which allows for efficient and sustained protection against ectoparasites (e.g., fleas and ticks) and, in certain embodiments, protection against endoparasites that harm animals. The use of two or more polymeric matrices may also be desirable for purposes such as drug compatibility, drug release profile, superior mechanical properties, cost, etc. Furthermore, by utilizing two or more polymer matrices at different concentrations and / or compositions, it is possible to produce a collar or other external device according to the present disclosure that ensures efficient and long-lasting protection against ectoparasites (e.g., fleas and ticks), and in certain embodiments, is also active against endoparasites that harm animals. In one embodiment of the present invention, a blend of two or more polymers can be used in the antiparasitic external device composition. Blending polymers with different affinities for the active agent contained in the composition can be used to modify the release rate of the active agent from the polymer matrix. Blends can also be used to shorten or extend the period of effectiveness of the antiparasitic composition.

[0185] The antiparasitic collar or other antiparasitic external device of the present invention can be made to provide at least 70% effectiveness against ectoparasites for greater than 3, 6, 8, or 9 months. In other embodiments, the antiparasitic collar or antiparasitic external device of the present invention provides at least 80% or at least 90% effectiveness against ectoparasites for at least 3, 6, 8, or 9 months. In yet other embodiments, the antiparasitic collar or antiparasitic external device of the present invention provides at least 95% effectiveness against ectoparasites for at least 3, 6, 8, or 9 months. In some embodiments, the collar of the present invention can provide up to 12 or 15 months of effectiveness against parasites, even when the collar or external device is removed for a relatively long period of time. When the collar or external device is removed, the effective period of protection for the animal can still range from an additional 1 to 2 months.

[0186] Generally, when the antiparasitic external device of the present invention is produced, the different components are mixed by known methods and molded by extrusion and injection molding methods known in the art.The choice of processing method for producing the external device technically depends in principle on the rheological properties of the polymer matrix and the shape of the antiparasitic external device desired.In an embodiment, the process for producing the external device of the present invention can include one or more of the following methods; casting, injection molding, extrusion, calendaring, rolling, kneading, stamping, bending, and thermoforming. It is envisioned that the anti-parasitic external devices of the present invention may be provided with a coating.

[0187] For the purposes of this disclosure, the term external device should be considered to refer to any device that can be attached externally to an animal to provide the same function as a collar. By varying the concentration and / or composition of the matrix, an antiparasitic collar or other antiparasitic external device according to the present disclosure can be made that allows for efficient and long-lasting protection against fleas and ticks. An antiparasitic collar or other antiparasitic external device can be made with an efficacy of at least 3, 6, 8 or 9 months, particularly greater than or equal to 12 or 15 months, even when the antiparasitic collar or other antiparasitic external device is removed for a relatively long period of time. When the antiparasitic collar or other antiparasitic external device is removed, the period of efficient protection continues, in some embodiments lasting for a period ranging from 1 to 2 months.

[0188] The long-acting antiparasitic external device of the present disclosure may include a pharma- ceutically acceptable additive or excipient. Pharmaceutically acceptable additives and excipients include, but are not limited to, colorants, fillers, surfactants, antioxidants, UV stabilizers, preservatives, pH stabilizers (e.g., buffers), lubricants, flow agents, and other inactive excipients. In another embodiment, the antiparasitic external device of the present disclosure may include about 0.01% to about 20% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof. In other embodiments, the antiparasitic external device may include about 0.01% to about 5% (w / w), about 0.1% to about 10% (w / w), or about 0.1% to about 5% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof. In other embodiments, the antiparasitic external device can comprise about 5 to about 15% (w / w) or about 5 to about 10% (w / w) of a pharma- ceutically acceptable additive, excipient, or mixture thereof, hi yet another embodiment, the antiparasitic external device can comprise about 7 to about 10% of a pharma- ceutically acceptable additive, excipient, or mixture thereof.

[0189] The novel and inventive antiparasitic external device may contain other inactive ingredients, such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the composition art. Antioxidants, such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxy-anisole), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol, tert-butylhydroquinone (TBHQ), and the like, may be added to the antiparasitic external device of the present invention. Antioxidants are generally included in the antiparasitic external device of the present disclosure in an amount of about 0.01% to about 3%, or about 0.01 to about 2% (w / w) based on the total weight (w / w) of the antiparasitic external device. In another embodiment, the antiparasitic external device contains about 0.05 to about 1.0% (w / w) of one or a mixture of antioxidants.

[0190] Preservatives, such as parabens (methylparaben and / or propylparaben), are suitably used in the composition in amounts ranging from 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, and the like. Preferred ranges for these compounds include about 0.01 to about 5%.

[0191] Compounds that stabilize the pH of the composition are also envisaged.Again, such compounds are well known to practitioners in the art, and the use of these compounds is well known.The buffer system includes, for example, a system selected from the group consisting of acetic acid / acetate, malic acid / malate, citric acid / citrate, tartaric acid / tartrate, lactic acid / lactate, phosphoric acid / phosphate, glycine / glycinate, Tris, glutamic acid / glutamate and sodium carbonate. Compounds that affect the release of active agents from the antiparasitic external device are also contemplated.

[0192] The dosage form may contain about 0.5 mg to about 5 g of an active agent or combination of active agents. More typically, the amount of active agent in the antiparasitic external device of the present disclosure is about 1 mg to about 3 g. In another embodiment, the amount of active agent in the antiparasitic external device is about 20 mg to about 3 g. In another embodiment, the amount of active agent present in the antiparasitic external device is about 20 mg to about 2 g, about 20 mg to about 1.5 g, or about 20 mg to about 1 g. In other embodiments, the amount of active agent in the antiparasitic external device is about 20 mg to about 500 mg, about 30 mg to about 200 mg, or about 50 mg to about 200 mg. In yet another embodiment, the amount of active agent present in the antiparasitic external device is about 50 mg to about 2 g, about 50 mg to about 1 g, or about 50 mg to about 500 mg. In yet other embodiments of the present disclosure, the amount of active agent present is 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.

[0193] In another embodiment, the amount of active agent present in the antiparasitic external device of the present disclosure 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 yet another embodiment, the amount of active agent present in the antiparasitic external device is from about 10 mg to about 50 mg, or from about 10 mg to about 100 mg. In another embodiment, the amount of active agent present in the antiparasitic external device 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. In some embodiments, the amount of active agent present in the antiparasitic external device of the present disclosure is preferably greater than 1000 mg, greater than 2000 mg, greater than 3000 mg, greater than 4000 mg, and greater than 5000 mg, for example, about 5500 mg, or greater than 5500 mg.

[0194] Many collars have a mass of about 20-50 g, and thus an active agent constituting about 11% (w / w) of the collar exemplified herein is equivalent to about 5.5 g or 5500 mg of active agent. Thus, in some embodiments, the amount of active agent present in the antiparasitic external device of the present disclosure is about 1-40% (w / w) of at least one isoxazoline active agent. In still other embodiments, the amount of active agent is about 1-30% (w / w), about 1-20% (w / w), and about 1-15% (w / w). In one embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 1 to about 40% (w / w) of at least one isoxazoline active agent, such as those described above, from about 30 to about 80% (w / w) of a polyvinyl polymer, from about 1 to about 40% (w / w) or from about 10 to about 40% (w / w) of a plasticizer, and optionally from about 0.5 to about 5% (w / w) of a stabilizer, a lubricant, and one or more pharma- ceutically acceptable additives or excipients.

[0195] In another embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 5 to about 30% (w / w) of at least one isoxazoline active agent, such as those described above, from about 40 to about 70% (w / w) of a polyvinyl polymer, from about 5 to about 35% (w / w) or from about 15 to about 35% (w / w) of a plasticizer, and optionally from about 0.5 to about 5% (w / w) of a stabilizer, lubricant, and one or more pharma- ceutically acceptable additives or excipients. In another embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent, such as those described above, from about 45 to about 65% (w / w) of a polyvinyl polymer, from about 15 to about 35% (w / w) or from about 25 to about 35% (w / w) of a plasticizer, and optionally from about 0.5 to about 5% (w / w) of a stabilizer, a lubricant, and one or more pharma- ceutically acceptable additives or excipients.

[0196] In one embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 1 to about 40% (w / w) of at least one isoxazoline active agent, such as those described above, from about 30 to about 80% (w / w) of a polymer, from about 1 to about 40% (w / w) of a plasticizer, and optionally from about 0.5 to about 5% (w / w) of a stabilizer, lubricant, and one or more pharma- ceutically acceptable additives or excipients. In another embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 5 to about 30% (w / w) of at least one isoxazoline active agent, such as those described above, from about 40 to about 70% (w / w) of a polymer, from about 5 to about 35% (w / w) of a plasticizer, and optionally from about 0.5 to about 5% (w / w) of a stabilizer, lubricant, and one or more pharma- ceutically acceptable additives or excipients. In another embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent, such as those described above, from about 45 to about 65% (w / w) of a polymer, such as from about 15 to about 35% (w / w) of a plasticizer, and optionally from about 0.5 to about 5% (w / w) of a stabilizer, lubricant, and one or more pharma- ceutically acceptable additives or excipients.

[0197] In one embodiment, the antiparasitic external devices (e.g., parasitic collars) of the present invention can comprise about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (I) described above, about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, about 25 to about 35% (w / w) of a phthalate ester plasticizer, and about 1 to about 5% (w / w) of a stabilizer, lubricant (e.g., a stearate salt), and one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of formula (Ia) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0198] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (Ib) described above, about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, about 25 to about 35% (w / w) of a phthalate ester plasticizer, and about 1 to about 5% (w / w) of a stabilizer, lubricant, e.g., a stearate salt, and one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (Ic) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0199] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of formula (Id) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (II) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0200] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula II-1.001 to II-1.025 described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0201] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula II-2.001 to II-2.018 described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of formula (III) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0202] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of formula (IV) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (V) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0203] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of formula (Va) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (VI) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0204] In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of formula (VIa) described above, from about 45 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, such as a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of an isoxazoline active agent of Formula (S)-Ia described above, from about 50 to about 65% (w / w) of a polyvinyl chloride (PVC) polymer, from about 25 to about 35% (w / w) of a phthalate ester plasticizer, from about 1 to about 5% (w / w) of a stabilizer or lubricant, e.g., a stearate salt, and optionally one or more pharma- ceutically acceptable additives or excipients.

[0205] In one embodiment, the antiparasitic external devices (e.g., parasitic collars) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (I) described above, from about 65 to about 95% (w / w) of a polybutylene succinate-co-adipate (PBSA) polymer, from about 0 to about 35% (w / w) of a plasticizer, and from about 0 to about 5% (w / w) of one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external devices (e.g., parasitic collars) of the invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (I) described above, from about 65 to about 95% (w / w) of a polybutylene succinate (PBS) polymer, from about 0 to about 35% (w / w) of a plasticizer, and from about 0 to about 5% (w / w) of one or more pharma- ceutically acceptable additives or excipients.

[0206] In one embodiment, the antiparasitic external devices (e.g., parasitic collars) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (I) described above, from about 65 to about 95% (w / w) of ethylene-vinyl acetate copolymer (EVA), from about 0 to about 15% (w / w) of a plasticizer, and from about 0 to about 5% (w / w) of one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the antiparasitic external device (e.g., parasitic collar) of the present invention can comprise from about 5 to about 20% (w / w) of at least one isoxazoline active agent of formula (I) described above, from about 65 to about 95% (w / w) of ethylene-vinyl acetate copolymer (EVA) with vinyl acetate (VA) (content 5-40%), from about 0 to about 15% (w / w) of a plasticizer, and from about 0 to about 5% (w / w) of one or more pharma- ceutically acceptable additives or excipients. In one embodiment, the present disclosure provides a method for producing i) an effective amount of at least one parasiticidal active agent which is a compound of formula (Ia) or (Id):

[0207] [ka] ii) a polymer matrix consisting of at least one of polybutylene succinate (PBS), polybutylene succinate adipate (PBSA), ethylene-vinyl acetate copolymer (EVA), and polyvinyl chloride; iii) optionally a plasticizer, and iv) optionally, stabilizers and / or antioxidants; The present invention provides an anti-parasitic external device for treating and / or preventing a parasitic infestation or infection in an animal, comprising:

[0208] In another embodiment, the present disclosure provides a method for producing i) Formula (Ia) or (Id):

[0209] [ka] an effective amount of at least one parasiticidal active agent, ii) a polymer matrix consisting of ethylene-vinyl acetate copolymer (EVA) having 5-95% vinyl acetate; iii) optionally a plasticizer, and iv) optionally, stabilizers and / or antioxidants; The present invention provides an anti-parasitic external device for treating and / or preventing a parasitic infestation or infection in an animal, comprising:

[0210] In one particular embodiment according to the invention, the above-mentioned EV polymer matrix contains 10-50% vinyl acetate. In another embodiment, the vinyl acetate content is preferably 10-30%. In yet another embodiment, the vinyl acetate content is about 12%. In one particular embodiment according to the invention, the above-mentioned EV polymer matrix contains 5-50% vinyl acetate. In another embodiment, the vinyl acetate content is preferably 5-30%. In yet another embodiment, the vinyl acetate content is about 12%.

[0211] In certain embodiments of the antiparasitic external device of the present invention, the polymer matrix is ​​comprised of polybutylene succinate, hi certain embodiments, the antiparasitic external device of the present invention does not contain a plasticizer. In another embodiment of the antiparasitic external device of the present invention, the polymer matrix is ​​comprised of polybutylene succinate and the antiparasitic external device comprises a plasticizer, hi one embodiment, the polymer matrix is ​​comprised of polybutylene succinate with triethyl citrate as a plasticizer, for example about 10% triethyl citrate. In one embodiment, the present disclosure provides a method for producing i) an effective amount of a compound of formula (Ia) or (Id):

[0212] [ka] at least one parasiticidal active agent which is a compound of the formula ii) a polymer matrix consisting of polybutylene succinate adipate (PBSA); iii) optionally a plasticizer, and iv) optionally, stabilizers and / or antioxidants; The present invention provides an anti-parasitic external device for treating and / or preventing a parasitic infestation or infection in an animal, comprising:

[0213] Treatment Method In another aspect of the present disclosure, there is provided a method for preventing and / or treating parasitic infestation and / or infection in an animal, comprising administering to the animal a long-acting antiparasitic external device of the present invention comprising an effective amount of at least one isoxazoline compound, a pharma- ceutically acceptable polymer matrix, and, optionally, plasticizers, antioxidants, pharma- ceutically acceptable additives and / or excipients. The compositions of the present disclosure have sustained efficacy against ectoparasites (e.g., fleas and ticks), and in certain embodiments, when combined with other active agents, can also have activity against endoparasites that harm animals.

[0214] The compositions of the present disclosure are administered / released from the antiparasitic external device of the present disclosure in a parasiticidally effective amount suitable to control the parasite of interest to a desired extent as described below. In each aspect of the present disclosure, the compounds and compositions of the present disclosure released from the antiparasitic external device may be applied against a single pest or a combination thereof. In some embodiments for companion animals, the dose of isoxazoline active agent administered from the antiparasitic external device of the present disclosure is between about 0.1 and about 50 mg per kg of body weight. More typically, the dose of isoxazoline active agent administered is about 0.5 to about 30 mg / kg or about 0.5 to about 30 mg / kg of body weight. In yet other embodiments, the dose of isoxazoline active agent is 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 of body weight. In other embodiments, the dose is about 0.5 to about 2.5 mg / kg of body weight. In other embodiments, the dose of 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 of body weight.

[0215] In other embodiments, the dose administered may be lower depending on the animal and the isoxazoline to which it is administered. For example, if the antiparasitic external device contains an active additional enantiomer of the isoxazoline compound, a lower dose may be administered. In some embodiments, the dose is about 0.1 to about 30 mg / kg (body weight). In other embodiments, the dose may be about 0.1 to about 20 mg / kg or about 0.1 to about 10 mg / kg (body weight). In other embodiments, doses of about 0.1 to about 5 mg / kg, about 0.1 to about 2.5 mg / kg (body weight) are used. In other embodiments, the dose may be about 1 to about 20 mg / kg (body weight) or about 1 to about 10 mg / kg. In yet other embodiments, the dose may be about 5 to about 20 mg / kg or about 10 to about 20 mg / kg (body weight).

[0216] In other embodiments, for treatment of livestock animals, such as cattle or sheep, the dose of the isoxazoline active agent administered may be about 0.1 to about 40 mg / kg body weight. More typically, the dose administered is about 1 to about 30 mg / kg, about 1 to about 20 mg / kg, or about 1 to about 10 mg / kg body weight. In yet other embodiments, the dose is about 10 to about 25 mg / kg, about 15 to about 30 mg / kg body weight, or about 20 to 30 mg / kg body weight. In some embodiments, the dose of the isoxazoline active agent is the dose administered by the antiparasitic external device of the present disclosure over a period of 1, 2, or 3 months. In some embodiments, the dose of the isoxazoline active agent administered by the antiparasitic external device of the present disclosure is the dose of the isoxazoline delivered by the external device for 3 months or more, for example, at least 4, 5, 6, 7, 8, and 9 months or more. In some embodiments, the dose of isoxazoline active agent administered over a period of time may be greater than about 100, 200, 300, 400, or 500 mg / kg of body weight of the animal. In one embodiment, the dose is at least 550 mg / kg of body weight. In another embodiment, the dose is at least 600, 650, 700, 750, 800, 850, or 900 mg / kg of isoxazoline delivered by the long-acting antiparasitic external device over the period the animal wears the device.

[0217] In one embodiment of the method of use in livestock animals (e.g., cattle or sheep), the long-acting antiparasitic external device of the present disclosure comprising an isoxazoline compound has an efficacy of at least about 90.0% or greater against ectoparasites, including but not limited to, ticks, mites, lice and parasitic flies, for about three months or longer. In another embodiment, the long-acting antiparasitic external device of the present disclosure provides an efficacy of at least 95.0% or greater against ectoparasites for about three months or longer. In another embodiment, the long-acting antiparasitic external device of the present disclosure provides at least about 80% efficacy against ectoparasites of livestock animals (e.g., cattle or sheep) for 2 months or longer. In another embodiment, the long-acting antiparasitic external device of the present disclosure provides about 90% efficacy against ectoparasites of livestock animals (e.g., cattle or sheep) for at least about 2 months. In yet another embodiment, the antiparasitic external device provides about 95% efficacy for about 2 months or longer. In another embodiment, the long-acting antiparasitic external device of the present disclosure provides about 90% efficacy against ectoparasites of livestock animals (e.g., cattle or sheep) for about 3 months, 6 months, 9 months, or longer. In yet another embodiment, the antiparasitic external device provides about 95% efficacy for about 3 months or longer. In yet another embodiment, the antiparasitic external device provides about 95% effectiveness for about 6 months or longer, hi another embodiment, the antiparasitic external device provides about 95% effectiveness for about 9 months or longer.

[0218] In another embodiment, the long-acting antiparasitic external device of the present disclosure has at least about 80% efficacy against ectoparasites for about 3 months or longer. In yet another embodiment, the long-acting antiparasitic external device of the present disclosure provides at least about 90% efficacy against ectoparasites for about 3 months or longer. In yet another embodiment, the long-acting antiparasitic external device of the present disclosure provides at least about 95% efficacy against ectoparasites for about 3 months or longer. In yet another embodiment, the long-acting antiparasitic external device of the present disclosure provides at least 80% or at least 90% efficacy against ectoparasites of livestock animals (e.g., cattle or sheep) for about 3 months to about 6 months or longer. In yet another embodiment, the long-acting antiparasitic external device of the present disclosure provides at least 80% or at least 90% efficacy against ectoparasites of livestock animals (e.g., cattle or sheep) for about 9 months or longer. EXAMPLES

[0219] The present invention is further described by the following non-limiting examples which further illustrate the present invention, but are not intended, nor should they be construed, as limiting the scope of the invention. Collars containing representative isoxazoline compounds, the isoxazoline active agent afoxolaner (Ia), esafoxolaner, the active enantiomer of afoxolaner ((S)-Ia), and the active enantiomer of an analogue bearing a 3-chloro-4-fluoro-5-trifluoromethyl substitution on the phenyl ring (i.e., esafoxolaner modified to contain a 4-fluoro group) ((S)-Id), were prepared in various polymer matrices and evaluated for their effectiveness in controlling ectoparasites in dogs.

[0220] Example 1 Preparation of collars containing isoxazoline active agents.

[0221] Collars were produced for each given polymer using the conditions listed in Table 1 below. Extrusion was performed using a Thermo Scientific HAAKE Minilab II micro-compounder with a conical twin-screw. The cycle time was sufficient to achieve mixing of the active agent and polymer. The active agent loading was gradually increased until the collar produced for a given polymer was tacky to the touch, and the active agent loading was kept below the threshold for testing. The extruder was cleaned between samples to prevent cross contamination. After extrusion, samples were made using the same method for both in vitro and in vivo experiments, except that samples for animal studies were heated and expanded to ensure that the collar was long enough to comfortably encircle the dog's neck. As noted in Table 1, higher loadings of the isoxazoline active agents are possible in PBS compared to PVC, indicating a higher affinity of the active agents for PBS.

[0222] [Table 3]

[0223] FTIR was used to confirm the presence of the active agent. After extrusion, ATR-FTIR was performed at grazing angles to characterize the structure of the active agent within the polymer matrix. Comparison of the polymer matrix used, PVC80, and the different molecules revealed peaks at 1160 and 1640 cm as shown in Figures 1 to 3. -1 The collar samples, 11% (S)-Ia in PVC80, 11% (S)-Id in PVC80, and 11% Ia in PVC80, showed overlapping peaks to the characteristic isoxazoline activator peak, confirming the presence of the isoxazoline activator in the PVC matrix after extrusion and processing in either (S)-Ia, (S)-Id, or Ia.

[0224] Differential scanning calorimetry (DSC) was performed on the above collars with pure isoxazoline compounds and PVC matrix materials. Figure 4 is a comparison to (S)-Ia. Pure (S)-Ia has a characteristic melting peak around 145°C. After incorporation into the PVC matrix, the melting peak completely disappeared, resulting in a totally amorphous dispersion of (S)-Ia in the PVC. A similar phenomenon was observed for the PVC collars with isoxazoline compounds Ia and (S)-Id. Without wishing to be bound by theory, it is believed that this transformation indicates that the drug can move relatively freely within the polymer matrix, ultimately allowing diffusion of the drug out of the collar and into the dog's body.

[0225] The present disclosure is further illustrated by the following non-limiting examples illustrating exemplary compositions of external antiparasitic collar compositions containing an isoxazoline active agent: Formulation 1: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 34.5% (w / w) Isoxazoline activator 10.0% (w / w) Formulation 2: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 30.0% (w / w) Isoxazoline activator 14.5% (w / w)

[0226] Formulation 3: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 30.0% (w / w) Compound of formula (Ia) 14.5% (w / w) Formulation 4: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 14.5% (w / w) Compound of formula (Ia) 30.0% (w / w) Formulation 5: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 34.5% (w / w) Isoxazoline activator 10.0% (w / w)

[0227] Formulation 6: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 30.0% (w / w) Isoxazoline activator 14.5% (w / w) Formulation 7: EPDM 50.0% (w / w) Stearate 0.5% (w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 30.0% (w / w) Compound of formula (Ia) 14.5% (w / w) Formulation 8: EPDM 50.0% (w / w) Stearate 0.5% (w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 14.5% (w / w) Compound of formula (Ia) 30.0% (w / w)

[0228] Formulation 9: PVC 50.0% (w / w) Stearate 0.5% (w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 34.5% (w / w) Isoxazoline activator 10.0% (w / w) Formulation 10: PVC 50.0% (w / w) Stearate 0.5% (w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 30.0% (w / w) Isoxazoline activator 14.5% (w / w) Formulation 11: PVC 50.0% (w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 30.0% (w / w) Compound of formula (S)-Ia 15.0% (w / w)

[0229] Formulation 12: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) 2-Ethyl diphenyl phosphate 19.5% (w / w) Compound of formula (S)-Ia 30.0% (w / w) Formulation 13: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 34.5% (w / w) Compound of formula (S)-Ia 10.0% (w / w) Formulation 14: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 30.0% (w / w) Compound of formula (S)-Ia 14.5% (w / w)

[0230] Formulation 15: EPDM 50.0% (w / w) Stabilizer 0.5% (w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 30.0% (w / w) Compounds of formula Ic, where X 1 , X 3 =Cl, and X 2 is F) 14.5% (w / w) Formulation 16: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 14.5% (w / w) Compounds of formula Ic, where X 1 , X 3 =Cl, and X 2 is F) 30.0% (w / w)

[0231] Formulation 17: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 14.5% (w / w) Compound of formula (Id) 30.0% (w / w) Formulation 18: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 34.5% (w / w) Compound of formula (Id) 10.0% (w / w) Formulation 19: PVC 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) 2-Ethyl diphenyl phosphate 14.5% (w / w) Compound of formula (Id) 30.0% (w / w) Formulation 20: EPDM 50.0% (w / w) Stabilizer 0.5%(w / w) Epoxidized soybean oil 5.0% (w / w) Diisooctyl adipate 34.5% (w / w) Compound of formula (Id) 10.0% (w / w)

[0232] In addition, collar formulations were produced comprising a polyvinyl chloride (PVC) matrix and afoxolaner, as described in Table 2. For each given formulation described in Table 2, collars were produced by extrusion or injection molding. Extrusion conditions were 155° C., 25 rpm feed rate, and no cycling. Injection mold conditions were 150° C. cylinder, 45° C. mold, and 600 psi for 5 seconds.

[0233] [Table 4]

[0234] Example 2 In vitro efficacy of antiparasitic external device compositions containing isoxazoline active agents against fleas (Nectariniformes cati). The in-vitro susceptibility of cat fleas exposed to treated filter paper and external device compositions (antiparasitic collars) containing the isoxazoline active agents (S)-Ia, (S)-Id, and (Ia) was determined. The collars comprised a polyvinyl chloride (PVC) matrix or a polybutylene succinate (PBS) matrix.

[0235] [Table 5]

[0236] To determine in-vitro susceptibility of cat fleas exposed to treated filter paper or collar compositions containing isoxazoline active agents, approximately 20 fleas were transferred to vials containing either a collar or filter paper according to the test groups outlined in Table 3. On day 0, approximately 20 fleas were placed into 27 x 55 mm, 5 dram glass vials containing collars containing the active agents outlined in Table 3 or 60 mm x 40 mm glass vials containing treated filter paper. Tested filter papers in groups 9-12 were filled with 500 μL of a 10 mg / mL solution containing the active agent dissolved in acetone. Each strip of collar was 10 cm long and each filter paper was 21 cm long. 2 The test vials were placed in an environmental chamber at approximately 28° C. and approximately 80% RH.

[0237] On day 1, the number of dead fleas in each vial was counted at 24 (± 1) hours after the first exposure. Fleas were counted as dead if they were unable to maintain an upright position. The in-vitro flea exposure efficacy of the various test groups, outlined in Table 3, is summarized in Table 4.

[0238] [Table 6] These experimental data demonstrate that antiparasitic collar compositions containing isoxazoline active agents formulated in PVC effectively kill fleas that come into contact with the collar material. In contrast, groups containing PBS containing isoxazoline compounds and collar strips made from filter paper had no effect on fleas in an in vitro contact assay.

[0239] Example 3 In vivo efficacy of PVC collar compositions containing isoxazoline active agents against fleas (Flea fleas) and ticks (Rhipicephalus sanguineus) on the body of dogs. Twenty-four dogs were tested to determine the effectiveness of a collar containing an isoxazoline active agent formulated in a PVC matrix against induced infestations of cat fleas and Rhipicephalus sanguineus. Dogs were infested with approximately 100 C. felis fleas on day -5 (i.e., before collar application) prior to treatment application, and treatment groups were randomized based on these flea counts determined at 48 (±2) hours post-infestation. Four treatment groups were formed, each containing six dogs. Dogs in Group 1 were untreated (a blank collar containing no isoxazoline active was applied). Dogs in Groups 2, 3, and 4 were treated with the collar compositions described in Table 5. All dogs were treated once on day 0 (i.e., the collars were placed on the dogs on day 0).

[0240] Dogs were reinfested with approximately 100 Chlamydia felis on days 4, 12, 27, 41, 89, and 109 after collar application. Flea counts were performed 48 hours after infestation, except for days 89 and 109, when flea counts were assessed at 24 hours after infestation. All dogs were also infested with approximately 50 R. sanguineus ticks on days 19 and 55, or approximately 50 D. variabilis ticks on day 67. Ticks were counted 72 hours after infestation on day 19 and 48 hours after infestation on days 55 and 67.

[0241] The efficacy against fleas is listed in Table 6 and the efficacy against ticks is listed in Table 7 below. The percent flea reduction (based on the arithmetic mean flea count for each treatment group compared to the untreated group, also referred to as efficacy) was at least 89% up to and including day 166 for all treatment groups (see Table 6). The percent reduction in ticks was at least 58% up to and including day 153 for all treatment groups (see Table 7). These experimental data demonstrate that parasite collar compositions containing isoxazoline active agents provide superior efficacy against fleas and ticks on the body of dogs.

[0242] [Table 7]

[0243] [Table 8]

[0244] [Table 9]

[0245] PK Data: Blood samples were taken periodically from all dogs and analyzed for drug concentration in plasma (shown in FIG. 5). As shown, significant amounts of all three isoxazoline compounds were present in the dog blood, suggesting that they permeated transdermally through the dog's skin into the bloodstream. In other words, these compounds likely act by a systemic mechanism even though they were applied in a topical collar formulation. These PK data also appear to correlate with the flea and tick efficacy data in Tables 6 and 7 (e.g., compound (S)-Ia was best, (S)-Id was second, and Ia was third).

[0246] Isoxazoline compounds in dog hair: On day 110, hair samples were collected from five different regions from each dog: (1) mid-thorax, (2) lower back / caudal region, (3) right thorax, (4) left thorax, and (5) upper neck / base of skull above the collar site. Appropriate bioanalytical methods were used for the analysis of the three isoxazoline compounds in dog hair. Figure 6 shows the results for (S)-Id. Predominantly, there were detectable levels of isoxazoline compounds throughout the dog's body, with the highest drug levels in the "upper neck" where the PVC / isoxazoline collar was located. The results for the other two isoxazoline compounds, Ia and (S)-Ia, are very similar. This pattern suggests that the isoxazoline compounds first migrated from the collar to the dog's hair and then permeated through the skin into the bloodstream.

[0247] Example 4 Collars with other polymer matrices Several novel polymers were evaluated for making collars using isoxazoline compounds including polybutylene succinate (PBS), polybutylene succinate adipate (PBSA), ethylene vinyl acetate copolymer (EVA), polycaprolactone (PCL), and polylactic acid (PLA). Triethyl citrate (TEC) was used as a plasticizer to soften the rigidity of some of the polymers. Table 8 summarizes the collar formulations using compound (S)-Ia as a model isoxazoline compound. All polymer resins were cryomilled to a fine powder and then individually mixed with Compound (S)-Ia. Samples were made in 600 g batches targeting an active loading of 11% by weight in each batch. All mixtures were mixed manually with a spatula to ensure uniformity in the formulation. The formulations are shown in Table 8. Collars were formed in a Leistritz 18 mm twin screw extruder with process parameters listed in Table 9. After extrusion, buckles were manually attached for PK (i.e., pharmacokinetic) studies.

[0248] [Table 10]

[0249] [Table 11]

[0250] DSC Testing The resulting collars were analyzed by DSC along with the isoxazoline compound (S)-Ia and the corresponding polymer. Figure 7 is a comparison to an EVA-based collar, and Figure 8 is a comparison to a PBSA-based collar. As shown in Figures 7 and 8, compound (S)-Ia became completely amorphous in the collars. This also plasticized both EVA and PBSA by depressing their melting points.

[0251] Collar Mechanical Properties For each polymer and sample type, 7-8 grams of polymer resin material was added to a HAAKE MiniLab II twin screw extruder (Waltham MA, USA) equipped with PolySoft OS and PolySoft Monitor Software. The extruder was equilibrated at the desired temperature before adding the material, which was cycled and then loaded into the barrel of a HAAKE MiniJet Injection Molding Unit. Two ASTM Type V dog bones were injection molded for each sample set.

[0252] The extruded "dog bone" samples were tested on a Shimadzu Autograph AGS-X tensile strength tester (Kyoto, Japan) equipped with a 1 kN load cell and gas clamp. The samples were pulled at a rate of 10 mm / min and data was recorded until the sample broke. Tensile tests were performed in duplicate to establish a rough standard deviation. The built-in TRAPEZIUMX software was used to calculate Young's modulus, strain at break, yield strength (if present), and stress at break.

[0253] [Table 12]

[0254] [Table 13]

[0255] Pharmacokinetic (PK) studies: Thirty healthy beagle dogs, 10 females and 20 males, weighing 7.85-16.87 kg (mean 11.93 kg) and aged 8.3-94.0 months (mean: 46.4), were divided into five treatment groups, with six dogs in each group. Experimental cervical collars were applied to all dogs on day 0 of the study. Blood samples were collected on days 1, 4, 7, 14, 21, 28, 35, and 42 after collar application. A pre-dosing blood sample was collected on day -7. No dogs lost their collars during the study.

[0256] Figure 9 shows the PK profiles of the four groups with EVA, PBS, PBS / TEC, and PBSA collars, each containing compound (S)-Ia. The Cmax of all four groups was between 50 and 300 ng / mL, which is similar to the PK study with the PVC collar (Figure 5). Therefore, it can be expected that the collars with EVA, PBS, PBS / TEC, and PBSA will have similar efficacy against fleas and ticks as the PVC collar.

[0257] The invention is further described by the following numbered paragraphs: #1. An antiparasitic external device for treating and / or preventing parasitic infection or infestation in an animal, comprising: i) an effective amount of an isoxazoline activator of formula (I):

[0258] [ka] (I) [In the formula, A 1 , A 2 , A 3 , A 4 , A 5 and A6 Independently, CR 3 and N, where A 1 , A 2 , A 3 , A 4 , A 5 and A 6 up to three of them shall be N, B 1 , B 2 and B. 3 Independently, CR 2 and N, W is O or S; R 1 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 6 and Each R 2 are independently H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, C 2 -C 4 Alkoxycarbonyl, -CN, -SF 5 OR -NO 2 and Each R 3 are independently H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Halocycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, -CN, -SF 5 OR -NO 2 and R 4 , H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl, C4 -C 7 Cycloalkylalkyl, C 2 -C 7 Alkylcarbonyl or C 2 -C 7 is an alkoxycarbonyl; R 5 H, OR 10 , N.R. 11 R 12 Or Q 1 or C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 7 or R 4 and R 5 together with the nitrogen to which they are attached form a ring containing 2 to 6 carbon atoms and, optionally, one additional atom selected from the group consisting of N, S and O, said ring being 1 -C 2 Alkyl, halogen, -CN, -NO 2 and C 1 -C 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy; Each R 6 are independently halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Alkylsulfonyl, -CN or -NO2 and Each R 7 are independently halogen or C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 8 Dialkylamino, C 3 -C 6 Cycloalkylamino, C 2 -C 7 Alkyl carbonyl, C 2 -C 7 Alkoxycarbonyl, C 2 -C 7 Alkylaminocarbonyl, C 3 -C 9 Dialkylaminocarbonyl, C 2 -C 7 Haloalkylcarbonyl, C 2 -C 7 Haloalkoxycarbonyl, C 2 -C 7 Haloalkylaminocarbonyl, C 3 -C 9 Dihaloalkylaminocarbonyl, hydroxy, -NH 2 , -CN or -NO 2 or Q 2 and Each R 8 are independently halogen, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, C 2 -C 4 Alkoxycarbonyl, -CN, -SF 5 OR -NO 2 and Each R 9 are independently halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Halocycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Haloalkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6 Haloalkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Haloalkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 6 Dialkylamino, -CN, -SF 5 , -NO 2 , phenyl or pyridinyl; R 10 is H or C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is optionally substituted with one of further halogens; R 11 , H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl, C 4 -C 7 Cycloalkylalkyl, C 2 -C 7 Alkylcarbonyl or C 2 -C 7 is an alkoxycarbonyl; R 12 is either H or Q 3 or C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 7 or R 11 and R 12together with the nitrogen to which they are attached form a ring containing 2 to 6 carbon atoms and, optionally, one additional atom selected from the group consisting of N, S and O, said ring being 1 -C 2 Alkyl, halogen, -CN, -NO 2 and C 1 -C 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy; Q 1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-, or 10-membered fused bicyclic ring system optionally containing 1 to 3 heteroatoms selected from up to 1 O, up to 1 S, and up to 3 N, each ring or ring system being selected from R 8 and Each Q 2 are independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring being 9 and Q 3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring being 9 and n is 0, 1, 2 or 3; or a pharma- ceutically acceptable salt thereof; ii) a polymer matrix; 13. An anti-parasitic external device comprising:

[0259] #2.R 1 C 1 -C 3 The antiparasitic external device of paragraph 1, which is a haloalkyl. #3.B 1 , B 2 and B. 3 CR 2 and R 2 is hydrogen, halogen or C 1 -C 3The antiparasitic external device of paragraph 1 or 2, wherein the haloalkyl. #4.A 1 , A 2 , A 3 , A 4 , A 5 and A 6 Each is independently CR 3 and R 3 are hydrogen, halogens, C 1 -C 3 Alkyl or C 1 -C 3 The antiparasitic external device of any one of paragraphs 1 to 3, wherein the is haloalkyl. #5.R 4 is hydrogen, C 1 -C 3 Alkyl or C 1 -C 3 5. The antiparasitic external device of any one of paragraphs 1-4, wherein the is haloalkyl. #6.R 5 C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 7 Alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each of which is R 7 6. The antiparasitic external device of any one of paragraphs 1 to 5, optionally substituted with one or more substituents independently selected from:

[0260] #7.R 7 is halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6Alkylsulfinyl, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylamino, C 2 -C 8 Dialkylamino, C 3 -C 6 Cycloalkylamino, C 2 -C 7 Alkyl carbonyl, C 2 -C 7 Alkoxycarbonyl, C 2 -C 7 Alkylaminocarbonyl, C 3 -C 9 Dialkylaminocarbonyl, C 2 -C 7 Haloalkylcarbonyl, C 2 -C 7 Haloalkoxycarbonyl, C 2 -C 7 Haloalkylaminocarbonyl or C 3 -C 9 7. The antiparasitic external device of paragraph 6, which is a dihaloalkylaminocarbonyl. #8.R 7 C 2 -C 7 Alkylaminocarbonyl, C 3 -C 9 Dialkylaminocarbonyl, C 2 -C 7 Haloalkylcarbonyl, C 2 -C 7 Haloalkoxycarbonyl, C 2 -C 7 Haloalkylaminocarbonyl or C 3 -C 9 8. The antiparasitic external device of paragraph 7, which is a dihaloalkylaminocarbonyl. #9. The compound of formula (I) has the formula (Ia) or (Id):

[0261] [ka] 9. The antiparasitic external device of any one of paragraphs 1 to 8, comprising: #10. The compound of formula (I) has the formula (S)-Ia or (S)-Id:

[0262] [ka] 9. The antiparasitic external device of any one of paragraphs 1 to 8, comprising: #11. An antiparasitic external device described in any one of paragraphs 1 to 10, wherein the compound of formula (I) is present in a concentration of about 1 to about 40% (w / w). #12. An antiparasitic external device for treating and / or preventing parasitic infestation or infection in an animal, comprising: i) a) an effective amount of at least one parasiticidal active agent, a) a compound of formula (VII):

[0263] [ka] (VII) and / or b) a pharma- ceutically acceptable salt or derivative of a compound of formula (VII), ii) a polymer matrix; 13. An anti-parasitic external device comprising: #13. The antiparasitic external device of any one of paragraphs 1 to 12, wherein the polymer matrix comprises at least one polymer that is a vinyl polymer, a polyester, a nylon, a polyacrylate, a cellulosic polymer, or a thermoplastic polyurethane.

[0264] #14. The antiparasitic external device of paragraph 13, wherein the vinyl polymer comprises polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polyvinylidene fluoride (PVDF), polyethylene (PE), polypropylene (PP), chlorinated polyethylene (CPE), chlorinated polypropylene (CPP), ethylene-propylene copolymer, polyvinyl acetate (PVAc), ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride-vinyl acetate, polyvinyl fluoride, polystyrene, polyisobutylene (PIB), styrene-butadiene rubber (SBR), styrene-isoprene rubber (SIS), or a combination thereof. #15. The antiparasitic external device of paragraph 13, wherein the polyester comprises polyethylene terephthalate (PET), PET copolymer, polylactic acid (PLA), PLA copolymer, polylactic acid-co-glycolide (PLGA), polycaprolactone (PCL), PCL copolymer, polyhydroxyalkanoate (PHA), polybutylene succinate (PBS), polybutylene succinate-co-adipate (PBSA), polybutylene adipate terephthalate (PBAT), or a combination thereof.

[0265] #16. The antiparasitic external device of paragraph 13, wherein the polymer matrix comprises a biodegradable polyester selected from polybutylene succinate (PBS); polybutylene succinate-co-adipate (PBSA); polylactic acid (PLA) and / or copolymers; polylactic acid-co-glycolide (PLGA); polycaprolactone (PCL), PCL copolymers, polyhydroxyalkanoates (PHA), polybutylene adipate terephthalate (PBAT), or combinations thereof. #17. The antiparasitic external device of paragraph 16, wherein the polymer matrix comprises a biodegradable polyester that is polybutylene succinate-co-adipate (PBSA) and / or polybutylene succinate (PBS) and / or polybutylene adipate terephthalate (PBAT).

[0266] #18. The antiparasitic external device described in paragraph 13, wherein the polymer matrix comprises a nylon selected from the group consisting of Nylon 6, Nylon 66, and Nylon 12. #19. The antiparasitic external device described in paragraph 13, wherein the polymer matrix comprises at least one polyacrylate selected from the group consisting of polymethyl methacrylate (PMMA), polymethyl acylate (PMA), polyethyl methacrylate (PEMA), polybutyl methacrylate (PBMA), and copolymers thereof. #20. The antiparasitic external device described in paragraph 13, wherein the cellulose-based polymer is cellulose acetate (CA) and / or ethyl cellulose (EC).

[0267] #21. The antiparasitic external device of paragraph 13, wherein the polymer matrix comprises any one of polyvinyl acetate (PVAc), ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride-vinyl acetate, or a mixture thereof. #22. The antiparasitic device of paragraph 21, wherein the polymer matrix comprises ethylene-vinyl acetate copolymer (EVA). #23. The antiparasitic external device of any one of paragraphs 1 to 22, wherein the external device further comprises a plasticizer, optionally a stabilizer, and optionally an antioxidant. #24. An antiparasitic external device for treating and / or preventing parasitic infestation or infection in an animal, comprising: i) Formula (Ia) or (Id):

[0268] [ka] an effective amount of at least one parasiticidal active agent, which is a compound of the formula ii) a polymer matrix comprising at least one of polybutylene succinate (PBS), polybutylene succinate adipate (PBSA), ethylene-vinyl acetate copolymer (EVA), and polyvinyl chloride; iii) optionally a plasticizer; iv) optionally with stabilizers and / or antioxidants; 13. An anti-parasitic external device comprising:

[0269] #25. The antiparasitic external device according to paragraph 24, wherein the polymer matrix consists of ethylene-vinyl acetate copolymer (EVA) with 5-95% vinyl acetate, preferably 5-50% vinyl acetate, and most preferably 5-30% vinyl acetate. #26. The antiparasitic external device of paragraph 24, wherein the polymer matrix is ​​made of polybutylene succinate having triethyl citrate.

[0270] #27. The antiparasitic external device of any one of paragraphs 1 to 26, further comprising one or more additional active agents. #28. A method for treating and / or preventing parasitic infestation and / or infection in an animal, comprising applying an antiparasitic external device described in any one of paragraphs 1 to 27 to an animal in need thereof. #29. Use of an isoxazoline active agent of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of an antiparasitic external device.

[0271] Although various embodiments of the present invention have been described in detail, it is to be understood that the invention defined in the above paragraphs is not limited to the particular details set forth in the above specification, since many obvious variations thereof are possible without departing from the spirit or scope of the present invention.

Claims

1. 1. An antiparasitic external device for treating and / or preventing a parasitic infection or infestation in an animal, comprising: i) an effective amount of an isoxazoline activator of formula (Ia) or (Id): 【Chemistry 1】 ii) a polymer matrix comprising ethylene-vinyl acetate copolymer (EVA); wherein the isoxazoline active agent is dispersed in a polymer matrix.

2. The isoxazoline activator has the formula (S)-Ia or (S)-Id: 【Chemistry 2】 2. The anti-parasitic external device of claim 1, comprising:

3. An antiparasitic external device as described in claim 1 or 2, wherein the isoxazoline active agent is present at a concentration of about 1 to about 40% (w / w).

4. The antiparasitic external device of any one of claims 1 to 3, wherein the external device further comprises a plasticizer, and optionally a stabilizer, and optionally an antioxidant.

5. 1. An antiparasitic external device for treating and / or preventing a parasitic infestation or infection in an animal, comprising: i) Formula (Ia) or (Id): 【Chemistry 5】 an effective amount of at least one parasiticidal active agent, which is a compound of the formula: ii) a polymer matrix consisting of ethylene-vinyl acetate copolymer (EVA) with 5-50% vinyl acetate; iii) optionally a plasticizer; iv) optionally with a stabilizer and / or antioxidant; wherein the parasiticidal active agent is dispersed in the polymer matrix.

6. 6. The antiparasitic external device of claim 5, wherein the polymer matrix consists of ethylene-vinyl acetate copolymer (EVA) with 5-30% vinyl acetate, iii) optionally a plasticizer, and iv) optionally a stabilizer and / or antioxidant.

7. The antiparasitic external device of any one of claims 1 to 6, further comprising one or more additional parasiticidal active agents.

8. 13. A method for treating a parasitic infestation and / or a parasitic infection in an animal (excluding humans), comprising applying an antiparasitic external device according to any one of claims 1 to 7 to the animal (excluding humans) in need thereof.

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