NZ742345B2 - Parasiticidal compositions comprising an isoxazoline active agent, methods and uses thereof - Google Patents

Parasiticidal compositions comprising an isoxazoline active agent, methods and uses thereof Download PDF

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Publication number
NZ742345B2
NZ742345B2 NZ742345A NZ74234512A NZ742345B2 NZ 742345 B2 NZ742345 B2 NZ 742345B2 NZ 742345 A NZ742345 A NZ 742345A NZ 74234512 A NZ74234512 A NZ 74234512A NZ 742345 B2 NZ742345 B2 NZ 742345B2
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New Zealand
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alkyl
composition
topical
active agent
day
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NZ742345A
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NZ742345A (en
Inventor
Carol Belansky
James Pate
Joseph K Rosentel
Natalya Shub
Mark D Soll
Monica Tejwanimotwani
Motwani Monica Tejwani
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Boehringer Ingelheim Animal Health Usa Inc
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Priority claimed from NZ725115A external-priority patent/NZ725115A/en
Publication of NZ742345A publication Critical patent/NZ742345A/en
Publication of NZ742345B2 publication Critical patent/NZ742345B2/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N2300/00—Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
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    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract

Provided are topical veterinary compositions comprising at least one parasiticidal isoxazoline compound of Formula (I), and a pharmaceutically acceptable carrier, optionally in combination with one or more additional active agents. A preferred active agent 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-naphthalanecarboxamide. A preferred pharmaceutically acceptable carrier is liquid polyethylene glycol (PEG). ]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide. A preferred pharmaceutically acceptable carrier is liquid polyethylene glycol (PEG).

Description

TITLE OF THE ION PARASITICIDAL COMPOSITIONS COMPRISING AN ISOXAZOLINE ACTIVE AGENT, METHODS AND USES THEREOF.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of New Zealand Patent ation No. 725115, the contents of which are incorporated herein by reference, which is a divisonal application of New Zealand Patent Application No. 710442, which is a divisional application of New Zealand Patent Application No. 622466. This application also claims the benefit of priority to U.S. Provisional Application No. 61/533,308 filed September 12, 2011, which is orated herein by reference in its entirety.
FIELD OF THE INVENTION The present invention provides l veterinary itions comprising at least one isoxazoline active agent for controlling ectoparasites and rasites in animals; the use of these compositions against ectoparasites and/or endoparasites, and methods for preventing or treating parasitic infections and infestations in animals.
BACKGROUND OF THE INVENTION Animals such as mammals and birds are often susceptible to parasite infestations/infections. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Domesticated animals, such as cats and dogs, are often ed with one or more of the following ectoparasites: - fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis and the like); - ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., and the like); - mites (e.g. Demodex spp., tes spp., Otodectes spp., and the like); - lice (e.g. Trichodectes spp., Cheyletiella spp., Lignonathus spp. and the like); - mosquitoes (Aedes spp., Culux spp., Anopheles spp. and the like); and - flies (Hematobia spp., Musca spp., Stomoxys spp., Dematobia spp., mia spp. and the like).
Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals and , such as dog tapeworm (Dipylidium caninum).
W0 20131039948 PCT/U8201210547l9 Similarly, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are the vector of pathogenic agents in both humans and animals. Major diseases which are caused by ticks include borrelioses (Lyme disease caused by Borrelia burgdorferi), babesioses (or asmoses caused by Babesia spp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks also release toxins which cause ation or paralysis in the host. Occasionally, these toxins are fatal to the host. se, farm animals are also susceptible to te infestations. For example, cattle are ed by a large number of parasites. A parasite which is very prevalent among farm animals is the tick genus Rhipicephalus, especially those of the species microplus (cattle tick), decoloratus and annulatus. Ticks such as Rhipicephalus microplus (formerly Boophilus microplus) are particularly difficult to control because they live in the pasture where farm animals graze. This species of ticks is considered a one-host tick and spends immature and adult stages on one animal before the female es and falls off the host to lay eggs in the environment. The life cycle of the tick is approximately three to four weeks. In addition to cattle, Rhipicephalus microplus may infest found on buffalo, horses, donkeys, goats, sheep, deer, pigs, and dogs. A heavy tick burden on animals can decrease production and damage hides as well as transmit diseases such as babesiosis (“cattle fever”) and anaplasmosis caused by protozoan parasites. s and humans also suffer from endoparasitic infections ing, for example, helminthiasis which is most frequently caused by a group of parasitic worms categorized as ccstodes (tapeworm), nematodes (roundworm) and odes (flatworm or flukes). These parasites adversely affect the nutrition of the animal and cause severe economic losses in pigs, sheep, horses, and cattle as well as affecting domestic animals and poultry. Other tes which occur in the gastrointestinal tract of s and humans include Ancylostoma, Nccator, s, yloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strogyloides, Toxocara and Trichinella.
Recently, isoxazole and isoxazoline-containing compounds have been demonstrated to be effective t parasites that harm animals. For example, US 2010/0234219 A1 (to DuPont) PCT /US2012/054719 discloses oline compounds according to a (I) below, which are active t ectoparasites and/or endoparasites. w (I) In addition, published patent application nos. US 2010/0254960 Al, A2, WO 2007/123855 A2, Al, US7951828 & US7662972, US 2010/0137372 Al, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al and WO 2007/075459 A2 and U.S. Patent Nos. 7,951,828 and 972 describe various other parasiticidal isoxazoline compounds. bes l localized isoxazoline formulations comprising glycofurol.
Notwithstanding the compositions comprising isoxazoline active agents alone or in combination with other active agents described in the documents above, there is a need for veterinary compositions and methods with improved efficacy, bioavailability, and um of coverage to protect animals t endoparasites and/or ectoparasites. Optimal compositions should provide contact and/or systemic activity, be efficacious, have a quick onset of activity, have a long duration of activity, and be safe to the animal recipient and their human owners. This invention addresses this need.
ORATION BY REFERENCE Any foregoing applications, and all documents cited therein or during their prosecution ("application cited documents") and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or nced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the ion.
Citation or identification of any document in this application is not an admission that PCT /US2012/054719 such document is available as prior art to the present invention.
SUMMARY OF THE INVENTION The present ion is directed to topical compositions compnsmg at least one isoxazoline, alone or in combination with other active agents, and their use to control parasites in or on warm-blooded animals and birds. In accordance with this ion, it has been discovered that these compositions generally show desirable bioavailability, and can provide contact and/or ic activity. The compositions also provide desirable safety profiles toward the warmblooded and bird animal recipients. In addition, it has been discovered that a single administration of such compositions generally provides potent activity against one or more rasites, while also g to provide fast onset of activity, long duration of ty, and/or desirable safety profiles.
The invention encompasses uses or veterinary uses of the isoxazoline compositions for the treatment or prophylaxis of parasitic infections and ations of animals ( either wild or domesticated), including livestock and companion animals such as cats, dogs, , chickens, sheep, goats, pigs, turkeys and cattle, with the aim of g these hosts of parasites ly encountered by such animals.
In a particularly preferred embodiment, the composition is a topical spot-on formulation.
In another preferred embodiment particularly well suited for livestock animals, the composition is a topical pour-on formulation. The invention also includes other topical itions comprising an isoxazoline active agent including sprays, aerosols, foams and the like.
In some embodiments, the topical nary composition comprises a pharmaceutically acceptable carrier wherein the carrier comprises a diester of a dicarboxylic acid, a glycol ester, a glycol ether, a fatty acid ester, a polyethylene glycol, or hylene glycol ester, an oil, an alcohol, a glycerol ester, a glycerol ether, propylene glycol, ethylene , a glycol ate, dimethyl isosorbide, N-methylpyrrolidone, or a mixture thereof.
In one embodiment, the diester of a dicarboxylic acid is a diester of a C6-C 16 dicarboxylic acid including, but not limited to, diethyl sebacate or diisopropyl adipate.
In another embodiment of the invention, the pharmaceutically acceptable carrier of the compositions comprises mixture of a diester of a dicarboxylic acid and a propylene glycol ester, a fatty acid ester, a polyethylene glycol ester, a polyethylene glycol, an oil, a C6-C20 long-chain PCT /US2012/054719 aliphatic alcohol, a C1-C8 alcohol, glycol ether, or a combination thereof.
In certain embodiments, the pharmaceutically acceptable carrier of the topical veterinary ition of the invention further comprises a mixed ester of sucrose and acetic and isobutyric acid, a low melting wax, a hard fat or a block co-polymer of ethylene oxide and ene oxide, or a combination thereof.
In another ment, the pharmaceutically acceptable earner compnses dimethyl isosorbide, glycerol formal, propylene carbonate, triacetin, diethyleneglycol monoethyl ether, polyethylene glycol 400 or benzyl alcohol, or a mixture thereof.
The invention also es methods for the treatment or tion of parasitic infections and infestations in animals, sing administering an effective amount of a composition comprising at least one isoxazoline to the . Surprisingly, it has been found that the inventive compositions and formulations described herein exhibit superior broad spectrum efficacy against harmful ectoparasites more rapidly, and over a long duration compared to compositions known in the art.
In one embodiment, the invention provides topical nary compositions comprising effective amounts of at least one isoxazoline of formula (I) below, in combination and a pharmaceutically or veterinarily acceptable liquid carrier, where variables A1, A2, A3, A4, As, A6, B 1 B 2 B 3 1 2 3 .
, , , R , R , R , R 4, Rs, W are d fie 1ne d here1n. w (I) In some embodiments, the topical veterinary compositions and methods comprise 4-[5- [3-chloro(trifluoromethyl)phenyl]-4,5-dihydro(trifluoromethyl)isoxazolyl]-N-[2-oxo- 2-[(2,2,2-trifluoroethyl)amino]ethyl]naphthalenecarboxamide as the active agent.
In other embodiments, the compositions may further comprise one or more additional active agents. In one embodiment, the compositions comprise at least one macrocyclic lactone active agent, including, but not d to, avermectins or ycins. In some embodiments, PCT/U82012/054719 the avermectin or milbemycin active agent is eprinomectin, ivermectin, ctin, milbemectin, milbemycin D, ycin oxime, or moxidectin.
In another embodiment, the topical compositions of the invention include a combination of an isoxazoline active agent with the neonicotinoid active agent yram.
In other embodiments, the compositions and s of the invention may further comprise an insect growth regulator (IGR) active agent, including but not limited to, methoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron, or novaluron. In another preferred embodiment, the compositiOns of the invention comprise a neonicotinoid active agent such as nitcnpyram. In other embodiments, the compositions and methods comprise at least one of IO thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, lon, an amino acetonitrile active agent, or an aryloazol-Z-yl cyanoethylarnino active agent.
It is an object of the invention to not encompass within the invention any previously known product, process of making the product, or method of using the product such that the Applicants reserve the right and hereby disclose a disclaimer of any previously known product, s, or method. It is r noted that the invention does not intend to encompass within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the Evritten description and ment ements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and hereby disclose a imer of any previously described product, s of making the product, or method of using the product.
These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.
BRIEF PTION OF THE DRAWINGS Fig. I is a plot showing the long lasting efficacy of a spot-on composition comprising Compound A against Ctenocepha/idesfelis fleas in cats le 9).
Fig. 2 is a plot showing the long lasting efficacy of a pour-on composition comprising Compound A against Rhipicephalus (Boophi/zis) microplus in cattle based on the number of ticks dropped (Example 15).
PCT/U82012/054719 Fig. 3 is a plot showing the long lasting efficacy of a pour-on composition comprising Compound A against Rhipicephalus (Boophz'lus) microplus in cattle based on the weight of ticks that drop (Example 15). _ DETAILED DESCRIPTION The present invention provides novel and inventive topical compositions comprising at least one isoxazoline nd together with a pharmaceutically acceptable carrier or diluent that is suitable for topical application to an animal.
In some embodiments of the invention, the compositions preferably include spot-on or pour-on formulations that are applied to a localized area on an animal. Topical spray, aerosol or IO foam formulations, which typically include the active agent in lower concentrations, are also encompassed by the invention. These formulations provide surprisingly effective protection of the animals t parasites for an extended period of timefThe formulations also provide extremely rapid killing of parasites infesting s. _ Also ed are s and uses for the treatment and/or prophylaxis of parasitic ions and infestations of animals, comprising administering an effective amount of a formulation of the invention to the animal.
The invention includes at least the following features: (a) topical veterinary formulations that exhibit superior activity against animal tes comprising at least one isoxazoline active agent together with a pharmaceutically acceptable carrier or t that is suitable for l ation to an animal; (b) topical veterinary compositions that exhibit superior long lasting efficacy that comprise at least one oline compound of formula (I) described herein er with a pharmaceutically acceptable carrier or t that is suitable for topical application'to an animal; (c) topical Veterinary compositions that exhibit superior long lasting efficacy that comprise at least one isoxazOline active agent in combination with one or more other active agents together with a pharmaceutically acceptable carrier or diluent that is suitable for topical ation to an animal; (d) topical veterinary compositions comprising an effective amount of an isoxazoline active agent together with a pharmaceutically acceptable r or diluent that is suitable for PCT/U82012/054719 topical ation to an animal, wherein the carrier does not comprise glycofurol; (e) topical veterinary compositions comprising an effective amount of an isoxazoline active agent together with a pharmaceutically acceptable carrier or diluent that is suitable for topical application to an animal, wherein the carrier is not a binary mixture of propylene glycol and glycerol formal; _ _ ’ i (f) methods for the treatment or prevention of parasitic infections and infestations in an animal comprising administering an effective amount of a composition comprising at least one isoxazoline ’active’agent together with a ceutically able carrier or diluent; (g) methods for the treatment or prevention of parasitic infections and infestations in an IO animal comprising administering an effective amount of a composition comprising at least one isoxazoline active" agent with a pharmaceutically acceptable earfier or diluent that is suitable for l application to an animal_{ (h) methods for the treatment or prevention of parasitic ions and ations in an animal comprising administering an effective amount of a topical ition comprising at least one isoxazoline active agent in combination with one or more other active agents together with a pharmaceutically acceptable carrier or diluent that is suitable for topical ation to an animal; (i) use of veterinary compositions comprising at least one oline compound, including a compound of formula (I), together with a pharmaceutically acceptable carrier or t in the prevention or treatment of animal parasites.
In this disclosure and in the claims, terms such 39 LL as “comprises, comprising," “containing” and “having” and the like can have the meaning ascribed to them in US. Patent law and can mean “includes.” “including,” and the like; “consisting ially of” or “consists essentially” likewise has the meaning ascribed in US. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the ce of mere than that which is recited, but excludes prior art embodiments.
Definitions “ firmsused herein will have their customary meaning in the art unless specified otherwise. The organic moieties ned in the definitions of the variables of formula (I) are - like the term n — collective terms for individual listings of the individual group members.
PCT/U82012/054719 The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.
The term “animal” is used herein to include all mammals, birds and fish and also include all vertebrate animals. Animals include, but are not d to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also includes an dual animal in all stages—of development. including embryonic and fetal . In some embodiments, the animal will be a non-human animal.
' ' The term “fatty acid” refers to carboxylic acids having from 4 to 26 carbon atoms.
The terms “fatty l” or “long-chain tic alcohol” refer to aliphatic alcohols containing from 6 to 20 carbon atoms.
IO The term “low melting” refers to substances that are solids at room temperature but melt into liquids below 50° C.
’The term “alkyl” refers to saturated straight, branched, cyclic, primary, secondary or tertiary hydrocarbons, including those having 1 to 20 atoms. In some embodiments, alkyl groups will include C1-C12, Cl-Cm, C1-C3, C1-C6 or C1-C4 alkyl . Examples of C1-Cm alkyl include, but are not limited to, methyl, ethyl, , l-methylethyl, butyl, l-methylpropyl, 2- mcthylpropyl, 1,1-dimcthylcthyl, , l-mcthylbutyl, 2-mcthylbutyl, 3-mcthylbutyl, 2,2- dimethylpropyl, l-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylperityl, 3-metliylpentyl, 4-methylpentyl, “1,l“-dimethylbutyl, 1,25dimethylbutyl, 1,3- dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, l-ethylbutyl, 2- ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-l-methylpropyl, l-ethyl methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C1-C4-alkyl means for example methyl, ethyl, propyl, 1-methylethyl, butyl, l-methylpropyl, 2-methylpropyl or 1,]- dimethylethyl. * i V " _ ' W * Cyclic alkyl groups or “cycloalkyl”, which are encompassed by alkyl include those with 3 to 10 carbon atoms having single or multiple condensed rings. In some embodiments, cycloalkyl groups e C4LC7 or C3-C4 cyclic alkyl groups. Non-limiting examples of cycloalkyl groups include tyl, cyclopropyl, cyclobutyl, cntyl, cxyl, cycloheptyl, cyclooctyl and the like. ' ' The alkyl groups described herein can 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 lamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, PCT/U82012/054719 thiol, imino, sulfonie acid, e, yl, sulfanyl, sulfinyl, sulfamonyl, ester, onyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoric acid, phosphate, onate, or any other viable functional group that does not inhibit the biological ty of the compounds of the invention, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons; Third Edition, 1999, hereby incorporated by reference.
Terms including the term “alkyl” such as “alkylcycloalkyl,” “cycloalkylalkyl,” “alkylamino,” or “dialkylamino” will be tood to se an alkyl group as defined above IO linked to the other functional group, where the group is linked to the compound h the last group listed, as understood by those of skill in the art.
The term “alkenyl” refers to both straight and ed carbon chains which have at least one carbon-carbon double bond. In some embodiments, alkenyl groups may include C2-Czo alkenyl groups. In other embodiments, alkenyl includes C2-C12, C2-Cm, C2-C8, C2-C6 or C2-C4 alkenyl groups. In one embodiment of alkenyl, the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one or two. Other ranges of carbon- carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule. “CZ-Clo-alkenyl” groups may include more than one double bond in the chain. Examples include, but are not limited to, l, enyl, 2-propenyl, 1- methyl-ethenyl, l-butenyl, 2-butenyl, 3-butenyl, l-methyl-l-propenyl, 2-methyl-l-propenyl, l- methylpropenyl, 2-methylpropenyl; l-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- methyl-l-butenyl, 2-methylbutenyl, 3-methyl-l-butenyl, 1-methylbutenyl, 2-methyl butenyl, 3-methylbutenyl, l-meth'ylbuteny‘l, 2-methylbutenyl, 3-methylbutenyl, 1,1- dimethyl-Z-propenyl, 1,2-dimethyl-l4propenyl,i1,2-dimethylpropenyl, l-ethyl-l-propenyl, 1- ethyl-2Fpropenyl, nyl, 2-hexenyl, 3-hexeny1, 4-hexenyl, iS-liexenyl, l-methyl-l-pentenyl, 2-methyl-llpentenyl, 3-methylpentenyl, 4-methyl-l-pentenyl, l-methyl-Z-pentenyl, 2-methyl- 2-pcntcnyl, 3-methylpentenyl, 4—mcthylpentenyl, 1-methylpentenyl, 2-methyl pentenyl, 3-methylpenfenyl, 4-methylpentenyl, l-methylpenteny1, 2-methylpentenyl, ylpentenyl, 4-methyl—4-pentenyl, 1,1-dimethylbutenyl, 1,1-dimethylbutenyl, 1,2- dimethyl-l-butenyl, 1,2-dimethylbutenyl, 1,2-dimethylbutenyl, 1,3-dimethyl-l-butenyl, 1,3-dimethylbutenyl, 1,3 -dimethylbutenyl, 2,2-dimethylbutenyl, 2,3-dimethyl- l -butenyl, WO 39948 PCT/U82012/054719 2,3-dimethylbutenyl, 2,3-dimethylbutenyl, 3,3-dimethyl-l-butenyl, 3,3-dimethylbutenyl, l-ethyl-l-butenyl, 1-ethylbutenyl, l—3-butenyl, lbutenyl, 2-ethylbutenyl, 2- ethylé3-butenyl, 1,1,2-trimethyl-24propenyl, l-l-methyl-Z-propenyl, l-ethylmethyl propenyl and 1-ethylmethylpropenyl.
“Alkynyl” refers to both straight and ed carbon chains which have at least one earbon-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 one or two. In some embodiments, l groups e from C2-Czo alkynyl groups. In other embodiments, alkynyl groups may include , C2-Clo, C2-C8, C2-C5 or C2-C4 alkynyl groups. Other ranges of carbon-carbon IO triple bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule. For example, the term ”CZ-Cld-alkynyl” as used herein refers to'a straight-chain or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-l-yn-l-yl, prop-Z-yn-l-yl, n-but-l-ynl-yl , n-but-l-ynyl, n-but-l-ynyl, n-but-Z-yn-l-yl, n-pent-l-yn-l-yl, -l-ynyl, n- pent-l-ynyl, n-pent-l-yn-S-yl, n-pent-Z-yn-l-yl, n-pentynyl, n-pent-Z-yn-S-yl, 3- methylbut-l-ynyl, 3-methylbutynyl, n-hex-l-yn-l-yl, n-hex-l-ynyl, n-hex-l-ynyl, n-hex-l-yn-S-yl, n-hex-l-ynyl, n-hexyn-l-yl, n-hexynyl, Z-yn-S-yl, n-hex-Z- ynyl, 'n-hexyn-l-yl, 'n-hexynyl, 3-methylpent-l-ynyl, 3-methylpent-l-ynyl, 3- methylpent-l-ynyl, 3-methylpentynyl, 4-methylpentynyl, 4-methylpentynyl or 4-methylpentynyl and the like.
The term lkyl” refers to an alkyl group, as defined herein, which is substituted by one or more n atoms. For example C1-C4—haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, l-chloroethyl, l-bromoethyl, l-fluoroethyl, 2-fluoroethyl, 2,2-difluor0ethyl, 2,2,2-trifluoroethyl, 2-chlor042- fluoroethyl, 2-chloro-2,Z-difluoroethyl, 2,2-dichlorofluoroethyl, 2,2,2—trichloroethyl, pcntafluorocthyl and the like.
The term “haloalkenyl” refers to an alkenyl group, as defined herein, which is substituted by one or more halogen atoms.
The term “haloalkynyl” refers to an alkynyl group, as defined herein, which is substituted by one or more halogen atoms.
PCT/U82012/054719 “Alkoxy” refers to alkyl-O-, wherein alkyl is as defined above. Similarly, the terms “alkenyloxy, 3? $6alkynyloxy,” “haloalkoxy,” lkenyloxy,” “haloalkynyloxy,3) alkoxy,” “cycloalkenyloxy,” “halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groups alken'yl- 0-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-_, kynyl-O-, eyeloalkyl-O-, cycloalkenyl-O-, haloeyeloalkyl-O-, and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cyeloalkyl, cyeloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, C2H5-CH20-, (CH3)2CHO-, n-butoxy, Csz-CH(CH3)O-, (CH3)2CH-CH20-‘ (CH3)3CO-, n- pcntoxy, ylbutoxy, 2-methylbutoxy, 3-mcthylbutoxy, mcthylpropoxy, IO l,2—dimethy|propoxy, 2,2-dimethyl-propoxy, l-ethylpropoxy, xy, l-methylpen’toxiy, 2- methylpentoiy, hylpentoxy, 4-methylpentoxy, _ 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3—dimethylbutoxy, 2,2-dimethylbutoxy, 7 methylbutoxy, methylbutoxy, l- ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, l-ethyl-lmethylpropoxy , 1-ethylmethylpropoxy and the like.
The term “alkylthio” refers to alkyl-S-, wherein alkyl is as defined above. Similarly, the terms “haloalkylthio,” “eyeloalkylthio,” and the like, refer to haloalkyl-S- and cyeloalkyl-S- where haloalkyl and eyeloalkyl are as defined above.
The term “alkylsulfinyl” refers to alkyl-S(O)-, wherein alkyl is as defined above.
Similarly, the term “haloalkylsulfinyl” refers to kyl-S(O)- where haloalkyl is as defined above.
The term “alkylsulfonyl” refers to alkyl-S(O)2-, wherein alkyl is as defined above.
Similarly, the term “haloalkylsulfonyl” refers to haloalkyl-S(O)z- where haloalkyl is as defined above.
The term alkylamino and dialkylamino refer to alkyl-NH- and )2N- where alkyl is as defined above. Similarly, the terms “haloalkylamino” refers to haloalkyl-NH- where haloalkyl is as defined above.
The terms “alkylcarbonyl,” “alkoxycarbonyl,” aminocarbonyl,” and “dialkylaminocarbonyl” refer ‘ alkylamino-C(O)- to alkyl-C(O)-, alkoxy-C(O)-, and dialkylamino-C(O)- where alkyl, alkoxy, alkylamino and dialkylamino are as defined above.
Similarly, the terms “haloalkylearbonyl,” “haloalkoxyearbonyl,” "‘haloalkylaminoearbonyl,” and “dihaloalkylaminocarbonyl” refer to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, PCT/U82012/054719 haloalkylamino-C(0)- and dihaloalkylamino-C(O)- where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.
“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. In some embodiments, aryl groups include C6- Cm aryl . Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphtyl, phenyleyelopropyl and indanyl. Aryl groups may be ’unsubstituted or substituted by one or more moieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, eyeloalkyl, eyeloalkenyl, haloalkyl, haloalkenyl, haloalkyhyl, halocycloalkyl, halocycloalkcnyl, alkoxy, alkenyloxy, alkynyloxy, koxy, haloalkenyloxy, IO haloalkynyloxy, eyclOalkoxy, cycloalkenyloxy, haloCycloalkoxy, halocycloalkcnyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, lsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl. haloalkenylsulfinyl, haloalkynylsulfmyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino, alkynylamino, yl)amino, di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl.
The terms “aralkyl” or “arylalkyl” refers to an aryl group that is bonded to the parent compound through a diradical alkylene bridge, (-CH2-)n, where n is 1-12 and where “aryl” is as defined above.
“Heteroaryl” refers to a monovalent ic group of from 1 to 15 carbon atoms, ably from 1 to 10 carbon atoms, having one or more oxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such aryl groups can have a single ring (e.g., pyridyl or furyl) or multiple sed rings ed that the point of attachment is thrbugha heteroaryl ring atom. Preferred heteroaryls' include pyridyl, pifidazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quin’azolinyl,’ quinoxalinnyl, l, thiophenyl, fiiryl, pyrrolyl, imidazolyl‘, oxazolyl, isOxazolyl, isothiazolyl, pyrazolyl bcnzofuranyl, and bcnzothiophcnyl. Heteroaryl rings may be unsubstituted or tuted by one or more moieties as described for'aryl above.
“Heterocyclyl,” “heterocyclic” or “heterocyclo” refer to fully saturated or unsaturated, cyclic groups, for example, 3 to’7 membered monocyclic or 4 to 7 membered monocyclic; 7 to 11 membered bicyclic, or 10 to 15 membered lic ring systems, which have one or more PCT/U82012/054719 oxygen, sulfur or nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized and the en heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or tuted by one or more moieties as described for aryl groups above.
Exemplary monoéyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl; is0xazolyl, thiazolyl, thiadiazolyl, lidinyl, 'isothiazolyl, isothiazolidinyl, furyl, tctrahydrofuryl, thicnyl, oxadiazolyl, pipcridinyl, pipcrazinyl, 2- IO oxopiperazinyl, 2-0Xopiperidinyl, yrrol0dinyl, 2-oxoazepinyl, azepinyl,‘ 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridaiinyl, tetrahydropyranyl; morpholinyl, thiamorpholinyl, thiamorphélinyl sulfoxide, rpholinyl ‘ 1,3-dioxolane sulfone,’ and tetrahydro-l,l- hienyl, triazolyl, triazinyl, and the like.
Exemplary bicyclic heterocyclic groups include. but are not limited to, indolyl, benzothiazolyl, azolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra- hydroisoquinolinyl, isoquinolinyl, idazolyl, bcnzopyranyl, indolizinyl, bcnzofuryl, chromonyl, coumarinyl, bcnzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, opyridyl, ridinyl (such as furo[2,3-c]pyridinyl, fi1r0[3,2-b]pyridinyl]or furo[2;3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydrooxo-quinazolinyl), tetrahydroquinolinyl and the like.
Exemplary lic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
V Halogen means the atoms fluorine, chlorine, bromine and iodine. The designation of “halo” (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitutions from a single substitution to a perhalo substitution (e.g. as illustrated with methyl as chloromethyl (-CHzCl), dichloromethyl (-CHC12), trichloromethyl (-CC13)).
Stcrcoisomcrs and polymorphic forms It will be appreciated by those of skill in the art that certain compounds within the itions of the invention may exist and be isolated as optically active and c forms.
Compounds having one or more Chiral centers, including at a sulfur atom, may be present as single enantiomers or diastereomers or as es of enantiomers and/or diastereomers. For PCT/U82012/054719 example, it is well known in the art that ide compounds may be optically active and may exist as single enantiomers or racemic mixtures. In addition, compounds within the compositions of the invention may include one or more chiral centers, which results in a theoretical number of optically active s. Where compounds within the compositions of the invention e n chiral centers, the compounds may comprise up to 2" optical isomers. The t invention encompasses the specific enantiomers or diastereomers ofeach compound as well as mixtures of different enantiomers and/or diastereomers of the nds of the invention that possess the useful properties described herein. The optically active forms can be prepared by, for example, tion of the c forms by selective llization techniques, by synthesis from IO optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution. _ _ The compounds Within the compositions of present invention may also be present in different solid forms such as different crystalline forms or in the form of an amorphous solid.
The present invention encompasses different crystalline forms as well as ous forms of the inventive nds.
In addition, the compounds within the compositions of the invention may exist as es or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in the crystalline form. The compositions of the invention may include hydrates and solvates of the active agents. In some embodiments, the compositions of the invention may include up to 15% (w/w), up to 20% (w/w), or up to 30% (w/w) of a particular solid form.
Salts Also contemplated within the scope of the invention are acid or base salts, where applicable, of the compounds of the invention provided for herein.
The term "acid salt" contemplates salts of the compounds with all pharmaceutically acceptable inorganic or organic acids“. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carbOXylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment of the acids. the acids are straight chain or branched, ted 0r rated C1-C20 aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C6-C12 PCT/U82012/054719 aromatic ylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valcric acid, et-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, e sulfonic' acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids e all pharmaceutically acceptable saturated or unsaturated tic or aromatic carboxylic acids having 4 to 24 carbon atoms. es include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and steric acid. Other acids include gluconic acid, eptonic acid and lactobionic acid.
The term “base salt” contemplates salts of the compounds with all pharmaceutically acceptable inorganic or c bases, including hydroxides, carbonates or bicarbonates of alkali metal or alkaline earth metals. Salts formed with such bases include, for example, the alkali metal and alkaline earth metal salts, including, but not limited to, as the lithium, sodium, potassium, magnesium or calcium salts. Salts formed with organic bases include the common hydrocarbon and heterocyclic amine salts, which include, for example, ammonium salts (NH4' ), alkyl- and dialkylammonium salts, and salts of cyclic amines such as the morpholine and piperidine salts.
In one embodiment. the invention provides l veterinary compositions comprising effective amounts of at least one isoxazoline of formula (I) belOw, in‘ combination—and a pharmaceutically or vcterinarily acceptable liquid carrier: A6” \ 4 O—N wherein AKA], A“, A4, A5 and A6 are independently CR3 or N, provided that at most 3 of Al, A2, A3, A4, A5 and A6 are N; - I - B], B2 and B3 are independently CR2 or N; PCT/U82012/054719 W is O or S; R1 is alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R2 is independently H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl. haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, —CN‘or —N02; ' each R3 is independently H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, hio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, lamino, —CN or —NOz; IO R4 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, lkylalkyl, alkylcarbonyl or alkoxycarbonyl; ' ' V ' V I R5 is H, OR"), NRHR'2 or Q]; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally tuted with one or more substituents independently selected from R7; or R4 and R5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom cd from the group consisting of N, S and 0, said ring optionally substituted with 1 to 4 substituents independently selected from the group consiSting of alkyl, n, —CN, —NOZ and alkoxy; each R6 is independently halogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, —CN or —NOZ; each R7 is independently n; alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbohyl, haloalkoxycarbonyl. haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, hydroxy, —NH2, —CN or —N02; or Q2; each R8 is independently halogen, alkoxy, haloalkoxy, hio, haloalkylthio, alkylsulflnyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, —CN or —N02_; each R9 is independently halogen, alkyl, haloalkyl, lkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, kylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl; alkylamino, dialkylamino, —CN, —N02, phenyl or pyridinyl; PCT/U82012/054719 R10 is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkyleycloalkyl or cycloalkylalkyl, each optionally substituted with one of more halogen; 7 R11 is H, alkyl, alkenyl, alkynyl, icycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl; R12 is H; Q3; or alkyl, alkenyl, alkynyl, lkyl, alkyleyeloalkyl or cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or RH and R12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the IO group consisting of N, S and 0, said ring optionally substituted with l to 4 substituents independently ed from the group ting of alkyl, halogen, —CN, —NOz and alkoxy; Q' is a phenyl ring, a 5- or 6-mernbered heterocyclie ring, or an 8-, 9- or '10- membered fused bieyclic ring system optionally containing one to three heteroatoms selected from up to l 0, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents independently selected from R8; each Q2 is independently a phenyl ring or a 5- or 6-membered heterocyclie ring, each ring optionally substituted with one or more substituents independently selected from R9; _ Q3 is a phenyl ring or a 5- or 6-membered heterocyclie ring, each ring optionally substituted with one or more substituents independently selected from R9; and n is 0, l or 2.
In one embodiment, the invention provides topical veterinary compositions sing ive amounts of at least one isoxazoline of formula (1) below, in combination and a pharmaceutically or narily acceptable liquid carrier: A5 ' O—N A” \A4 W (1) wherein: PCT/U82012/054719 A', A2, A3, A4, A5 and A6 are independently CR3 or N, provided that at most 3 of A', A2, A3, A4, A5 and A6 are N; 8‘, B2 and B3 are independently CR2 or N; W is O or S; R1 is C1-C6 alkyl, C2-C(, alkenyl, C2-C(, alkynyl, C3-C6 cycloalkyl, C4-C7 ycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R2 is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C l-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, IO C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C5 alkylamino, C2-C6 dialkylamino, C2-C4 carbonyl, —'CN or —NO2; each R3 is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3- C6 halocycloalkyl, C 1- C6 alkoxy, C1-C6 koxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1- C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C7-C6 alkylsulfonyl, Cl-C6 kylsulfonyl, C l-C(, alkylamino, C2-C6 dialkylamino, —CN or —NO2; R4 is H, C 7-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; ' R5 ' is H, on”, NRI'R'Z or Q‘; or (:.'.C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R4 and R5 are taken together with the nitrogen to which they are ed to form a ring ning 2 to 6 atoms of carbon and optionally one additional atom selected from the group ting of N, S and 0, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, —CN, —NO2 and ' 7 ' 7 C1-C2alkoxy; each' R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C 7-C6 alkylthio, C1-C6 alkylsulfinyl, C 1-C6 ulfonyl, —CN or —NO2; I each R7 is independently halogen; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, Cz-Cg dialkylamino, C3- C6 'cycloalkylamino, C2—C7‘ alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylarninocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 kylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 PCT/U82012/054719 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, —NH2, —CN or —N02; or Q2; each R8 is independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1- C6 haloalkylthio, C1- C6 alkylsulfinyl, C1-C5 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkoxycarbonyl, —CN or — N02; each R9 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 lkyl, C3-C6 halocycloalkyl, C1-C6 ’alkoxy, C1-C6’haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1- C6 alkylsulfonyl, C 1-C6 haloalkylsulfonyl, C 1—C6 IO alkylamino, C2-C6 dialkylamino —CN, —N02, phenyl or pyridinyl; R10 is H; or C1-C6 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one of more halogen; R” is H, C1C6 alkyl, C2-C6 alkenyl C2C6 alkynyl, C3C6 cycloalkyl, C4C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; R” is H; Q3; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each ally substitutcd with one or morc substituents independently selected from R7; or RH and R12 are taken together with the nitrogen to which they are attached to form a ring ning 2 to 6 atoms of carbon and optionally one onal atom selected from the group consisting of N, S and 0, said ring optionally substituted with l to 4 tuents independently ed from the group consisting of C1-C2 alkyl, halogen, —CN, —N02 and C1-Cz alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring. or an 8-, 9- or 10- membered fused bicyclic ring system optionally containing one to three heteroatoms selected from up to l 0, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents independently selected from Rs; each Q2 is indcpcndcntly a phcnyl ring or a 5- or 6-mcmbcrcd hctcrocyclic ring, cach ring optionally substituted with one or more substituents independently ed'f‘rom Rgi Q3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R9; and nisO,lor2.
PCT/U82012/054719 In one embodiment of formula (I), W is O. In another embodiment, W is S.
In r embodiment of formula (I), A', A2, A3, A4, A5 and A6 are each CR3.
In another ment of formula (I), B1 B2 and B3 are each CR2.
In still another embodiment of formula (I), W is O and Al, A2, A3, A4, A5 and A6 are each CR3.
In yet another embodiment of formula (I), W is O; A', A2, A3, A4, A5 and A6 are each CR3; and B1, B2 and B3 are each CR2 .
In another embodiment of formula (1), Al, A2, A3, A4, A5 and A6 are each CH.
In another embodiment of formula (I), B', B2 and B3 are each CR2; and R2 is H, IO halogen, C1-C6 alkyl or C1-C6 haloalkyl.
In still another embodiment of formula (I), R1 is C1-C3 alkyl optionally substituted by _ i one or more of R6; R2 is independently H, n, C1-C6 kyl, C1-C6 haloalkoxy or —CN; and each R3 is independently H, halogen, C1-C6 alkyl, Cl-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN or —N02.
In still another embodiment, the invention provides a composition comprising an oline of a (I) wherein: W is O or S; R4 is H or C1-C6 alkyl; R5 is —CH2C(O)NHCH2CF3; each of A'=A2=A-‘=A4=A5=A6 is CH; R1 is C1-C6 alkyl each optionally substituted with one or more substituents independently selected from R6; R6 is halogen or C1-C6 alkyl; and B' 133 are independently CH, C-halogen, C-C.-C6 alkyl, C-Cl-CGhaloalkyl, or C- , B2, and _ i C1-C6 alkoxy.
In another embodiment of formula (I), B], B2 and B3 are independently CR2; W is O; R4 is H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; and R5 is H, NR'IR12 or Q; or C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 lkyl, C4-C7 alkylcycloalkyl or C4-C 7 cycloalkylalkyl, each optionally substituted with one or more of R7. . a a _ a PCT/U82012/054719 In still another embodiment of formula (1), RI is C1-C3 alkyl optionally substituted with halogen; each R2 is independently H, CF3, OCFg, halogen or —CN; each R3 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C 1-C4 ' I alkoxy or —CN; and each R7 is independently halogen, C1-C4 alkyl, C1-C4 , C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C2-C4 alkylcarbonyl, C2-C4 alkoxyearbonyl, C2-C5 alkylamin0carbonyl, C2-C5 haloalkylearbonyl, C2-C5 haloalkoxycarbonyl, C2-C5 haloalkylaminoearbonyl, -NH2, -CN or N02; 01' Q2.
IO In yet another embodiment of a (I), R4 is H; R5 is C1-C4 alkyl optionally substituted with one or more R7; each R7 is independently halogen or Q2; and each Q2 is independently phenyl, pyridinyl or thiazolyl.
In still another embodiment of formula (I). R1 is CF3; A', A2, A3, A4, A5 and A6 are each CR3; B2 is CR2; and each R3 is independently H, C1-C4 alkyl or —CN.
In another embodiment, B2 is CH; BI and B3 are each CR2 where each R2 is independently halogen or C1-C3 haloalkyl; A', A2, A3, A4, A5 and A6 are each CR3; R3 is H; and n is 2.
In still r embodiment of a (I). R1 is CF}; A', A2, A3, A4, A5 and A6 are each CR3; B2 is CH; each of B1 and B3 are CR2; each R3 is independently H or C1-C4 alkyl; each R2 is independently halogen or C1-C3 haloalkyl; R4 is H; R5 is C1-C4 alkyl optionally substituted with one or more R7; and PCT/U82012/054719 R‘ is C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl. ' ' In yet another embodiment of formula (l), R1 is CF3; Al. A2, A3, A4. A5 and A6 are each CH; B2 is CH; each of B1 and B3 are CR2; each R2 is independently halogen or C1-C3 haloalkyl; R4 is H; IO R5 is C1-C4 alkyl optionally substituted with one or more R7; and R‘7 is Cz-C 7 alkylarninocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl or C3-C9 dihaloalkylaminocarbonyl.
In a preferred embodiment, a topical composition comprising an isoxazoline active agent of formula (I) is provided, n: R1 is CF3; W is O; A', A2, A3, A4, A5 and A6 are each CH; 132 is CH; BI is chloro; 132 is CF3; R4 is H; R5 is CH2C(O)NHCH7CF3; and n is 2.
In a red embodiment, the isoxazoline nd is 4-[5-[3-chloro (trifluoromethyl)phenyl]-4,5-dihydro(trifluoromethyl)isoxazolyl]-N-[2-oxo[(2,2,2- trifluoroethyl)amino]ethyl]naphthalanecarboxamide (Compound A).
In anothcr embodiment, the compositions of the invention may include one or more compounds of the isoxazolines disclosed in , WO' 2007/075459 and US 2009/0133319, and US 2009/0143410, , WO 02809, , WO 85216 and US 2007/0066617 and , all of which are incorporated herein by reference in their entirety.
PCT/U52012/054719 In other preferred embodiments, the invention provides topical compositions comprising an isoxazoline active agent bed in WC 2009/02451A2 and A1, both incorporated herein by reference in their entirety, in combination with a pharrnaceutically acceptable carrier or diluent.
In another red embodiment, the invention es topical compositions comprising compound ll-l described in W0 2009/02451A2, which has the structure: mt; ‘3‘“ 3’ M" i 33% We. H's; , 3 "'3 t Ls ‘ 3,- '. «f {ig 5;.
K. v.~\-§.\ in combination with a pharmaceutically acceptable r or diluent bed herein.
In still another embodiment the invention provides topical compositions comprising one or more of the isoxazoline compounds of formulae 1.001 to 1.025 and 2.001 to 2.018 described in WO 2011075591 in combination with a pharmaceutically acceptable carrier described : (2)9 4%/ :N//%N B3 BYE]\\B2R15 0 .N_/ Compounds 1.001 to 1.025 Compound in:1:a- - RT LCMS «a in) No. (Z) I 5" EH3: (“11“) Method 3,5-C12 m a: H CH3C(O)NHCH3CF3 5 k) 1“) 1.002 2 O :1: oI oE c:1: CH3CF3 u. N u. N DJ k).— 1.003 3.5- (CFg): (" I]: (I‘: :1: (K CH2C02C‘H3 HJ1 \C N CO" 1.004 3,5-(CF3)2 O :1: oI CHzCOZH V' 00 U.) .NO\l 1.005 3,5-(CF3)3 0 :1: om: $32: oneIII, QI 0H CH2C(O)NHCH3CF3 E .N '— J:- 3,5-(CF3)3 on I-H can:‘1: 00:1: 000 CH2C(O)NHCH3CF3 0\ £1! 0 N . _. 00 1.007 3,5-(CF3)2 '3 CH2CHQSCH3 I90UI N . DJ 3,5-(CF3)2 C-H 9:i: 0 H CH2C(O)NHCH3CF3 648 1" —- 00 PCT/U52012/054719 9:1: on U1 00A Ix) I‘QJ) ”P:1: O o 1.011 (‘0‘ III: 0“”? :z: 90‘.” :1::1:: (:1 :L'. Gonna‘ =:1:::1:::1: s OC N NC 1.012 0 :1: 1.013 3,5-C12 - 9C3It: U1 1— O\ h) Ix) O\ 1.014 3-C].5-CF; - O:1: CH2C(O)NHCH3CF; 1.015 noI: W?I: 1.016 00 1.017 3,5-C12 00000000— IE’I‘IZIII 00‘? :1::1::1: 0000($ng 099::m E!0 N —- N 3,5-C12 - 0 Z(I? N .— \1 1.019 OE(D n UIU1 flu:to N ,_. 00 1.020 OO z('5 noI}: 0CD )NHCH;CF3 1.021 C-:1: 0:1: 0Z(D 0.:1: an E(D 1022 3,5-(CF3)2 0Z0 CH2CH2$CH3 1.023 3-Cl.5-CF3 rpm:m 90:n: 0ZO rpm :12: rpm33(DO )NHCH3CF3 1.024 3-Cl,5-CF; E 0C- :L‘ ‘9LI: 0 z('D CH2CF; 1.025 3-C1,5-CF3 C-H 0x I 7‘Z(O..Qa('D (7I (-s Z CD\ CHgCHgSC-H3 N0. III-nl—l-105 13.4 B3 132 R15 R'6 MH' (mm) Method 2001 ‘ . cmuochuzcm -- 2.002 2.003 2.004 1 2.005 2.006 -_-- 2.007 CH2C(O)NHCH2CF_~, -- 2.008 --_-- 2.009 --_-- 2.010 ‘ ,. 2(‘(O)NHCH2CF3 -- 2.011 2.012 - c-H--_-- PCT/U82012/054719 on on CH.C(0)NHCH,CF. -- 2.014 - - -_-- 2.015 —--‘ ‘ -_-- 2.016 - - cnzc<o>Nchzcm -- 2.017 —-- - - -_-- 2.018 - - -_-- In one embodiment, the invention es a topical composition comprising at least one isoxazoline of formula (I) in combination at least one other active agent, and a phannaeeutieally acceptable carrier or diluent.
Additional veterinary/pharmaceutical active ingredients may be used with the compositions of the invention. _ In some ments, the additional active agents may include, but are not limited to, aearieides, anthelminties, anti-parasitics and insecticides. Anti-parasitic agents can include both ectoparasiticidal and/or endoparasiticidal agents.
Veterinary pharmaceutical agents that may be included in the compositions of the invention are well-known in the art (see e.g. Plumb’ Veterinary Drug Handbook, S‘h Edition, ed.
Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9‘h Edition, (January 2005)) and include but are not limited to aearbose, acepromazine e, acetaminophen, aeetazolamide, aeetazolamide sodium, acetic acid, aeetohydroxamie acid, acetylcysteine, acitretin, acyclovir, azole, albuterol sulfate, anil, rinol, alprazOlam, altrenogest, amantadine, amikaein sulfate, aproie acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, ptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxieillin, clavulanate potassium, amphotericin B desoxycholate, amphotericin B lipid-based, ampicillin, amprolium, ds (oral), antivenin, apomorphione, apramycin sulfate, ascorbic acid, asparaginase, aspiring, atenolol, atipamezole, atraeuriitm besylate, atropine sulfate, , hioglueose, azaperone, azathioprine, azithromycin, baelofen, barbituates, pril, betamethason‘e, bethanechbl de, bisacodyl, bismuth subsalieylate, bleomyein sulfate, boldenone undecylenate, bromides, bromoeriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin , calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, eamitine, carprofen, carvedilol, eefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime , cefotetan disodium, cefoxitin sodium, oxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, _ 26 _ _ _ PCT/U82012/054719 cephapirin, charcoal (activated), chlorambucil, mphenicol, chlordiazepoxide, chlordiazepoxide +/- clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, nic gonadotrdpin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine te, clenbuterol, clindamycin, clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, azine, dactinomycin/actinomycin 7D, arin sodium, danazol, dantrolene sodium, dapsonc, dccoquinatc, dcfcroxaminc mcsylatc, dcracoxib, dcslorclin acctatc, IO desmopressin acetate, corticosterone te, detOmidine, dexamethasone, dexpanthenol, dexraaioxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamaiine citrate, diethylstilbestroln (DES), difloxacin, n, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate, domperidone, dopamine, ctin, doxapram, doxepin, doxorubicin, clinc, cdctatc calcium disodium.calcium EDTA, cdrophonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, antel, erythromycin, esmolol, estradiolicypionate, ethacrynic acid/ethacrynate sodium, ethanol (alcohol), etidronate , etodolac, etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, fllgrastim, finasteride, fipronil, icol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, n meglumine, fluorouracil (S-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, izole (4-MP), furazolidone, furosemide, gabapentin,“ gemcitabine, gentamicin sulfate, glimepiride, ide, glucagon, glucocorticoid agents, gluCosamine/chondroitin sulfate, ine,’glyburide, glycerine , glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin,‘halothane,hemoglobin glutamer—ZOO (OXYGLOBINCEXRD, heparin, hctastarch, hyaluronatc sodium, hydrazalinc, hydrochlorothiazidc, odone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate, impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, eron alfal2a (human recombinant), iodide (sodium/potassium), ipecac (syrup), ipodate sodium, iron n, isoflurane, isoproterenol, isotretinoin, isoxsuprine, PCT/U82012/054719 itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole, levetiracetam, levothyroxine sodium, ine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, nin, can, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine ate/hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, ’methoxyflurane, methylene blue, phcnidatc, mcthylprcdnisolonc, mctoclopramidc, mctoprolol, mctronidaxolc, mcxilctinc, IO mibolerlone, midazolam’milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazo‘xanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazinc sodium, omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, lin sodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline, oxytocin, pamidronatc disodium, pancrcplipasc, pancuronium e, paromomycin sulfatc, parozetine, pencillamine, general information penicillins, llin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfafe sodium, péntoxifyllinerergolide mesylate, phenobarbital, phenoxybenzamine, utazone, phenylephrine, phenypropanolamine, oin sodium, pheromones, parenteral phosphate, phytonadione/vitamin K-l, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone/prednisone, primidone, procainamide, rbazine, prochlorperazine, propantheline“ bromide, propionibacteriumacnes injection, “propofol, propranolol, protamine e, pseudoephedrine, um hydrophilic mucilloid, pyridostigmine bromide, pyrilamine e,“ pyriméthamine, “quinacrine, quinidine, ranitidine, in, s-adenosyl-methionine (SAMc), salinc/hypcrosmotic ve, sclamcctin, sclcgilinc /l-dcprcnyl, scrtralinc, mcr, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene ate, sodium stibogluconate, sodium sulfate, sodum thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, ozocin, succimér, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim, sulfadimentoxine, imethoxine/ormetoprim, sulfasalazine, taurine, tepoxaline, terbinafline, terbutaline e, testosterone, tetracycline, thiacetarsamide sodium, thiamine, anine, thiopental sodium, thiotepa, thyrotropin, tiamulin, ticarcilin um, tiletamine /zolazepam, tilmocsin, nin, tobramycin sulfate, tocainide, tolazoline, telfenamie acid, topiramateftramadol, trimcinolone acetonide, ine, trilostane, trimepraxine tartrate w/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vanedmycin, 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.
IO In one embodiment of the invention, arylpyrazole compounds such as pyrazoles, known in the art may be combined with the isovaoline compounds in the topical compositions of the invention. Examples of such arylpyrazole compounds include but are not limited to those described in US. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 and 6,998,131 (all of which are incorporated herein by reference, each assigned to Merial, Ltd., Duluth, GA).
In another embodiment of the invention, one or more macrocyclic cs or lactams, which act as an acaricide, anthelmintic agent and/or insecticide, can be added to the compositions of the invention.
The macrocyclic lactoncs e, but are not limited to, ctins such as abamectin, dimadectin, doramectin, emameetin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and ML-1,694,554, and milbemycins such as milbemeetin, milbemycin D, moxidectin and etin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemyeins. Examples ofcombinations Of arylpyrazoleeompounds With’maeroeyclie lactoncs include but are not“ d to those described in US. Patent Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998,131 (all incorporated herein by reference - each assigned to Merial, Ltd., Duluth, GA). _ ' ‘ The macrocyclic lactone compounds are known in the art and can easily be obtained commercially or through synthesis techniques known in the art. nce is made to the widely available technical and commercial literature. For avermectins, ivennectin and tin, reference may be made, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H.
Fischer and H. Mrozik, William C. ll, published by er Verlag., or Albers- WO 39948 PCT/U82012/054719 Schonberg et a1. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216- 4221. For doramectin, “Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may be consulted. For milbemycins, reference may be‘ made, inter alia, to Davies H.G. et al., 1986, “Averrneetins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, US. Patent No. 4,134,973 and EP 0 677 054.
Macrocyclic es are either natural products or are semi-synthetic derivatives thereof.
The structure of the avcrmcctins and milbemycins are closely related, e.g., by sharing a complex 16-membered macrocyclic c ring. The natural product ctins are disclosed in US.
IO Patent No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosed in US. Patent No. 4,199,569. Mention is also made Of US. Patent Nos. 4,468,390, 5,824,653, EP 0 007 812 Al, U.K. Patent Specification 1 390 336, EP 0 002 916, and New d Patent No. 237 086, inter alia. Naturally occurring milbemycins are described in US. Patent No. 3,950,360 as well as in the various references cited in “The Merck Index” 121h ed., S. ri, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin cribed in the “International Nonproprictary Names for Pharmaceutical Substances (INN)”, WHO Drug Information, vol. 17, no. 4, pp. 263- 286, (2003). Semisynthetic derivatives of these classes of compounds are well known“ in the art and are described, for example, in US. Patent Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 596, 711, 4,978,677, 4,920,148 and EP 0 667 054.
In preferred embodiment of the invention, the invention comprises a topical composition sing an isoxazoline compound in combination with a class of acarieides or insecticides known as insect growth regulaters (IGRs). Compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. ‘These nds all act by’interfering with the development or growth of the insect pests. Insect growth regulators are described, fer e, in US. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022 or UK. 2 140 010 as well as US. Patent Nos. 6,096,329 and 6,685,954 (all orated herein by reference).
In one embodiment the IGR is a compound that mimics juvenile hormone. es of juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kindprene, PCT/U82012/054719 methoprene, pyriproxyfen, ydroazadirachtin and ro-2(2-chloromethyl-propyl) (6-iodopyridy1methoxy)pyridazine-3(2H)-one.
In a particularly preferred embodiment, the compositions of the invention comprise an isoxazoline compound of formula (I) in combination with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier. It has been surprisingly found that compositions Comprising an isoxazoline compound of formula (I) in combination with methoprerie or pyriproiyphen exhibit superior long lasting efficacy that is not table based on the activity of each active alone. 7 In another embodiment, the IGR nd is a chitin synthesis inhibitor. Chitin IO synthesis tors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucyeloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, triflumoron, novaluron, 1-(2,6-difluorobenzoyl)—3-(2-fluoro(trifluoromethyl)phenylurea, l-(2,6-difluoro- benzoyl)(2-fluoro(I,1,2,2-tetrafluoroethoxy)-phenylurea and I-(2,6-difluorobenzoyl)(2- fluorotrifluoromethyl)phenylurea.
In yet another embodiment of the ion, adulticide insecticides and acaricides can also be added to the composition of the invention. These include pyrethrins (which include n I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof) and pyrethroids, and carbamates including, but are not limited to, benomyl, olate, carbaryl, carbofuran, iocarb, metolcarb, promacyl, propoxur, aldicarb, rboxim, oxamyl, thiocarboxime and thiofanox.
In some embodiments, the itions of the invention may include one or more antinematodal agents including, but not limited to, active agents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organophosphate class of compounds. In some embodiments, benzimidazolés including, but not limited to, thiabendazole, ciambendazole, parbendazole, oxibendazole, mebendazole, azole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and its o,o-dimethyl ue may be included in the compositions.
In other embodiments, the compositions may include an imidazothiazole compounds including, but not limited to, tetramisole, sole and butamisole. In still other embodiments, the itions of the invention may include tetrahydropyrimidine active agents including, but not limited to, pyrantel, oxantel, and morantel. Suitable organophosphate active agents include, PCT/U82012/054719 but are not limited to, coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.
In other embodiments, the itions may include the matodal compounds phenothiazine and piperazine as the neutral compound or in various salt forms, diethylcarbamazine, s such as disophenol, cals such as arsenamide, ethanolamines such as bephenium, thenium closylate, and methyridine; e dyes ing pyrvinium de, pyrvinium pamoate and dithiazanine iodide; isothiocyanates including bitoscanate, n , phthalofyne, and various natural products including, but not limited to, hygromycin B, a-santonin and kainic acid.
In other embodiments, the compositions of the invention may include antitrematodal agents. Suitable antitrematodal agents—include, but are not limited to, the miracils such as miracil D and mirasan; praziquantel, clon’azepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthonc, oxamniquine, nate, niridazolc, nitroxynil, s bisphenol compounds known in the art including hexachlorophene, bithionol, bithionol sulfoxide and menichlopholan; various salicylanilide compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, nide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetolin and emetine.
'Anticestodal nds may also be advantageously used in the compositions of the invention including, but not limited to, arecoline in various salt forms, bunamidine, niclosamide, canatc, paromomycin and paromomycin II.
In yet other embodiments, the compositions of the invention may include other active agents that are ive against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methokychlor, ene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, yrifos, crotoxyphos, cythioate, diazinon, dichlorenthion,, diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stirofos, allethrin, cyhalothrin, cyperrnethrin, deltamethrin, fenvalerate, flucythrinate. permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato e, methoprene, monosulfiram, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, deet, dimcthyl phthalate, and the compounds l,5a,6,9,9a,9b-hcxahydro-4a(4I-I)- PCT/U82012/054719 dibenzofurancarboxaldehyde (MGK-l 1 ), thylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H- isoindole-1,3(2H)dione (MGK-264), yl-2,5-pyridinedicarboxylate (MGK-326) and 2- (octylthio)ethanol 74). ' _ In a particularly preferred embodiment, the topical compositions of the invention will include perrhethrin in combination with the isoxazoline active agent.
An antiparasitic agent that can be combined with the compound of the invention to form a composition can be a biologically active e or protein including, but not limited to, depsipeptides, which act at the neuromuscular’ junction by stimulating ’presynaptic receptors belonging to the sccrctin receptor family resulting in the paralysis and death of parasites. In one IO embodiment of the depsipeptide, the depsip’eptide is side (see ’Willson et al., Parasitology, Jan. 2003, I26(Pt 1):79-86).
In another embodiment, the compositions of the ion may comprise an active agent from the neonicotinoid class of pesticides. The otinoids bind and inhibit insect specific nic acetylcholine receptors. In one embodiment, the neonicotinoid insecticidal agent that can be combined with an isoxazoline compound to form a topical composition of the invention is imidacloprid. Imidacloprid is a well-known neonicotinoid active agent and is the key active ingredient in the l parasiticide products Advantage'fi, Advantage® II, K9 Advantix®, and K9 Advantix® I] sold by Bayer Animal Health. Agents wof this class are described, for example, in US. Patent No. 4,742,060 or in EP 0 892 060.
In another embodiment, the topical compositions of the invention may se nitenpyram, another active agent of the neonicotinoid class of pesticides. Nitenpyram has the following chemical structure and is the active ingredient in the oral product CAPSTARTM Tablets sold by Novartis Animal Health.
Nitenpyram is active against adult fleas when given daily as an oral tablet. Nitenpyram works by interfering with normal nerve transmission and leads to the death of the insect. yram has a very fast onset of action against fleas. For example. CAPSTARTM Tablets begin to act t fleas in as early as 30 minutes after administration and is indicated for use as often as once a day. However, nitenpyram is only known to be effective when administered orally as PCT/U82012/054719 a systemic parasiticide, as with CAPS'I‘ARTM Tablets. Therefore, it is surprising and cted that the l compositions of the invention sing a ation of “nitenpyram with an isoxazoline active agent t the very fast onset’of action of nitenpyram because this active agent is not known to be 'active when administered topically. The l compositions of the invention comprising a combination of a long-lasting isoxazoline active agent with a very fast acting active agent such as the neonicotinoid active agent nitenpyram provide optimal speed of onset and long lasting activity against ectoparasites.
' Nitenpyram has a very low log octanol-water partition coefficient of -0.64 and a relatively high solubility in water of 840 g/L at 20° C and pH of 7 (see Supplement to IO Compendium 0n Continuing Education/or the practicing veterindrian, vol. 23, n0.’3(a), march 2001), indicating that it is not a likely candidate for topical delivery. Based on the very low log p of nitenpyram and the very high water solubility, one of skill in the art would have a very high level of cism that this active agent could be effectively delivered in a topical composition.
The effectiveness of topical compositions of the invention that comprise nitenpyram are all the more cted in view of the physicochemical properties of the compound.
In another preferred embodiment of the invention, topical compositions comprising at least one isoxazoline compound in combination with an IGR and a otinoid active agent are provided. In still anothef preferred embodiment, the invention es topical compositions comprising an isoxazoline compound of Formula (I) together with an IGR that mimics juvenile e and nitenpyram. In yet another preferred embodiment, the invention provides topical spot-on or pour-on compositions comprising 4-[5-[3-chloro(trifluoromethyl)phenyl]-4,5- dihydro-S-(trifluoromethyl)isoxazolyl]-N-[2-oxo[(2,2,2-trifluoroethyl)amino]ethyl]- l - naphthalanecarboxamide' (Compound A) in combination with (S)-methoprene or pyriproxyfen and nitenpyram. H M In another ment, the topical itions of the invention provide topical n or pour-on compositions that comprise 4-[5-[3Schloro-S-(trifluoromethyl)phenyl]-4,“5-dihydro (trifluoromethyl)isoxazolyl]-N-[2-oxo[(2,2,2-trifluoroethyl)amino]ethyl] naphthalanecarboxamide (Compound A) in combination with nitenpyram, (S)-methoprene or pyriproxyfen and an avermectin or milbemyein compound. In yet another embodiment of the invention, topical compositions are provided that comprise 4-[5—[3-chloro (trifluoromethyl)phenyl]-4,5-dihydro(trifluoromethyl)isoxazolyl]-N-[2-oxo[(2,2,2- PCT/U82012/054719 trifluoroethyl)amino]ethyl]naphthalanecarboxamide (Compound A) in combination with nitenpyram and/or (S)-methoprene or pyriproxyfen and/or an avermeetin or milbemycin compound and/or praziquantel. In this embodiment, the presence of an avermectin or milbemycin compound and/or praziquantel provides potent activity against endoparasites in addition to activity against ectoparasites. i In certain ments, an insecticidal agent that can be combined with the compositions of the ion is a semicarbazone, such as metaflumizone.
In r embodiment, the compositions of the invention may ageously include a combination of isoxazolinc compounds known in the art. These active agents are described in IO W0 2007/079162, W0 2007/075459 and US 2009/0133319, W0 2007/070606 and US 2009/0143410, , WO 02809, W0 2009/024541, and US 2007/0066617 and W0 2008/122375, all of which are incorporated herein by reference in their entirety.
In r embodiment of the invention, nodulisporic acid and its derivatives (a class of known acaricidal, anthelmintic, anti-parasitic and insecticidal ) may be added to the compositions of the invention. These compounds are used to treat or prevent ions in humans and animals and are described, for example, in US. Patent No, 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are hereby incorporated by reference in their entirety. The compositions may include one or more of the known nodulisporic acid derivatives in the art, including all stereoisomers, such as those described in the patents cited above.
In another embodiment, anthelmintic compounds of the amino acetonitrile class (AAD) of compounds such as monepantel (ZOLVIX), and the like, may be added to the compositions of the invention. These compounds are described, for example, in W0 2004/02470’4 and US.
Patent No. 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 compositions of the invention may also include aryloazol-Z-yl cyanoethylamino compounds such as those bed in US Patent No. 8,088,801 to 8011 et al., which is incorporated herein in its ty, and thioamide derivatives of these compounds, as described in US. Patent No. 7,964,621, which is incorporated herein by reference.
The compositions of the invention may also be combined with rquamide compounds and derivatives of these nds, including derquantel (see 0stlind et al., WO 39948 PCT/U82012/054719 Research in nary e, 1990, 48, 260-61; and Ostlind et al., l and Veterinary Entomologv, 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds that include a spirodioxepino indole core with aetivity against certain parasites (see Tet. Lett. 1981, 22, . Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). In addition, the structurally related marefortine family of compounds, such as marcfortines A-C, are also known and may be combined with the formulations of the ion (see J. Chem. Soc. — Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to the paraherquamide derivatives can be found, for example, in WC 91/0996], WO 92/22555, WO 97/03988, WO 01/076370, W0 09/004432, US. Patent 5,703,078 and US. Patent 5,750,695, all IO of which are hereby incorporated by reference in their entirety.
In general, the additional active agent is included in the composition in an amount of between about 0.1 ug and about 1000 mg. More typically, the additional active agent may be included in an amount of about 10 pg to about 500 ing, 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 invention, the additional active agent may be included in the composition to deliver a dose of about 5 ug/kg to about 50 mg/kg per weight of the . In other embodiments, the additional active 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 weight of animal. In other embodiments, the onal active agent may be present in a dose of about 5 gag/kg to about 200 ug/kg or about 0.1 mg/kg to about 1 mg/kg of weight of animal. In still another embodiment ofthe invention, the additional active agent is included in a dose between about 0.5 mg/kg to about 50 mg/kg.
The topical compositions of the invention,iwhieh include at least an isoxazoline active agent and a pharmaceutically acceptable carrier that is suitable for topical ation to an animal, have been surprisingly discovered to be stable and ive t a broad spectrum of eetoparasites for an extended period of time. ' In a preferred embodiment of the inventive compositions, the topical composition will be in the form‘ of a liquid solution or suspension that comprises a pha‘rmaeeutie‘ally acceptable carrier or diluent that is suitable for application to the skin of an animal. Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on formulations, ready-to-use formulations, spot-on solutions and suspensions.
PCT/U82012/054719 In a preferred embodiment of the invention, topical compositions suitable for l administration to a localized area of an animal are provided, ing compositions in the form of spot-on or pour-on compositions. In another embodiment, the topical compositions will be in the form of a spray formulation, an aerosol or a foam formulation suitable for administration to an . In Some embodiments, the liquid on or suspension ations comprising isoxazoline active agents will be in a form’that can be sprayed’on via a metered dose pump or a metered dose aerosol.
Isoxazoline active , such as those of Formula (I), are ically active such that the ectoparasite is affected when taking a blood meal from the host. Accordingly, a minimum IO concentration of the compounds in the systemic circulation of the animal is required. However, in some situations the isoxazoline active agent may also be active by contacting the parasite on the surface of the animal. Thus, in some embodiments, topical application or the inventive compositions can allow for the active agents to be delivered and distributed throughout the hair coat topically and/or may also provide distribution of the active agent via the sebaceous glands of the animals. When the compound is distributed hout sebaceous glands, the sebaceous glands can act as a oir, whereby there can be a long-lasting effect, c.g. at least one month or longer. For example, Cochet and co-workers reported the distribution of fipronil, a I- arylpyrazole compound, to the stratum comeum, the viable epidermis and the sebaceous glands and epithelial layers of beagle dogs after spot-on administration (see Cochet et al., Eur. J. Drug Metab. Pharmacokinet.., 1997, 22(3), 211-216). Using 14C radiolabeled drug, the publication demonstrated that l is displaced from the point of application and distributed to the whole skin, where it was persistently detected for up to 56 days after treatment.
Topical application of the inventive compositiOns enables effective delivery of the active agent transdermaIly through the skin into the systemic circulation at a concentration sufficient to provide ent y against ectoparasites. In another preferred embodiment, the compositions of the invention aChieve distribution of the active agent both topically over the hair coat of the animal and also transderrnally into the blood stream. In this embodiment, the topical compositions provide a high level of efficacy at unexpectedly low plasma concentrations of the isoxazoline active agent.
The outer layer of the mis, the m comeum, forms the major barrier to both the egress of water and the ingress of xenobiotics into the circulatory system. It is a unique PCT/U82012/054719 membrane comprised of dead thin flat cells, comeocytes, which are filled with dense keratin, between which is a lipid-rich layer comprised of numerous lipid bilayers. The general sus is that most xenobiotics pass through the lipid-rich layer between the flat cells. Delivering an active through the skin ts a significant challenge, given the role of the skin as a barrier for keeping foreign substances out. In 'order for an active—ingredient to pass through the stratum comeum, it must pass sequentially across bilayers and ore cross many hydrophilic- lipophilic interfaces. Because of the efficient barrier of the skin, transdermal delivery is only typically appropriate for potent compounds that e only a small dosage.
Only materials which have good solubility properties in both oils and water will be able IO to effectively pass across the skin With relative ease. One of the major problems in treating the skin or using the skin to deliver a substance into the systemic Circulation arises from the requirement that the active has to possess the correct physicochemical ties to allow it to reach the site of action or circulation. If it is extremely hydrophilic it will reside on the skin surface. If it is extremely lipophilic it will pass into the lipid-rich layer n the cells and will have difficulty penetrating . Only compounds that are small, have balanced solubility in oils and water and a log (octanol—water partition coefficient) of ~2 (log P) will pass through the stratum comeum and into the ic circulation to any significant degree (see Kenneth B.
Sloan (ed.) (1992) Prodrugs: Topical and Ocular Drug Delivery, p.6, Marcel , New York). Examples include ne and nitroglycerin (GTN). However even these are not absorbed to a large degree. Thus, many compounds are not suitable for transdermal delivery e of their inherent physicochemical properties.
It will be understood that the ability of an active agent to be distributed either topically or transdermally is dependent both on the physicochemical characteristics of the nd and also on the non-active excipients of the formulation, which may induce penetration of the active agent into the skin. While there is no general method to r any active agent either topically over the hair coat of an animal or transdermally to an animal, some techniques for enhancing the penetration of active agents into the skin of animals are known. Substances termed ation enhancers,’ 9 are typically used in compositions designed to deliver drugs transdermally to increase the amount of the active that is delivered into the systemic circulation. Permeation enhancers constitute various classes of compounds including certain solvents such as dimethylsulfoxide (DMSO), pyrrolidones, ethanol, propylene glycol, ethyl acetate, PCT/U82012/054719 dimethylacetamide, and others that are capable of disrupting the barrier function of the stratum comeum. Other substances have also been shown to increase the flux of certain active agents through the skin. These include lipophilic compounds such as laurocapram (Azone); fatty acids or alcohols such as oleic acid, oleyl alcohol, linoleic acid and the like; certain fatty acid esters such as isopropyl ate, methyl noanoate, methyl caprate and others. Mixtures of n tion enhancers with propylene glycol are also known to improve the delivery of certain active ingredients. For example, see Pharmaceutical Skin Penetration Enhancement edited by h A. Walters and Jonathan Hadgraft, Marcel Dekker, Inc. New York, 1993; ISBN 0 9017-0.
IO In some ments of the invention, the itions are ated to control the rate of permeation of the isoxazoline compound in order to maintain efficacious levels of the active in the plasma for a prolonged period of time and significantly extend the duration of efficacy. Thus, in one embodiment, the topical compositions of the ion are formulated with a carrier system that induces the containment of the isoxazoline active s) within the skin to achieve a reservoir effect and controls the permeation rate of the compound into the systemic circulation over a longer period of time. In this manner, the invention es topical compositions that exhibit sing long lasting efficacy against ectoparasites. It must be noted that “this approach is only applicable to potent active agents thatgmay achieve the desired ticidal efficacy with low plasma concentrations, since less potent compounds would not be able to establish an efficacious concentration.
It has been found that the topical compositions of the present invention comprising an isoxazoline active agent in a carrier comprising a lipophilic solvent or lipophilic solvent system result in superb efficacy against ectopar’asites’for an extended duration of time. Although not wishing to “be bound by , it is believed that non-active ents in certain topical formulations of the invention prOmote the containment of the isoxazoline active agent within the skin for longer periods of time while allowing the active agent to constantly diffuse into the circulatory system at a rate that provides the required concentration of the active in the blood stream to be'efficacious against ectoparasites fora longer period of time. This is contrary to the approaches used with typical topical formulations that are designed to enhance the passage of active agents through the skin of an animal into the systemic circulation quickly to n the desired biological effect. Thus, in one embodiment the present invention utilizes non-active 2012/054719 excipients that discourage the fast permeation of isoxazoline active agents into the systemic circulation.
In one embodiment, the invention provides topical compositions sing an isoxazoline active agent in a ceutically acceptable carrier wherein the carrier does not include a compound that enhances the permeation of the isoxazoline active agent. In another embodiment, the invention provides topical compositions comprising an isoxazoline active agent and a pharmaceutically acceptable r wherein the carrier comprises a solvent or solvent system’that promotes the containment of the isoxazoline active agent in the skin of the animal for a longer period of time.
IO In one embodiment of the ion sing a carrier that extends the duration of efficacy of the topical compositions, the carrier may comprise a solvent selected from carboxylic acid esters, diesters of dicarboxylic acids, fatty acid esters or diesters of fatty diacids, Or a combination thereof, including, but not limited to, isopropyl palmitate, isostearyl lactate, diisopropyl adipate, dibutyl adipate, diethyl sebacate, dibutyl sebacate, octyl palmitate, polyethyleneglycol (PEG) stearate and cetearyl octanoate; oils including, but not limited to, mineral oil, crides, triglycerides, jojoba oil, lecithin and castor oil, or a combination thereof; long chain tic alcohols such as isostearyl alcohol and the like; fatty alcohols and their esters, ding for example, cetyl alcohol, cetearyl l and the like, or a combination thereof; polyethylene glycols of different molecular weight ranges ing, but not limited to, PEG 300, PEG 400, PEG 600 and PEG 1000, or a combination thereof; and glycol ethers including, but not limited to, leneglycol monoethyl ether (Transcutol’m), butyl diglycol, ene glycol monomethyl ether, propylene glycol monoethyl ether, ylene glycol n- butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether’and dipropylene glyCol monomethyl ether, or a combination thereof; or a combination Of two or more of these Solvents.
Exeipients that may also promote the containment of the active agent in the skin for longer periods of time and may be included in the compositions of the invention include, but are not limited to, mixed esters ofsucrose and carboxylic acids including sucrose acetate yrate (SAIB) and the like; low temperature melting waxes, hydrogenated vegetable oils, caprylic/capric glycerides; glycerol esters, including for example, triacetin, glycerol monooleate, ol monolinoleate, glycerol stearate, glyceryl distearate and the like; triglycerides, including PCT/U82012/054719 for example, caprylic, capric/ myristic/ stearic triglyceride; therrnoreversible polymers, such as Pluronic and poloxamers, including for example, Lutrol F127 by itself or in mixture with other poloxamers; or a ation thereOf.
In another embodiment of the invention the ceutically acceptable carrier for the topical itions comprise a mixture of a diester of a dicarboxylic acid alone or in co’mbination’with one or more of additional solvents listed above, and/0r an “oily” lipophilic substance, including a liquid or low melting lipophilic active agent such as (S)-methoprene, pyriproxyfen and/or’perme’thrin; and/or a mixed ester of e and carboxylic acids including a mixed ester of sucrose and acetic and isobutyric acids such as sucrose acetate isobutyrate IO (SAIB), and/or low melting waxes and/or hard fats.
Although not wishing to be bound by theory, the ion of certain lipophilic solvents in the topical compositions of the invention e the residence time of the oline active agent within the skin while allowing an effective concentration of the active agent to pass slowly into the atory system to achieve the desired efficacy for longer s of time.
In a preferred embodiment, the diester of a dicarboxylic acid is diethyl sebacate or diisopropyl adipatc. In another embodiment, the blend of solvents comprising a dicarboxylic acid ester comprises a glycol or polyglycol, or a glycol or ycol ether or ester including, but not limited to, ethylene glycol“(EG),' propylene glycol “(PG)‘, liquid polyoxyethylene glycols (PEGs) of various grades including PEG 400, EG or PG monocaprylate, EG or PG caprylate, EG or PG monolaurate, EG or PG dicaprylate/dicaprate, diethyleneglycol monoethyl ether (DGME, Transcutol'zm), butyl diglycol, dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monOethyl ether, and the like, or a combination thereof; an ether including, but not limited to, dimethyl isosorbide; an ester or di- ester including, but not limited to, triaCetin, lauryl lactate; and other solvents including glycerol formal, or mixtures thereof.
In preferred embodiments, the carrier for the topical compositions comprises a dialkyl ester of a dicarboxylic acid such as diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, dibutyl adipate, or a ation thereof, alone or in ation with solvents selected from: ' _ a) a propylene glycol (PG) ester ing PG monocaprylate, PG ate, PG urate, PG dicaprylate / ate, or a combination thereof; PCT/U82012/054719 b) an ether solvent ing yl isosorbide, diethylene glycol monoethyl ether (also known as DGME or Transcutol®), or a combination thereof; 0) a carboxylic acid ester including, but not limited to, triacetin, lauryl lactate, isopropyl palmitate, diisopropyl sebacate, or a combination f; and d) other “oily” or lipophilic organic solvents including glycerol formal and the like.
In some embodiments, the amount the additional solvents ed with the carboxylic acid ester or diester of a dicarboxylic acid are present in an amount of at least about 1% (v/v), at least about 5% (v/v), at least about 9.0% (v/v), at least about 13% (v/v), at least about 17% (v/v) IO or at least about 20% (v/v). Preferably the additional solvents will be in an amount of at least about 9% (v/v).
In other embodiments, the additional solvents will be present in an amount of about 5- 70% (v/v), about 10-60% (v/v), about 10-50% (v/v), about 15-60% (v/v) or about 15-50% (v/v).
In preferred embodiments, the additional solvents will be present in an amount of about 20-70% (v/v), about 20-60% (v/v), about 20-50% (v/v) or about 25-50% (v/v).
The pharmaceutically acceptable carrier may include suitable carriers or diluents commonly used in the formulation art including aqueous or organic solvents or mixtures of solvents. These organic solvents may be found, for example, in Remington Pharmaceutical es, 21St Edition (2005). Other solvents and/or additives that may be used in the topical itions include, but are not limited to, PEG ethers and PEG esters including, but not limited to, PEG esters of carboxylic acids and dicarboxylic acids and PEG esters of fatty acids, glycerol esters including triacetin, caprylic/capric cerides (Miglyol 8123‘) and the like; ol ethers includingnglycerol formal; propylene glycol dicaprylate/dicaprate (Miglyol 840®), lauryl lactate, triacetin, diisopropyl e (DIPA, also knownas CERAPHYL 230), diisobutyl e, dimethyl isosorbide (DMI), tributyl citrate, oleic acid; carboxylic acid esters including esters of diacids, ketones including acetone, methylisobutyl ketone (MIK), methyl ethyl ketone, and the like; acetonitrile, C1-C1; alcohols including benzyl alcohol, methanol, ethyl alcohol, isopropanol, and butanol; aromatic ethers such "as anisole; amides including dimethylacetamide, thylacetamide and dimethylformamide; dimethyl sulfoxide (DMSO), ethylene glycol, propylene glycol, a glycol carbonate including, but not limited to, propylene carbonate and, butylene ate; 2-pyrrolidone, N-methylpyrrolidone, C1-C1; alkyl PCT/U82012/054719 esters of carboxylie acids including butyl or octyl acetate and benzyl e; C1-C12 alkyl esters of dicarboxylic acids; aryl esters including benzyl te, ethyl benzoate and the like; and diethyl phthalate, or a miXture of at least two of these solvents.
However, in one ment, the invention provides topical compositions comprising at least one isoxazoline active agent, ally in combination with one or_ more additional active agents, in a pharmaceutically acceptable carrier, wherein the carrier does not comprise glyeofurol. In r embodiment, the pharmaceutically acceptable carrier of the topical Compositions does not comprise a binary mixture of propylene glycol and glycerol formal. ’ As vehicle or diluent, mention may also be made of plant oils such as, but not limited to IO soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral eils such as, but not limited to, petrolatum, paraffin, ne, etc.; aliphatic or cyclic hydrocarbons including limonene or alternatively, for example, medium-chain ’(such as C3 to C12) triglycerides, or mixtures f.
In one ment, solvents and/or additives that control the permeation rate of the active may be added to a composition comprising one of the formulation carriers described herein, including carriers comprising a dialkyl ester of a dicarboxylic acid such as dicthyl sebacate or the like. In another embodiment, solvents and/or additives that control the permeation rate of the active may be added to carriers comprising other ts described herein or may be used alone in the composition.
It will be appreciated by those skilled in the art that the skin of different animals will be different in nature and may be more or less permeable to the isoxazoline active agent. For example, the retainment of the isoxazoline active agent on the skin of a cat may be more difficult than dogs. Accordingly. in some situations with certain animals the topical compositions of the invention will utilize'solvents that enhance the permeation of the “isoxazoline active agent through the skin of the animal rather than solvents and excipients that retain the active agent on the skin of the animal for longer periods of time. Thus, in another embodiment of the invention, topical compositions are provided that include ts that e the permeation of iséxazoline active agents through the skin of the animal. These solvents provide a greater proportion of the active agent through the skin and thereby improve the efficacy and on of time. In this embodiment, the permeation enhancing solvent s a greater proportion of the isoxazoline active agent through the skin into the ic circulation. It will be appreciated by PCT/U82012/054719 those of skill in the art that this effect allows a greater level of efficacy at lower doses of the . Selected solvents that enhance the permeation of the isoxazoline active agent e, but are not d to, dimethyl bide; and glycol ethers including, but "not limited to, diethyleneglycol monoethyl ether (DGME, utol®), butyl diglyeol, dipropylene glycol n- butyl ether, neglchl monoethyl ether, ethyleneglycol monOmethyl ether, dipropylene glycol monomethyl ether, propylene glycol monOmethyl ether, propylene glycol monOethyl ether, and the like. Other solvents that enhance the permeation of the isoxazoline active agent bed below may also be used in the compositions.
In one embodiment of the invention, the pharmaceutically acceptable carrier of the IO formulation may comprise Cs-Czo long-chain aliphatic alcohols or esters f. In another embodiment, the r comprises C1-C1; alcohols or esters thereof, C1-C4 alcohols or esters thereof or C3-C8 alcohols or esters thereof. In some embodiments, the esters formed with the alcohol include esters of C1-C1; carboxylic acids or diacids, or esters of C6-C16 ylic acids or diacids. Esters include, but are not limited to, acetates such as ethyl acetate and the like; and esters of 0-02 alcohols and a diearboxylic acid or a hydroxy-substituted carboxylic acids.
In another embodiment, the pharmaceutically acceptable r ses C4-C22 fatty acids or esters thereof, including esters with C6-C20 long chain alcohols, Cl-C 12 alcohols, C1-C4 alcohols or C3-Cg alcohols; Clo-"C13 saturated fatty acids or esters thereof, including esters with C6-C20 long chain alcohols, C1-C12 alcohols, C1-C4 alcohols or C3-C3 alcohols; Clo-C13 rated fatty acids or esters thereof, including esters with C6-C20 long chain alcohols, C l—C 12 alcohols, C1-C4 alcohols or C3-C3 alcohols; monoesters or diesters of C6-C16 aliphatic carboxylic acids and carboxylie diaeids, including esters with C6-C20 long chain alcohols, C1-C12 alcohols, C1-C4 alcohols or C3-C3 alcohols, or mixtures thereof. In other embodiments, the carrier may include C1-Clo, C1-C8 or C1-C6 alcohols or esters thereof.
In another embodiment, the compositions of the invention comprise aromatic alcohols or esters thereof. In one preferred embodiment, the topical compositions of the ion may include benzyl alcohol as a solvent.
In another embodiment, preferred solvents include C1-C12 alkyl esters of carboxylic acids such as butyl acetate, octyl acetate, lauryl lactate or isopropyl palmitate, and C1-C12 alkyl esters of dicarboxylic acids, including diisopropyl adipate, diethyl‘s'ebacate and diisopropyl sebacate. In other embodiments, the carrier may e C1-C10, C1-C8 or C1-C6 alkyl esters of carboxylic PCT/U82012/054719 acids or C1-Clo, C1-C3 or C1-C6 alkyl diesters or dicarboxylic acids. In one embodiment, the carboxylic acid or dicarboxylic acid is a C4-C2; fatty acid or dicarboxylic acid. In another embodiment, the carboxylic acid or dicarboxylic acid is a C1-C1; ylic acid or diearboxylic acid. In other embodiments, the carboxylic acid or dicarboxylic acid is a C1-Clo, C1-C3 or C1-C6 carboxylic acid or dicarboxylic acid.
In some preferred ments, the carrier or diluent e a derivative of glycerol including, but not limited to, ol monoesters (e.g. monoglycerides), glycerol rs (e.g. diglycerides), glycerol triesters' (e.g. cerides such as triacetin), or glycerol formal, or mixtures thereof. Glycerol formal is a mixture of 5-hydroxy—l,3-dioxanc and 4-hydroxymethyl- IO 1,3- ane (approximately 60:40), which are cyclic ether compounds derived from glycerol and having 2 oxygen atoms in the ring structure and substituted by alcohol group. Glycerol Formal is a low Odor and low toxic solvent for a wide variety of applications in’pharmaceutical and cosmetics industry including anti-parasite veterinary formulations.
In r embodiment of the ion, the organic solvents may comprise diisopropyl adipate, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, 2- pyrrolidone, ylpyrrolidone, diethylenc glycol monoethyl ether, triacctin, butyl acetate, benzyl alcohol, octyl acetate, propylene carbonate, oleic acid, or a mixture of at least two of H A these solvents.
In some embodiments of the invention, the carrier comprises yl isosorbide.
Dimethyl isosorbide (DMI) is a high purity solvent and carrier which offers a safe, effective delivery enhancement mechanism for active ingredients in personal care products and pharmaceutical formulations. In addition dimethyl isosorbide is sometimes used as an epidermal penetration enhancer to provide enhanced penetration of active agents to the mis. It may also provide delivery of active agents into—the skin while avoiding crystallization of the active agent, which will severely the effectiveness of the ation. Dimethyl Isosorbide is e in a variety of ingredients including water, cottonseed oil, isopropanol, isopropyl ate, propylene glycol, polysorbate 20, and polysorbate 80.
In Other embodiments, the carrier or diluent may comprise a glycol derivative including, but not limited to, propylene glycol, ethylene glycol; glycol ethers and polyglyeol ethers including, but not limited to, butyl diglycbl, propylene glycol monomethyl—ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, PCT/U82012/054719 ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, and diethylene glycol monoethyl ether (DGME or Transcutol‘ai').
In a preferred embodiment, the topical compositions of the invention comprising isoxazoline active agent(s) are dissolved in a pharmaceutically acceptable carrier comprising one or more solvents. In some embodiments of the invention solvents include, but are not limited to, dimethyl isosorbide (DMI), glycerol formal (methylidinoglycerol or glycerin formal), tin, liquid polyethyleneglyeols ing PEG 400, diisopropyl adipate (DIPA), pyl palmitate, silicone fluid including SILICONE FLUID 200 and ne Fluid lest and /or ne Fluid Zest and the like; propylene glycol (or other aliphatic dihydric ls), benzyl alcohol, IO propylene glycol esters including propylene glycol dicaprylate / dicaprate, propylene carbonate, propylene glycol monocaprylate, “propylene glycol dicaprylate, propylenew glycol monolaurate and propylene glycol dilaurate; alkyl esters “of dicarboxylic acids including diethyl sebacate (DES), diisopropyl sebacate; and esters or diesters of fatty acid, or combinations thereof.
In an embodiment of the invention, the compositions of the ion may include tants. The surfactants may be anionic, cationic, non-ionic or amphoterie surfactants.
Anionic surfactants include, but are not limited to, alkaline tcs; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulfates; sodium dodeeylbenzenesulphonate, sodium dioctylsulphosuceinate; fatty acids, and the like. Examples of ic surfactantiinelude, but are not d to, water-soluble nary ammonium salts of formula; eetyltrimethylammonium bromide and oetadecylamine hydrochloride. Non-ionic surfactants that may be used in the compositions e, but are not limited to, polyoxyethylenated (PEGylated) esters including, but not limited to, sorbitan esters and fatty acid esters; polyethylene glycol stearate, polpoyethylenated derivatives of castor oil, polyglycerol esters, yethylenated fatty alcohols, polyoxyethylenated fatty acids, and eopolymers of ethylene oxide and propylene oxide including, but not limited to, block co-polymers Of ethylene oxide and propylene Oxide such as poloxamers and the like (e.g. Lutrol® F grades and L grades from EASF including Lutrol® F68, F87, F 108 and F 127 and others), and the like;. Further example of surfactants include, but are not limited to, CAPRYOLTM 90 (propylene glycol“ monoeaprylate), CAPRYOLTM PGMC (propylene glycol monoeaprylate) which are oily liquids having an HLB (hydrophilic-lipophilie balance) of 6 and 5, respectively. lly they can be used as a co- surfactant in microemulsions and as a solubilizer/penetration enhancer.
WO 39948 PCT/U82012/054719 As used herein, HLB values have the following general meanings: compounds with a HLB value of < 10 tend to be lipid soluble (water insoluble) and solvents with a HLB > 10 tend to be water soluble. tants having HLB between 4 and 8 are typically useful as anti-foaming agents. Surfactants having HLB from 7 to 11 may be useful as W/O (water in oil) emulsifiers.
HLB of 12 to 16 typically indicates a surfactant may be useful in oil in water emulsions, and HLB of II to 14 is indicative of a wetting agent. HLB of 12 to 15 is typical of detergents, and HLB of 16 to 20 indicates a solubilizer or hydrotrope. There is significant an overlap of ranges/uses, and a skilled person well understands that the HLB value alone cannot be used to predict whether a particular surfactant will serve a specific purpose (e.g. anti-foaming agent, IO emulsifier, wetting agent, solubilizer, hydrotrope). Therefore, in general, determination of a suitable system of solvent, active agent, surfactant(s) and other excipients necessarily involves non-routine experimentation and inventive effort.
The compositions may also include tants such as oleoyl macrogolglycerides (polyoxylglycerides, for example, LABRAFIL‘K‘ MI944CS and IL‘E‘ M2125CS both having an HLB of 4). These compounds may also be used, for example, as oily phase for emulsions, microemulsions, and as penetration enhancers.
In another embodiment, the polyoxylglycerides may include polyethyleneglycol caprylic/caprylic glycerides such as LABRAS'O—LB) (HLB of '14. Topically it is used. as a surfactant in microemulsions, and can also act as a solubility/penetration enhancer in l formulations.
In another embodiment the surfactant is LAUROGLYCOLTM90 (propylene glycol monolaurate) having an HLB of 5. It is a eo-surfactant for mulsions in topical formulations and can also act as a lizer/penetration er in topical formulations. In some embodiments, the surfactant is PLUROL® OLEIQUE CC497 (polyglyceryl oleate), having 7 V an HLB of 6.
Certain ts suitable for topical formulations may be characterized as having good ing properties while other solvents for l formulations may be characterized by an ability to “enhance tion of active agents through the skin barrier into the systemic circulation (see for example, Pharmaceutical Skin Penetration Enhancement, edited by Jonathan Hadgraft and Kenneth A. Walters, Marcel Dekker, Inc. New York 1993). In some ces, solvents suitable for l formulations may include both good spreading and good permeation PCT/U82012/054719 characteristics. DIPA, diisopropyl sebacate, DES and l 840 have both good spreading and permeation characteristics. Transcutol, DMI, lauryl lactate, propylene glycol caprylate, ene glycol monocaprylate and propylene glycol monolaurate have good permeation enhancing properties but are not considered to have particularly good spreading properties. In certain embodiments of the invention. the compositions will comprise mixtures of ts that will enhance the spreading ability and/or the permeation enhancing ability of the composition.
In some embodiments of the invention, formulations are provided wherein the carrier comprises solvents that exhibit both good spreading and permeationcharacteristics including, but not limitcd to, DIPA, diisopropyl scbacatc, DES and Miglyol® 840. In othcr cmbodimcnts, the IO invention provides formulations n the carrier comprises ts that exhibit good spreading characteristics. In still another embodiment of the invention, formulations are provided \vherein the carrier vehicle comprises solvents that enhance the permeation of the active agent through the skin into the systemic circulation.
In one ment, the composition exhibits long lasting efficacy and provides protection against parasites in domestic animals for at least one month. In one embodiment, the composition ses a carrier that includes a solvent system comprised of a carboxylic acid alkyl ester or diester of a dicarboxylic acid. In another embodiment, the composition comprises a blend of solvents comprising a ylic acid alkyl ester or a diester of a dicarboxylic acid.
In another embodiment, the compositions of the invention t very long lasting efficacy of at least 90% against fleas and/or ticks that for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months against fleas and/or ticks. In one ment, the long-lasting composition comprises a carrier that includes a carboxylic acid alkyl ester or a diester ’of a dicarboxylic acid, including diethyl sebacate and diisopropyl adipate. In r embodiment, the long-lasting composition ses a carboxylic acid’alkyl ester or a diester of a dicarboxylic acid combined with an co-solvent including, but not limited to, a propylene glycol (PG)'ester including PG monocaprylate, PG caprylatc, PG monolauratc and PG dicaprylatc/dicapratc; lcncglycol hyl cthcr (DGME, Transcutol‘fi’), mineral oil, triglycerides, diglycerides, isostearyl l, isostearyl lactate, dibutyl adipate, l sebacate; polyethylene glycols (PEGs) including PEG 400, PEG stearate; lecithin, r oil and castor oil derivatives, film formers, myristyl myristate, dimethiconol argenine, sucrose acetyl isobutyrate, and the like, or a combination thereof.
PCT/U82012/054719 In still r embodiment, the long-lasting compositions that provide an efficacy of at least 90% against fleas and/or ticks for at least 1 month, at least 2 months, at least 3 , at least 4 , at least 5 , or at least 6 months, comprise a carrier vehicle that includes dimethyl isosorbide. As mentioned above, DMl is a known permeation enhancer, and use of this solvent in some topical formulations of the invention results in increased delivery of the active agent into the systemic circulation. In particular, it was found that the use of DM1 in topical formulations for cats ed in surprising efficacy for up to at least 3 months, at least 4 months, at least 5 months or even at least 6 months, against fleas.
In yet another embodiment, the long-lasting compositions that provide an y of at IO least 90% t fleas and/or ticks comprises a“ glycol ether including, but not limited to, diethyleneglycol monoethyl ether (DGME, Transcutol®), butyl diglyeol, dipropylene glycol n- butyl ether, neglchl monoethyl ether, ethyleneglycol mOnOmethyl~ ether, diptopylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and the like.
As discussed above, isoxazoline active agents such as those of Formula (I), and in ular 4-[5-[3-chloro(trifluoromcthyl)phenyl]-4,5-dihydro(trifluoromcthyl) isoxazolyl]-N-[2-oxo[(2,2,2-trifluoroethyl)amino]ethyl]- l -naphthalanecarboxamide (Compound A), are systemically active such that the ectoparasite is affected when taking a blood meal from the host. ingly, a minimum concentration of the compounds in the systemic circulation of the animal is required to effectively control ectoparasites such as ticks and fleas. It was surprisingly found that the topical formulations of the invention comprising an isoxazoline active agent provide excellent efficacy t fleas and ticks at unexpectedly very low plasma concentrations. In some embodiments, the topical compositions of the invention comprising selected solvents and excipients, including dialkyl esters of dicarboxylic acids such as diethyl sebacate and the like, result in constant low levels of the active agent over a prolonged period of time. In some embodiments, the concentration of the active agent in the plasma that is sufficient to obtain at least 90% efficacy against flcas and/or ticks is less than or equal to about 200 ng/mL or less than or equal to about] 50 ng/mL. In other preferred embodiments, the concentration of the isoxazoline active agent in the plasma required to attain 90% efficacy against fleas and/or ticks is less than or equal to about 100 ng/mL, less than or equal to about 75' ng/mL or even less than or equal to about 50 ng/mL. In other embodiments of the invention, the concentration of the PCT/U82012/054719 isoxazoline active agent in the plasma required to attain 90% efficacy against fleas and ticks is about 75-100 ng/mL, about 50-75 ng/mL or about 30-50 ng/mL.
Furthermore, it was also surprisingly found that'the concentration of the isoxazoline active agent (Compound A) in the plasma required to attain an efficacy of at least 90% against certain tick species ed to an untreated control or a control group treated with a placebo was cantly less than the plasma concentration required to attain 90% cy from r mode of administration that achieves high systemic exposure, such as oral or injectable administration. It was found that the concentration of the isoxazoline active agent required to achieve 90% efficacy against the tick species A. anzericammz, D. variabilis and R. sanguineus in IO dogs was about 42%; 36% and 32% lower than the concentration required from oral administration (see Example 13). This effect is surprising and unexpected for an active agent that is active against ectoparaSites through ingestion of a blood meal, as with the isoxazolineclass of compounds. Although not wanting to be bound by theory, the lower plasma concentration required to e 90% efficacy from the l itions of the invention may indicate that the compositions provide protection against ectoparasites by acting both topically on the e of the animal and systemically. The improved efficacy of the topical compositions of the invention against these tick species at significantly lower plasma concentrations may allow for a longer duration of efficacy based on the ability of the non-active excipients in the inventive compositions to provide a slow delivery of ive amounts of isoxazoline active agents into the blood stream from the site of application.
As mentioned above, it was surprisingly discovered that the addition of certain other active agents with the isoxazoline active agent in the topical compositions of the ion significantly enhanced the long lasting cy of the corripositionsfFor example, inclusion of an IGR active agent such as the juvenile hormone mimic methoprene in the l compositions resulted in significantly longer lasting efficacy against ectoparasites. Thus; in one preferred embodiment the invention provides very long lasting topical “compositions comprising at least one oline active agent in combination with an insect growth regulator (IGR) active agent.
Preferably, the IGR will be a juvenile hormone mimic including azadirachtin, diofenélan, fenoxycarb, hydroprene, kinoprene, pyriproxyfen, tetrahydroazadirachtin or 4-chloro(2- chlorO-Z-methy[propyl)(6-iodopyridylmethoxy)pyridizin-3(2H)-one, as discussed herein.
More preferably, the IGR will be rene or pyriproxyfen. As described in the non-limiting PCT/U82012/054719 examples, the inclusion of the IGR (S)-methoprene with the isoxazoline active agent resulted in significantly longer lasting efficacy. This effect is sing and unexpected, as methoprene is not an adulticide'(see Examples 1-3). _ ' _ _ In another embodiment of the invention, it was surprisingly discovered that inclusion of a neonicotinoid active agent such as nitenpyram in the topical compositions of the invention significantly increased’the speed of kill’of the compositions against fleas. Thus, a topical composition sing nitenpyram in combination with an isoxazoline active agent and optiénally an IGR active agent and/or other oily active agents and/or active agents With low mclting points such as pcrmcthrin, provide cfficacy of at lcast 90% against flcas as carly as 12 IO hours after administration of the l formulation and also provide king lasting efficacy. In yet other embodiments of the invention, the topical compositions provide efficacy'of at least 90% against fleas as early as 9 hours or 6 hours afier administration. In one embodiment of the invention, the compositions comprising a combination of nitenpyram and an isoxazoline active agent provide efficacy of at least 90% against fleas as early as 12 hours, 9 hours or 6 hours after treatment and an efficacy of at least 90% for a period of at least 1 month. In other embodiments, the compositions comprising a combination of nitenpyram and an isoxazoline activc agcnt provide efficacy of at least 90% as early as 12 hours, 9 hours or 6 hours after treatment and an efficacy of at least 90% for a period of at least 2 months or at least 3 months, or . The fast acting and long lasting protection provided by a combination of the neonicotinoid nitenpyram and an isoxazoline active agent is very surprising and unexpected because yram is only known to be effective when stered orally, as with the product CAPSTARTM Tablets.
In other ments, the compositions of the invention may be in the form of oil-in- water or water-in-oil emulsions. In some embodiments the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of thesef Suitable emulsifying agents e naturally-occurring pholsphafides, for example, soy bean, lecithin, and esters or l esters derived from fatty acids and hexitol anhydrides, fOr cxamplc, sorbitan mono olcatc, and condensation products of thc said partial cstcrs with cthylcnc oxide”, for e, polyoxyethylene sorbitan mono oleate, and the like. In some embodiments, the emulsions may also contain preservatives.
In r embodiment of the formulation, the ition of the invention is in the form of a microemulsion. Microemulsions are well suited as the liquid r vehicle. Microemulsions PCT/U82012/054719 are typically quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a co-surfactant. They are y translucent and isotropic liquids. Microemulsions are composed of stable dispersions of micrddroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is typically less than—200 nm (1000 to 100,000 nrri for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
In one embodiment of the oily phase, the oily phase’can be formed from mineral or vegetable oils, from unsaturated polyglycosylatcd idcs or from triglycerides, or IO alternatively from mixtures of such compotmds.‘ In one embodiment of the oily phase, the oily phase comprises of cerides. In r embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example C3-C10 caprylic/capric‘ triglycerideI In another embodiment, the oily phase will represent a % v/v range selected from the group consisting of about 1 to about 20%; about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion; The aqueous phase typically includes, for example water or glycol derivatives, such as propylene , glycol , polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, lene glycol monoethyl ether, dipropylene glycol hyl ether and mixtures thereof.
Generally, the aqueous phase will represent a proportion from about 1 to about 10% v/v or about 1 to about 4% v/v in the microemulsion.
' ‘SurfaCtants for the microemulsion typically include diethylene glycol hyl ether, dipropyelene glycol monomethyl ether, polyglycolyzed Cg-Cm glycerides or polyglyceryl-6 dioleate, or a combination of these surfactants. In addition to these surfactants, them-surfactants include chain alcohols, such as ethanol and propanol. Additionally, poloxamers and Pluronic F127 can be used as tants. “ “ “ Some nds are common to the three components discussed above, i.c., aqueous phase, surfactant and co-surfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation.
Oily suspensions may be forniulated by suspending the active ingredient in a vegetable oil, for example, s oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid WO 39948 2012/054719 paraffin, and the like. The oily suspensions may contain a thickening agent, for example, x, hard paraffin or cetyl alcohol, and the like. These compositions may be ved by the addition of an anti-oxidant such as ascorbic acid or other know—n preservatives. _ Aqueous suspensions may contain the active agents in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include ding agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethyICellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-eccurring atide, for example in, or condensation products of an alkylcnc oxide with fatty acids, for example polyoxycthylcnc stcaratc, or condensation IO products of ethylene oxide with long ‘chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol s polyoxycthylene sorbitol mono-oleate, or condensation products of ethylene oxide, with l esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono-oleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agcnts.
Colorants may be added to the inventive formulations. Colorants contemplated by the present invention are'those commonly known in the art. Specific colorants include,“ for example, dyes, FD&C Blue #1 Aluminum Lake, caramel, colorant based upon iron oxide or a mixture of any of the foregoing. Especially preferred are organic dyes and titanium dioxide. Preferred ranges include fi'om about 0.01% to about 2% (w/v), more preferably from about 0.01% to about 0.5% (w/v).
In preferred embodiment, the compositions of the invention are in the form of a n formulation that is d to a localized“ area on an animal, rather than the entire coat “of the animal or a large portion of the animal’s coat. In one embodiment of a zed region, the location is betheen the shoulders. The spot-on formulation according to the present invention provide long-lasting and broad—spectrum efficacy against rasitcs and/or cndoparasitcs ivhen the so1ution ‘is applied toithe . The spot-on formulations provide for topical administration of a concentrated solution, suspension, microemulsion or on for ittent application to localized area on the animal, generally between the two shoulders.
Spot-on formulations are well known techniques for topically delivering certain PCT/U82012/054719 antiparasitic agents to a d area of the host. However, not all compounds are suited for formulation in spot-on formulations because the physicochemical characteristics of the active agent may not allow effective distribution of the compound topically or transderrnally. US.
Patent Nos. 536, 6,395,765; 329; 7,262,214; 6,426,333; 6,482,425; 713; 6,998,131; and 7,531,186, all incorporated herein by reference, describe spot-on ations.
W0 01/957715, also incorporated’ herein by reference, describes a method for controlling ectoparasites in small s as well as upting or preventing the diseases caused by arthropods in small rodents, which comprise applying topical formulations, such as spot-on compositions, to the skin, or hair of the rodents.
IO Spot-on formulations may be prepared by dissolving the active ingredients into the pharmaceutically or nary acCeptable vehicle. Alternatively, the spot-on formulation can be prepared by encapsulation of the active ingredients to leave a film of the therapeutic agent on the surface of the animal. These formulations will vary with regard to the weight of the eutic agent in the ation depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.
For spot-on formulations, the pharmaceutically acceptable carrier may be a liquid carrier vehicle as described , and other carriers described in the art, for example in US. Patent No. 6,395,765 and other patents listed in the previous paragraph. In some embodiments, the liquid carrier vehicle can optionally contain a crystallization inhibitor such as the crystallization inhibitors described below, or mixtures thereof, to inhibit the ion of crystals or precipitate of the active ents.
The veterinarily acceptable carrier will generally comprise a diluent or vehicle in which the active agents are soluble. It will be apparent to those of skill in the art that the carrier or diluent of the topical compositions mustibe able to deliver the active agents to the targeted location without’the active agents precipitating from solution or forming crystals. In Some embodiments, the carrier or diluent of mpdsitions will be suitable to avoid precipitation or crystallization of the active agents. In other embodiments, the compositions may include a crystallization inhibitor component in addition to the carrier or diluent. “ Crystallization inhibitors which are useful for the ion include but are not limited to: (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, 2-pyrrolidone including N-methylpyrrolidone, dimethylsulfoxide, polyethylene PCT/U82012/054719 glycols, co-polymers of polyoxyethylene and polyoxypropylene, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of an; lecithin or sodium carboxymethylcellulose; or‘ acrylic derivatives, such as polymers derived from acrylic monomers including polyacrylates or polymethacrylates; and, a solvent as described herein that inhibits the crystallization of the active agent, and r compounds; (b) anionic surfaCtants, such as alkaline stearates (e.g. sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include but are not limited to sodium lauryl sulfate and sodium cetyl sulfate; sodium dodccylbcnzcncsulfonatc or sodium dioctyl sulphosuccinatc; or fatty acids (c.g. coconut IO oil); (c) cationic surfactants, such as water-soluble quaternary ammonium salts of formula N+R'R"R"'R""Y_, in which the R radicals are identical‘or different optionally hydroxylatcd hydrocarbon radicals and Y7 is an anion of a strong acid, such as halide, e and sulfonate ; cetyltrimethylammonium bromide is one of the cationic tants which can be used; (d) amine salts of formula N+HR'R"R"' Y", in which the R radicals are identical or different optionally hydroxylatcd hydrocarbon radicals and Y" is the anion of a mineral or organic acid; octadecylamine hydrochloride is one of the cationic surfactants which can be used; (e) non-ionic surfactants, such as optionally polyoxyethylenated esters of an, e.g. Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, yethylenated derivatives of castor oil ing hydrogenated castor oil and its derivatives, ycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or mers of ethylene oxide and of propylene oxide; (f) amphoteric surfactants, such as substituted lauryl compounds of betaine; or (g) a mixture of at least two of the compounds listed in (a)-(f) above.
In one embodiment of the crystallization inhibitor, a crystallization inhibitor pair will be used. Such pairs e, for example, the combination of a film-forming agent of polymeric type and of a surface-active agent. Othcr crystallization inhibitor pairs include a hylene glycol and a nic surfactant. Additional crystallization pairs including other mixtures are also contemplated. These agents can be selected from the nds mentioned above as crystallization inhibitor.
In one embodiment of the film-forming agent, the agents are of the polymeric type which PCT/U82012/054719 include but are not limited to the s grades of nylpyrrolidone, polyvinyl alcohols, polyethylene glycols and copolymers of vinyl acetate and of vinylpyrrolidone.
In one embodiment of the surface-active agents, the agents include but are not limited to those made of non-ionic surfactants. In another embodiment of the surface active , the agent is a polyoxyethylenated ester of sorbitan. In yet another embodiment of the surface-active agent, the’agents include the various grades of pelysorbate, for example Polysorbate 80 and polyoxyethylenated derivatives of castor oil including hydrogenated castor oil derivatives. 7 In another embodiment of the invention, the film-forming agent and the surface-active agent can be incorporated in similar or cal amounts within the limit of the total amounts of IO crystallization inhibitor mentioned above.
In some embodiments, the crystallization inhibitor can be present in a proportion of about 1 to about 30% (w/v). Typically, the llization inhibitor may be present in‘a tion of about 1% to about 20% (w/v), about 1% to about 10% (w/v), or about 5% to about 15% (w/V). able inhibitors are those whose addition to the formulation inhibits the ion of crystals of the active agents when the formulation is applied. In some embodiments, formulations may include compounds that function as crystallization tors other than those listed herein.
In these embodiments, the suitability of a crystallization inhibitor may be determined by testing if it will sufficiently inhibit the formation of crystals so that a sample containing 10% (w/v) of the isoxazoline active agent in a solvent as described above with 10% (w/v) of the crystallization inhibitor will result in less than 20, preferably less than 10 crystals when placed on a glass slide at 20 0 C for 24 hours.
In some embodiments of the invention, an emollient and/or spreading and/or film- forming agent may be added to the topical compositions of the inventionfEmollients, spreading agents “and film forming agents are well known in the art. In s embodiments, the emollients, spreading agents and film forming agents that may be used in the l compositionsiinclude the components listed in (a) to (g) above, ineluding polymer derivatives such as polyvinylpyrrolidonc, polyvinyl alcohols and copolymers of vinyl acetate and vinylpyrrolidone; anionic surfactants; cationic tants; non¥ionic surfactants; eric surfactants; amine salts, and combinations thereof. In one embodiment, the emollient is used in a proportion of from about 0.1 to about 10%, or about 0.25 to about 5% (w/v).
Optionally, a fragrance may be added to any of the compositions of the invention.
PCT/U82012/054719 Fragrances which are useful for the invention include but are not limited to: (i) carboxylic acid esters such as octyl acetate, isoamyl acetate, isopropyl acetate and isobutyl e; (ii) fragrant oils such as lavender oil.
The inventive formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the formulation art.
Antioxidants such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium’ascorba’te, sodium metabisulfate, sodium metabisulfite, n- propyl gallate, BHA (butylatcd hydroxy anisole), BHT (butylatcd hydroxy toluene), BHA and IO citric acid, monothioglycerol, tert-butyl hydroquinone (TBHQ), and the like, may be added to the present formulation. The antioxidants are generally added to the formulation in amounts of from about 0.01 to about 2.0%, based upon total weight of the formulation, with about 0.05 to about 1.0% being ally preferred.
Preservatives, such as the parabens (methylparaben and/or propylparaben), are suitably used in the formulation in amounts ranging fiom about 0.01 to about 2.0%, with about 0.05 to about 1.0% being especially preferred. Other vatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl l, bronopol, butylparaben, cetrimide, chlorhexidine, ehlorobutanol, chlorocresol, cresol, ethylparaben, imidufea, methylparaben, , phenoxyethanol, phenylethyl alcohol, phenylmereuric acetate, phenylmereuric borate, phenylmereuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Preferred ranges for these compounds e from about 0.01 to about nds which stabilize the pH of the ation are also contemplated. Again, such compounds are well known to a practitioner in the art as well as how to use these compounds.
Buffering systems include, for example, systems selected from the group ting of acetic cetate, malic acid/malate, citric acid/citrate, ic artrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate. “ In other embodiments, the l compositions of the invention may be in the form of a pour-on ation. Pour-on forrriulations are described, for example, in US. Patent No. 6,010,710, which is incorporated herein by reference. Some pour-on formulations are PCT/U82012/054719 advantageously oily, and generally comprise a t or vehicle and also a solvent (e.g. an organic solvent) for the active ingredient if the latter is not soluble in the diluent. Other pour-on formulations may be in hydrophilic carriers, including in alcohol, glycol or glycol ether based carriers. Pour-on formulations are typically administered to ock animals such as cattle and sheep. Typically, pour-on formulations are administered to the animal as a stripe to an external surface of the animal, e.g. a stripe from head to tail of the animal. In one embodiment, the process comprises applying the solution to ock animals before they arrive in the Feed Lot, it being le for this application to be the final one before the animals are slaughtered.
Typically, the isoxazolinc(s) active agents are present in the formulation at a IO tration of about I to about 25% (w/v).’ In some embodiments of the invention, the isoxazoline active agents are present in the formulation as a concentration from about 1 to about % (w/v), about 1 to about 10% (w/v), about 5 to about 15% (w/v), or about 5 to 10% (w/v). In other embodiments, the isoxazoline active agent(s) are present in the compositions at a concentration of about 1 to about 5% (w/v), about 3-6 % (w/v) or about 0.5% to about 2.0% (w/v).
The volume of the topical composition applied is not restricted as long as the amount of substance administered is practical and shown to be safe and effective. lly, the volume applied depends on the size and weight of the animal as well as the tration of active, the extent of infestation by parasites and the type of administration. For spot—on compositions, the volume d is typically of the order of about 0.1 ml to about 10 ml, about 0.1 ml to about 5 ml, or about 0.1 to about 1 ml, or, or. In other embodiments, the volume may be about 4 ml to about 7 ml. For larger animals, the volume may be higher including, but not limited to, up to 10 ml, up to 20 ml or higher. In one embodiment of the volume, the vo1ume is on the order of about 0.5 nil to about 1 ml or about 0.5 ml to about 2 ml for cats, and on the order of about 0.3 to about 3 ml or 4 ml for dogs, depending on the weight of the animal.
For the pour-on form ofthe composition, the volume applied can be of the order of about 0.3 to about 100 mL. In other embodiments, volume applied of the pour-on formulations may be about 1 ml to about 100 ml or about 1 ml to about 50 ml. In still other embodiments, the volume may be about 5 ml to about 50 ml or about 10 ml to about 100 ml.
Dosage forms may contain from about 0.5 mg to about 5 g of a combination of active agents. More typically, the amount of active is present in an amount of from about 1 mg to about PCT/U82012/054719 500 mg of an active agent, about 1 mg to about 100 mg or about 1 mg to about 25 mg. In still other embodiments, the amount of the active agent present in the compositions is about 10 mg about 50 mg or about 10 mg to about 100 mg. In other embodiments, the amount of active agent present in the compositions is about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 600 mg, about 400 mg to about 800 mg, or about 500 mg to about 1000 mg.
The compositions of the invention are made by mixing the riate amount of the active agents, pharmaceutically acceptable carrier or diluent 'and optionally a crystallization inhibitor, antioxidant, preservative, film former, etc., to form a composition of the invention. In IO some embodiments the composition can be obtained by following the method of making these forms described above by the description of making these forrns'found in general formulation text known to those in the art, e.g. Remington — The Science and ce macy (21“ Edition) (2005), Goodman & Gilman’s The cological Basis of Therapeutics (ll'h Edition) (2005) and Ansel ’5 Pharmaceutical Dosage Forms and Drug Delivery .Sj.r.s'tenzs (8th Edition), edited by Allen et al., Lippincott ms & Wilkins, (2005).
Methods of Treatment In another aspect of the ion, a method for preventing or ng a parasite infestation/infection in an animal is provided, comprising administering to the animal aitopical composition comprising an effective amount of at least one isoxazoline active agent together with a pharmaceutically acceptable carrier that is suitable for application to the skin of the animal. The compositions or formulations of the invention have long-lasting efficacy against ectoparasites (e.g. fleas and ticks) and in certain embodiments may also active against endoparasites that harm animals.
In one embodiment of the invention, methods for the treatment or prevention of a parasitic infestation or infection in a ic animal are provided, which comprise stering a topical composition sing an ive amount of at least one isoxazoline active agent to the animal. Ectoparasitcs against which the methods and compositions of the invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies and lice. In n embodiments wherein the compositions include one or more additional active agents that are active against internal parasites—the compositions and methods of the invention may also effective against rasites including, but not limited to, cestodes, nematodes, PCT/U82012/054719 hookworms and orms of the digestive tract of animals and humans.
In one embodiment for ent against ectoparasites, the rasite is one or more insect or arachnid including those of the genera Ctenbcephalides, Rhipicephulus, Dermacentor, lxodes, Boophilus, Ambylomma, Haemaphysalis, I-Iyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes;Hypoclerma, Damalz'nia, az‘hus, Haematopinus, Solenoptes, Trichodectes, and Felicola.
In another embodiment for the treatment against ectoparasites, the ectoparasite is from the genera Ctenocephalides, ephalus, Dermbcentor, bedes and/or Booplzi/us. The rasites treated include but are not limited to fleas, ticks, mites, mosquitoes, flies, lice, IO bloWfly and combinations thereof. Specific examples include, but are notlimited to, eat and dog fleas (Ctenocephaliclesfilis, Ctenocebhalicles sp. and the like), ticks (Rhipiceplzalus sp., Ixodes ' sp., Dermacentor sp., Amblyoma sp. and the like), and mites (Demodex sp., Sarcoptes sp., 0t0dectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp., Lignonathus sp., and the like), mosquitoes (Aedes sp., Culex sp., Anopheles sp., and the like) and flies (Hematobia sp. including Haematobia irritans, Musca sp., Stomoxys sp. including Stomoxys calcitrans, Dematobia sp., Cochliomyia sp., and the like).
Additional examples of ectoparasites include but are not d to the tick genus lus, ally those of the species microplus (cattle tick), decoloratus and annulatus; myiases such as Dermatobia hominis (known as Beme in Brazil) and Cochliomyia vorax (greenbottle); sheep myiases such as Luci/fa sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa). Flies proper, namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly) and Stomoxys calcitrans (stable fly); lice such as Linognathus , etc.; and mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are Well known in the art tobe harmful to animals and humans. These include, for ekample ing dipterous larvae.
In some embodiments of the invention“, the cempos‘itioh can also be used to treat against cndoparasites such as those helminths selected from the group consisting locephala, smma, Anecamr, s, Capillaria, Cooperia, Dipylidium, Dirbfilaria, ococcus, Enterobius, Fascia/a, Haemonchus, Oesophagostumzmz, Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, and Tfichdstrongylus, among—others.
In one embodiment, the invention provides methods for the treatment and prevention of PCT/U82012/054719 parasitic infections and infestations of animals (either wild or domesticated), including livestock and companion animals such as cats, dogs, horses, birds including chickens, sheep, goats, pigs, turkeys and cattle, with the aim of ridding these hosts of parasites ly tered by such animals.
In a'preferred embodiment, the invention provides methods and compositions for the treatment or prevention of parasitic infections and infestations in ion animals including, but not limited to, cats and dogs. The methods and compositions are particularly effective for preventing or treating parasitic infestations of cats and dogs with fleas and ticks.
In another preferred embodiment, the methods and compositions of the invention are used for the IO treatment or prevention of parasitic infections and infestations in cattle or sheep. When treating livestock animals such as cattle or sheep, the methods and compositions are particularly effective against Rhipicephalus (Boophilus) micfoplus, Haematobia irritans (hem fly), Stomoxys calcitrans e fly), and sheep myiases such as Luci/fa sericata, Luci/id cuprina (known as blowfly strike in Australia, New Zealand and South Afi'ica).
The terms “treating” or “treat” or “treatment” are intended to mean the ation or administration of a composition of the invention to an animal that has a parasitic infestation for the eradication of the parasite or the reduction of the number of the parasites infesting the animal undergoing treatment: It is noted that the itions of the invention may be used to prevent such a parasitic infestation.
The compositions of the invention are administered in parasiticidally effective amounts which are which are suitable to control the parasite in question to the desired , as described below. In each aspect of the invention, the nds and compositions of the invention can be d against a Single pest or combinations thereof. _ _ The compositions of the invention may be administered continuously, for treatment or prevention of parasitic infections or ations. In this manner, the cempositions of the invention deliver an ive amount of the active compounds to the animal in need thereof to control the target parasites. By “effective amount” is intended a ient amount of a composition of the invention to eradicate or reduce the number of parasites infesting the animal.
In some ments, an ive amount of the active agent achieves at least 70% efficacy against the target te. In other embodiments, an effective amount of the active agent achieves at least 80%, or at least 90% efficacy against the target pests. Preferably, an effective PCT/U82012/054719 amount of the active agent will achieve at least 95%, at least 98% or 100% efficacy against the target parasites. _ Generally, a dose of from about 0.001 to about 100 mg per kg of body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but, of course, there can be instances where higher or lower dosage ranges are indicated, and such are within the scope of this invention. It is Well within the routine ’skill of the tioner to determine a particular dosing regimen for a specific host and parasite. 1n some’embodiments fer companion animals, the dose of the oline active agent administered from the topical compositions of the invention is between about 0.1 to about 30 mg IO per kg of body weight. More typically the dose of the isoxazoline active agent administered is about'0.5 to about 20 mg/kg or about 0.5 to about 15 mg/kg body weight. Preferably, the dose of the isoxazoline active agent administered is about 0.5 to about 10 mg/kg, about 0.5 to about 8 mg/kg or about 0.5 to about 5 mg/kg of body weight.
In certain embodiments for the treatment and prevention of te infestations and infections in cats, the dose of the isoxazoline active agent administered will be about 0.5 to about 2 mg/kg of body weight, preferably about 1 mg/kg of bodyweight. In other embodiments for the very long lasting treatment and protection of cats against parasitic infestations or infections a dose of about 2 "to about 15 mg/kg of bodyweight or preferably about 5 to about 15 mg’kg of ight will be administered.
In some embodiments for the ent and protection of dogs from parasitic infestations and ions, a dose of about 2 to about 15 mg/kg of ight of the isoxazoline active agent will be administered. In other embodiments, a dose of about 2 to about 8 mg/kg or about 2 to about 5 mg/kg of bodyweight will be administered.
In Other embodiments for the treatment of ock animals such as cattle or sheep, doses of the isoxazoline active agent administered may be about 1 to about 30 mg/kg of body’weight.
More typically the doses administered will be about 1 to about 20 mg/kg or about 1 to'about' 15 mg/kg. Preferably, a dose of the isoxazoline active agent administered to livestock animals will be abbut 1 to about 10 mg/kg ofbody weight.
Higher amounts may be provided for very prolonged release in or on the body of the animal. In another treatment embodiment, the amount of active agents for birds and other animals which are small in size is greater than about 0.01 mg/kg, and in r embodiment for PCT/U82012/054719 the treatment of small-sized birds and other animals, the amount of is between about 0.01 and about 20 mg/kg of weight of animal. More typically the dose of the isoxazoline for small-sized s and‘bir'ds is about 0.5 to about 15 mg/kg, about 0.5 to about 10 mg/kg of body weight, or about 0.5 mg/kg to about 5 mg/kg of body weight.
In one embodiment of the method of use in dogs or eats, a composition comprising an isoxazoline nd has an efficacy against fleas and/or ticks of at least about 90.0% or higher for about 1 month, or longer. In another embodiment, the compositions of the invention provide an efficacy against fleas and/or ticks of at least 95.0% or higher for about 30 days, or longer.
In another embodiment, the topical compositions of the invention e an efficacy IO against fleas and/or ticks in cats and dogs of at least about 80% for two months, or longer. In another ment, the topical compositions provide efficacy against fleas and/or ticks in cats and dogs of about 90% for about two months, or longer. In Still another embodiment, the itions provide an efficacy of about 95% for about 2 months or longer.
In another embodiment, the composition has an efficacy of at least about 80% t fleas and/or ticks for about 3 months, or longer. In still r ment, the topical compositions of the invention provide an efficacy of at least about 90% against fleas and/or ticks for 3 months or longer. In yet another embodiment, the topical compositions of the invention provide an efficacy of at leaSt about 95% against fleas and/or ticks for 3 months or longer. In still another embodiment, the topical itions of the invention provide an y against fleas and/or ticks in cats and/or dogs of at least 80% or at least 90% for about 3 months to about 6 months or longer.
In one embodiment of the invention, the topical spot-on compositions of the invention are administered to the animal over a localized region’of the’animal, cg. between the two shoulders.
In one embodiment of the invention, the localized region has a surface area of about 10 cm2 or larger. In r embodiment of the invention, the localized region has a surface area of between about 5 and about 10 cm2, or smaller.
In another embodiment of the invention, the pour-on topical compositions of the invention will be administered in a line along the back ofthe animal “approximately between the shoulders and the hind rs.
The solutions according to the invention may be applied using any means known per se, e.g. using an applicator gun or a metering flask, pipette, syringes, roll on, rs, capsules, foil PCT/U82012/054719 packages, vials, twist tip ners, metered-dose aerosols or sprays and other single dose and multi-dose containers.
' In'an'other aspect of the invention, a kit for the treatment or prevention of a parasitic infestation in an animal is provided, which comprises at least one isoxazoline active agent together with a pharmaceutically acceptable r and a dispensing device for topical application of the composition. The sing device may be a pipette, syringes, roll on, droppers, capsules, foil packages, vials, twist tip containers, metered-dose aerosols or sprays and other single’ dose and multi-dose containers, which includes an ive dose of each active agent in the ceutically acceptable carrier or diluent.
IO An important aspect of the‘invention is to provide a multiple-use container sing a l ition of the invention, from which accurate single dose aliquots of the long g topical forniulations may be administered. The ation must remain stable with repetitive exposure to the e environment, particularly oxygen and water. This embodiment may be particularly useful with the very long lasting formulations of the invention that require administration to an animal infrequently, such as once every 3-6 months, or similar. Some solvents such as ethcrs (including DMI, Transeutol® and the like) give rise to peroxides, which then yield ketones and aldehydes that may be further degraded to acids. The presence of acids may contribute to the degradation of acid hydrolysis-susceptible molecules, including isoxazoline active agents. Thus, formulation stability is particularly ant for the multi-dose container application, where the formulations can be exposed to oxygen and water during multiple rounds of opening and closing. Importantly, it was found that the use of certain antioxidants described herein, including BHT and BHA, efficiently inhibit the degradation of the active agent in ether solvents. For example, a 12% (w/v) solution of Compound A in DMI exhibited no significant change in assay over the course of an eleven week accelerated stability study at 50 °C in clear glass ners. In other embodiments, antioxidants such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbatc, sodium metabisulfate, sodium metabisulfitc, n-propyl gallate, BHA (butylatcd hydroxy anisole), BHT (butylatcd hydroxy toluene), BHA andcitri‘c acid, monothioglycerol and the like, may be added to the topical compositions to inhibit the formation of oxidative species.
The antioxidants are generally added to the formulation in amounts of from about 0.01 to about 2.0%, based upon total weight of the ation, with about 0.05 to about 1.0% being especially WO 39948 PCT/U82012/054719 preferred.
EXAMPLES lhe invention is further described by the following non-limiting es which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention.
Formulation Examples Liquid vehicles suitable for l isoxazoline—containing formulations for control of parasites Were investigated. As a non-limiting example, the isoxa’zoline nd 3- chloro-S-(trifluoromethyl)phcnyl]-4,5-dihydro(trifluoromcthyl)isoxazolyl]—N-[2—oxo IO [(2,2,2-trifluoroethy|)amin’o]ethy|]-l -naphthalanecarboxamide (Cmpd. A), was investigated for topical ry to s, including cats, dogs and livestock animals such as cattle.
Formulations comprising an isoxazoline compound in combination with one or more additional active agents, including (S)-methoprene, pyriproxyfen and nitenpyram, were also prepared and tested. ations were prepared with a variety of liquid carrier vehicles and evaluated for effectiveness to control eetoparasites, particularly fleas and ticks in cats and dogs, and ticks, mites and lice in cattle. Solvent systems comprising either one solvent, including a diester of a dicarboxylic acid and/or an ether such as dimethyl isosorbide, or a combination of solvents including a r of a dicarboxylic acid, specifically l sebacate, and at least a second solvent(s) are encompassed by the invention. In various embodiments, formulations comprising a single solvent such as DES or DMI or a combination of ts were investigated. Solvents combined with a diester of a dicarboxylic acid include, but are not limited to: l) a propylene glycol ester or ether, including PG monocaprylate, PG caprylate, PG monolaurate, PG ylate/dicaprate, PG caprylie/capric triglycerides (LABRASOLfi) or a combination thereof; 2) an ether (egfdimethyl isosOrbide); 3) a Second ester (triacetin, lauryl lactate); 4) a fatty acid ester including, but not limited to, isopropyl palmitate, isostearyl lactate, dibutyl adipate, dibutyl scbacatc, octyl palmitate, polyethyleneglycol stcarate and cctearyl octanoate; 5) a glycol or polyglycol ether such as ”l‘ranseutol'fi', PEG 400 and the like; 6) an oil such as mineral oil, diglycerides, triglycerides, jojoba oil, in and castor oil; 7) a long chain aliphatic alcohol 65 ' _ PCT/U82012/054719 such as isostearyl alcohol; and 8) mixed esters sucrose and carboxylic acids, including sucrose acetate isobutyrate (SAIB) and the like.
In other embodiments, the topical compositions of the invention comprise TranscutoliK, glycerol formal, triacetin, propylene carbonate, benzyl l or DMI.
' ' Non-limiting forrriulations comprising an isoxazoline nd (Cmpd. A) alone or in combination with the non-limiting additional active agents (S)-methoprene,’pyriproxyfen and nitenpyram are provided in below.
Formulation l -_ Add leneglycol monoethyl ether (Transcutol®) (50% of volume required); Polysorbatc 80 and Ethanol are added; the BHA, BHT, povidonc l7, and Cmpd. A are then IO added and mixed until dissolved, and the mixture is QS with Transcutol®.
Ingredients Function Cmpd. A Active 3 7, 6.0 w/v thoprcnc Active Polysorbatc 80 Surfactant Ethanol Spreading agent Butylated hydroxyanisole Antioxidant Butylated hydroxy toluene idant Povidone K- 1 7 Thickener 5.0 w/v Diethylene glycol monoethyl ether Solvent S Formulation 2 - Add glycerol formal (GF. 50% of required volume), add Cmpd. A, dissolve; add DMI; add (s)—methoprene; QS GF. . , . w/v w/v Glycerol formal (GF) Spreading agent QS Formulatlon 3 - Add diisopropyl adipate (DIPA, 50% of ed volume), add Cmpd. A, dissolve; add (s)-methoprene; QS DIPA PCT/U52012/054719 Diisopropyl adipate (DIPA) Spreading agent Formulation 4 - Add diethyl sebaeate (DES 517% ulred volume); add PG monolauratc; add Cmpd. A, dissolve; add (S)-methoprene; QS DES.
Formulatlon 5 - Add DES (56% of required volume); add PG monocaprylate; add Cmpd. A, dissolve; add (S)-methoprene; QS DES.
Propylene glycol monoeaprylate tion enhancer 25.0 (DCl:pryol 90) Formulat1on 6 - Add DIPA (30% of ed volume); add Ethyl hexyl pelargonate; add Cmpd.
A, dissolve; add (S)—methoprcne; QS DIPA DIPA Spreading agent PCT/U52012/054719 Formulation 7 - Add DIPA (50% of required volume); add diisopropyl sebaeate; add ne fluid; add Cmpd. A, dissolve; add (S)—methoprene; QS DIPA ooo-ooooooo Diisopropyl scbacatc 25.0 v/v ne fluid Spreading agent DIPA Spreading agent Formulation 8 - Add Miglyol 840 (50% of required volume); add lauryl lactate; add Cmpd. A, dissolve; add (S)-methoprene; QS Miglyol 840 ———ow Miglyol 840 Spreading agent/ QS permeation enhancer Formulation 9- Add Miglyol 840 (50% of required volume); add triacetin; add Cmpd. A, ve; add (S)--methoprene; QS Miglyol 840 Miglyol 840 Spreading agent/ QS permeation enhancer Formulation 10- Add Migly01840(50%ofrcqu1rcd volume); add Cmpd. A, dissolve; add (S)- methoprene; QS Miglyol 840 ients Function % PCT/U52012/054719 l 840 Spreading agent/ permeation enhancer Formulat1on I I - Add DES (5W of required volume); add Cmpd. A, dissolve; add (S)- methoprene; QS DES Spreading agent] permeation enhancer Formulation 12 - Add DES (50% of required volume); add Cmpd. A, dissolve; QS DES DES ing agent/ QS permeation enhancer Formulation 13 - Add DES (50% of required volume); add PG monocaprylate; add Cmpd. A, dissolve; QS DES.
Propylene glycol prylate Permeation enhancer (Capryol 90) DES Spreading agent Formulation l4 - Add DES (30% of required volume); adtfPG dicaprylate/dicaprate ancYPG monoeaprylate; add Cmpd. A, dissolve; add (S)-methoprene QS DES.
PCT/U52012/054719 (S)-methoprcne 9.0% w/v Propylene glycol dicaprylate/dieaprate Permeation er 25.0 v/v (Capryol PGMC) Propylene glycol monocaprylate (Capryol 90) 25.0 v/v Formulation 15 - Add DES (50% of required volume); add, with stirring, lauryl lactate; add Cmpd A, ve; QS DES Lauryl e 25.0 V/v Formulation 16- Add DIPA (50% of required volume); add DMI; add Cmpd. A (fissolvc; QS DIPA Formulation f7 - Add DES (30% of required volume); add UM]; add Cmpd. A, dissolve; QS Formulation 18 — Add DES (40% of required volume); add DMI; add Cmpd. A, dissolve; QS 7 7 PCT/U52012/054719 Dimcthyl isosorbide (DMI) QS 100% Formulat1on f9 — AddDTPA (50% of cd volume); add trlaeetm; add Cmpd. A, dissolve; QS DIPA Formulation 20 — AddDES (60% of ed volume); add m1neral 011, medium; add Cmpd. A, dissolve; QS DES Formulation 21 — Add DES (60% of required volume), add mineral oil, light, add Cmpd. A, dissolve; QS DES ' ' Formulation 22 - Add DES (60% of required volume); add, with stirring, Transcutol®; add Cmpd. A, mix until dissolved; add SAIB; QS with DES Cmpd. A Active 6.0 w/v PCT/U52012/054719 Sucrose acetate isobutyrate (SAIB) Controlled release agent Formulation 23 - Add DES (60% of required volume); add, with ng, Transcutolfl"; add, with stirring, PEG 400; add Cmpd. A, mix until dissolved; QS with DES Formulation 24- Add ’I‘ranscutol‘l‘ (60% of required volume); add, with stirring, PEG 400; add Cmpd. A, mix until dissolved; QS ’I‘ranscutol" Formulation 25 - Add DES (60% of required volume); add, with stirring, Transcutol'fi; add, with stirring, PEG 400; add Cmpd. A, mix until dissolved; QS with DES In . ts Function ML Cm dA PEG 400 Controlled release a- ent DES Spreading agent Formulat1on 26- Add DES (66% of required volume); add with stirring, PEG 400; add Cmpd.
A, mix until dissolved; QS with DES mm—__ PEG 400 t and Controlled release _a _ent _I-_— PCT/U82012/054719 ation 27 - Add GF (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, dissolve; add DMI; QS GF.
Glycerol formal Spreading agent Formulation 28 - Add BM] (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, dissolve; add (S)-methoprene and dissolve; QS with DMI. ation 29 - Add BM] (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, ve; add pyriproxyfen and dissolve; QS DMI.
Formulation 30 - Add Transcutol® (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, dissolve; add pyriproxyfen and dissolve; QS Transcutol®.
PCT/U82012/054719 Formulation 31 - Add GF (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, dissolve; add pyriproxyfen and ve; QS GF.
Formulation 32 - Add tin (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, dissolve; add pyriproxyfen and dissolve; QS triacetinf Formulation 33 - Add ene carbonate (50% of required volume), add Cmpd. A, dissolve; add nitenpyram, dissolvejadd pyriproxyfen and dissolve; QS propylene carbonate.
Cmpd. A was found to be stable in at least DES, DIPA, DMI, triacetin, GF and propylene carbonate (at 50°C in glass s).
Biological y Examples Example 1: Efficacy of a’Spot-on Composition Comprising a Combination of Cmpd. A and (S)- methoprene Against Dermacemor variabilis Ticks and Ctenocephalidesfizlz‘s Fleas in Dogs Twenty eight beagle dogs were studied to ine the effectiveness of a combination of Cmpd. A and (S)—methoprene when stered once as a topical solution against induced infestations ofDermacenior variabilis and Ctenocephalidesfe/is. _ Four Treatment Groups containing seven dogs each were formed. Dogs in Group 1 were untreated (control). Dogs in Groups 2, 3 and 4 were treated topically with n compositions comprising 3.7% (w/v) Cmpd. A and 9% (w/v) (S)-methoprene administered to deliver 2.5 mg/kg Cmpd. A and 6 mg/kg (S)-methoprene (Group 2: Transcutol with 10% (w/v) ethanol, 5% (w’/V)’TWEEN 80 and 5% (W/v) polyvin’ylpyrrolidon’e; Group 3: DM1 and glycerol formal (GF); and Group 4: DIPA). All dogs were treated once on Day 0.
IO All dogs were infested with imately 100 C. fall's on Days -I, 8, 15, 22, 29, 35, 43 and 57, and for all Groups except 5, on Day 71. All dogs were also ed with approximately 50 D. variabilis on Days-l, 7, 14, 21, 28, 34 and 42. Fleas were counted upon removal on Day ‘- 6. Both ticks and fleas were counted upon removal on Days 2, 9, 16, 23, 30, 36 and 44. Fleas only were d upon removal for all Treatment Groups on Day 58 and for all Treatment Groups except 5 on Day 72. Flea efficacy is listed in Table l and tick efficacy is listed in Table 2 below.
Blood samples were collected from all dogs in the study on Days -6, 0 (at 4 h and 12 h), l, 2, 9, 16, 23, 30, 36, 44, 51, 58, 64, 72, 79 and 86. Plasma samples were analyzed for the tration of Compound A using an LC/MS/MS analytical method that was GLP validated for the purpose.
Percent reduction (also ed as efficacy) t fleas was 100% through and including Day 30 for all treatment groups (see Table 1). Percent reduction against fleas was above 95% through Day 58 for Group 3.
The percent reduction against ticks was >94% through and including Day 23 (48 hours infestation, see Table 2). Percent reduction was >92% for Groups 6 and 7 on Day 30.
These study data demonstrate that topical formulations comprising Cmpd. A and (S)- methoprene in three different carrier vehicles provided 100% percent reduction for fleas through Day 30 for all treated groups. Tick efficacy“was 100% on Days 9 and 16 and two treatment groups (6 and 7) were 292% on Day 30.
Table 1: Efficacy of a n Composition Comprising a Combination of Cmpd. A and (S)- methoprene Ctenocephalidesfelis Treatment Group % Reduction Fleas " Day Day Day Day Day Day Day Day Day 2' 9 16 23 30 36 44 58 72 Group2 100.0 100.0 100.0 100.0 100.0 100.0 86.5 33.2 -- % Reduction Group3 100.0 100.0 100.0 100.0100.0 100.0 99.6 98.5 89.0 % Reduction 100.0 100.0 100.0 100.0100.0 99.8 95.2 89.3 68.9 Table 2: Efficacy of a Spot-on Composition Comprising a Combination of Cmpd. A and (S)- mcthoprcnc Against Dermacentor ilis Ticks Treatment Group ‘70 Reduction Ticks Dav Day Day Day Day Day Day 2‘ 9‘ 16 23' 30 36 44 Group2 % Reduction 89.0 100.0 100.0 94.8 65.0 23.3 20.7 Group3 % Reduction 88.5 100.0 100.0 99.2 94.6 88.3 77.6 Group4 % Reduction 84.3 100.0 100.0 97.2 92.0 52.2 57.0 Example 2: Efficacy of Spot-on Formulations Containing Compound A and (S)-methoprene Against Ctenocephalidesfelis.
Following the initial studies described in Example 1, additional topical formulations comprising Compound A in combination with an insect growth regulator, (S)-methoprene, in carrier vehicles comprising both a spreading solvent and a permeation solvent were d.
Thus, the efficacy of five ent topical formulations comprising Compound A and (S)- rcnc against the cat flca (Ctenécepha/ides felis) in dogs was dctcrmincd using to a protocol similar to that of Example 1.
Seven Treatment Groups with four dogs each were evaluated. Dogs in Group 1 were untreated, and served as a control group. Dogs in Groups 2-6 were d topically with PCT/U82012/054719 formulations comprising Cmpd. A and (S)-methoprene in different carrier vehicles administered at 4.0 mg/kg Cmpd. A + (S)—methoprene administered at 6 mg/kg (Group 2: Miglyol 840; Group 3: DIPA / 25% tin; Group—4: DIPA / 25% DMI; Group 5 DIPA / 25% ethyl hexyl pelargonate; and Group 6: DIPA + 25% diisopropyl sebacate + 3% silicone fluid). Dogs in Group 7 were treated at a dose level of 7.0 mg7kg“Compound A + thoprene at 6 mg/kg with ’a formulation comprising DIPA + 25%’diisoprop’yl sebacate + 3% silicone fluid. The trations of Compound A and (S)-methoprene in formulations of Groups 2-5 were 6.0% (w/v) and 9.0% (w/v), respectively, and the concentration of Compound A and (S)-methoprene in formulations of Groups 6 and 7 were 10.5% (w/v) and 9% (w/v), rcspcctivcly.
IO Dogs were ed with approximately 100 C. fizlz‘s fleas on Day -I. Dogs were treated with the respective topical formulations on Day 0. Fleas were removed'and counted on Day 2. ationsflwith about 100 fleas were also made on Days 8, 15, 22, 29, 36 and 43. Fleas were combed and counted 24 d: 3 hours after infestation on Days 9, 16, 23, 30, 37 and 44.
Table 3 below provides the % efficacy for each of the topical formulations. As demonstrated by the data, each of the formulations was highly ious against the cat flea through at least 44 days.
Table 3: Efficacy of Spot-on Composition Against Ctenocephalides/élis Geometric Mean Flea Count/ % Reduction Treatment Group Day2 Day9 Day Day Day Day Day ' ' 16 23' 30 37 44 Group2 % Reduction ' " ' ' l00.0 l00.0 l00.0 100.0 100.0 l00.0 98.6 Group3 % Reduction ‘ ” ‘ ’ 100.0 99.6 100.0 100.0 100.0 100.0 100.0 Group4 % Reduction 100.0 100.0 100.0 100.0 100.0 100.0 100.0 GroupS % Reduction ' " ' ' 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Group6 % Reduction ' ” ' ' 99.6 100.0 100.0 100.0 100.0 100.0 100.0 Group7 PCT/U82012/054719 % Reduction 100.0 100.0 100.0 100.0 100.0 100.0 100.0 e 3: Efficacy of Spot-on Formulations Containing Compound A and (S)-Methoprene Against Rhipz'cephalus neus. — h In another study, the efficacy against ticks of onal topical formulations comprising isoxazoline Compound A in combination with (S)-mcthoprcnc in further carrier vehicles comprising both a spreading solvent and a tion-enhancing solvent was ined. Thus, six topical formulations sing Compound A and (S)-methoprene were tested for efficacy againSt Rhipz'cephalus Sanguineus ticks iIi beagle dogs according to a protocol similar to that Of Example 1.
Seven Treatment Groups with four dogs each were evaluated. Dogs in Group 1 were untreated, and served as a control group. Dogs in Groups 2-6 were treated topically with Cmpd.
A in ent carrier vehicles stered at 4.0 mg/kg + (S)-methoprene administered at 6 mg/kg (Group 2: Miglyol 840 / 25% lauryl lactate; Group 3: DIPA / 25% triacetin; Group 4: DIPA/ 25% DMI; Group 5 DIPA / 25% Capryol 90/ 25% Capryol PGMC; and Group 6: DES / I5 25% propylene glycol monolaurate). Dogs in Group 7 were treated at a dose level of 7.0 mg/kg Compound A + (S)-methoprene at 6 mg/kg with a formulation comprising DES / 25% propylene glycol monolaurate. The concentrations of Compound A and thoprene in the formulations used with Groups 2—6 were 6.0% (w/v) and 9.0% (w/v), respectively. The concentrations of Compound A and (S)-methoprene in the formulation used with Group 7 were 10.5% (w/v) and 9% (w/v), respectively.
All dogs were infested with approximately 50 R. sanguineus on Days -1, 7, 14, 21, 28, , 42, 49, 56 and 63. Further, ent Groups '1, 5, 6 and 7only were infested on Days 70, 77 and 84, and Treatment Groups 1, 6 and 7 only on Day 91. Ticks were counted upon removal on Days 2, 9, 16, 23, 30, 37, 44,51, 58 and 65. Tick counts were conducted for Treatment Groups 1, 5, 6 and 7 only on Days 72, 79 and 86 and Treatment Groups 1, 6 and 7 only on Day 93.
Tables 4A and 48 below presents the efficacy of the spot-on formulations administered to Groups 2-7 against R. sanguineus.
PCT/U82012/054719 Table 4A: Efficacy Against Rhipicephalus Sanguineus in Dogs ‘70 ReductiOn Ticks Treatment Group Day2 Day9 Day 16 Day 23 Dav 30 Day 37 Day 44 Group2 19110" 96.9 100.0 100.0 100.0 100.0 100.0 98.6 Group3 %Reduction 94.5 100.0 100.0 100.0 94.5 97.9 97.7 Group4 ”/0 Reduction 98.2 100.0 100.0 100.0 97.5 94.5 98.6 Groups % Reduction 98.2 100.0 100.0 98.1 100.0 97.9 100.0 Group6 m 1qqp_1qqp_qu.9_1qq9_qu.9_10_q._0_1099_ Group7 %Reduction 96.9 100.0 100.0 100.0 100.0 100.0 100.0 Table 4B: Efficacy Against Rhipicephalus Sanguineus in Dogs (continued) % Reduction Ticks Treatment Group Day Day Day ' ' Day Day Day Day 51 58 65 72 79 86 93 Group2 ‘Zqfiejlicflm 10_Q,9 91.3 80.3 ND‘ ND ND ND Group3 % Reduction (is; 89.9 65.2 ND ND ND ND Group4 % Reduction 96.4 82.2 77.1 ND ND ND ND Groups % ion 9_6__7 94.7 87.6 32.1—86.9—612 ND Group6 % Reduction 96.7 100.0 100.0 94.7 90.1 56.0 42.1 Group7 % Reduction 98.3 97.7 95.5 94.7 100.0 84.5 75.] ND = not done As Tables 4A and 4B show, Groups 3 and 4 maintained at least a 90% reduction in tick count through Day 51, Groups 2 and 5 through Day 58, and Groups 6 and 7 through Day 79. In particular, Treatment Groups 6 and 7 demonstrated superior efficacy for an extended period of time. Thus, formulations sing a combination of an isoxazoline and an insect growth regulator in a carrier vehicle comprising a combination of a spreading solvent and a perrncation IO enhancer were determined to provide surprisingly long g efficacy against R. sanguineus.
PCT/U82012/054719 _Example 4: Dose Characterization of n Formulations of Cmpd. A Against Amblyomma americanum Ticks in Dogs The efficacy of 'a spot-on ition of the invention comprising an isoxazoline compound (Cmpd. A) in a carrier vehicle comprising either DES alone or DES + lauryl lactate (LL), against ticks (Amblyomma amerz’cammz),in dogs was d. The compositions contained 3.0 %, 4.5%, or 6.0% Cmpd. A in either DES alone or DES + lauryl lactate, which red doses of 4.0 mg/kg, 3.0 mg/kg, and 2 mg/kg, respectively, of Cmpd. A to dogs infested with A.
Americanum tidks.’ Seven Treatment Groups were evaluated. Treatment Group 1 was administered a placebo IO formulation and served as a control. Treatment Groups 2, 3 and 4 were administered a’ topical formulation comprising 6.0% (w/v), 4.5% (w/v) and 3.0% (w/v) of Cmpd. A in DES, respectively, corresponding to doses of 4.0 mg/kg, 3.0 mg/kg and 2.0 mg/kg, respectively.
Treatment Groups 5, 6 and 7 were administered a topical formulation comprising 6.0% (w/V), 4.5% (w/v) and 3.0% (w/v) of Cmpd. A in DES + 9% lauryl lactate, respectively, corresponding to doses of 4.0% mg/kg, 3.0 mg/kg and 2.0 mg/kg body weight Cmpd. A, respectively.
All dogs were treated once topically on Day 0 by parting the hair and applying the solution from a syringe ly onto the skin in a single spot on the midline of the neck between the base of the skull and the er blades.
All dogs were ed with approximately 50 A. amerz‘cammz on Days -1, 7, 14, 21, 28, 35 and 42. Ticks were counted upon removal on Days 2, 9, 16, 23, 30, 37 and 44. The % reduction of ticks for each Group is ted Table 5 below.
Blood samples were collected from all dogs on Days -5, 0 (at 4 h and 12 h), l, 2, 9, 16, 23, 30, 37 and 44.7Plasma samples were analyzed— for the concentration of Compound A using a LC/MS/MS method that was GLP validated fer the analysis of the compound.
Treatment Groups 5 and 6 (4.0 mg/kg and 3.0 mg/kg Cmpd. A in DES + LL, respectively) maintained at least 90% efficacy h five weeks, and Treatment Group 2 (4.0 mg/kg in DES alone) maintained at least 90% efficacy through Week 3.
PCT/U82012/054719 Table 5: Efficacy Against Amblyomma americanum in Dogs % Reduction Ticks Treatment Group Day Day Day' Day Day' Day Day 2 9 16 23 30 37 44 Group2 % Reduction 97.4 100.0 100.0 100.0 82.5 97.9 84.2 Group3 % Redu‘ction 90.0 100.0 97.6 82.0 70.0 80.4 56.0 Group4 % ion 95.4 100.0 100.0 79.5 90.3 57.1 38.8 GroupS ‘Zgfied_u_ct_ion 100.0 100.0 100.0 94.3 100.0 89.0 84.8 Group6 ‘Zgfied_u_ct_ion 98.4 100.0 100.0 93.1 92.1 89.0 53.6 Group7 "/0 Reduction 98.4 100.0 100.0 80.6 88.9 74.6 42.4 e 5: Dose Characterization and determination of Speed of Kill of a Single Spot-on Treatment with Formulations of Cmpd. A Against Ctenocephdlidesjélis fleas and Rh‘ipicephalus sanguineus ticks on Dogs The efficacy of a ation comprising an isoxazoline compound (Cmpd. A) in a r comprising 40% DES/DMI against Cténucephalide.s' felis fleas and Rhipicephalus sanguineus ticks in Dogs was studied. As sed above, DES is a solvent with good spreading properties and DM1 eXhibits good permeation properties. Three treatment groups containing three dogs each were evaluated. All dogs were treated once topically on Day 0 by parting the hair and applying the solution from a syringe directly onto the skin in a single spot on the midline of the neck n the base of the skull and the shoulder blades.
Treatment Group 1 was a placebo control and received 0.067 mL/kg of body weight.
Treatment Group 2 was—administered a l spot-on formulation comprising 6.0% (w/v) Cmpd. A in 40% DES/DMI to deliver a dose of4.0 mg/kg body weighthreat’ment Group 3 was administered a topical spot-on formulation comprising 12% (w/v) Cmpd. A in 40% DESZDMI to deliver a dose of 4.0 mg/kg body weight.
All dogs were infested with approximately 100 C. felis on Days -I, 7, 14, 21, 28, 35 and 42. Fleas were counted upon l from dogs approximately 24 hours post infestation on PCT/U82012/054719 Days 1, 8, 15, 22, 29, 36 and 43. The % reduction (efficacy) of each Treatment Group over time is listed in Tables 6A, 6B and 7, respectively.
Table 6A: Efficacy Against Ctenocéphalide'sfelis in Dogs - Day 0 to Day 22 Treatment Group Day 1 Day 8 Day 15 Day 22 Group2 % Reduction 100.0 100.0 100.0 100.0 Group3 % Reduction 100.0 100.0 100.0 100.0 Table 6B: Efficacy Against Ctenocephalidesfelis in Dogs - Day 28 to Day 43 Treatment Group Day 29 Day 36 Day 43 Group 2 % Reduction 100.0 100.0 99.2 % Reduction 100.0 100.0 100.0 The percent efficacy against ticks 1s presented in Table 7. Both Treatment Groups demonstrated good efficacy at least through 31 days.
Table 7: Efficacy against Rhipicephalus sanguineus Ticks Control— Group 2 % Reduction 100.0 91.5 100.0 85.2 —'ErBfiB?—m—_'—m—"— % Reduction 100.0 72 6 100 0 51 3 Example 6: y of Spot-on Formulations Comprising Compound A at Different Doses Against Rhipicephalus sanguineus Ticks in Dogs A further study was conducted to examine the efficacy of a topical ations sing Compound A in three different formulations containing DES against ticks in dogs. TWentyifour beagles were studied to ine the iveness against d infestations’of Rlzipz'cephalus sanguineus of spot-on formulations comprising Cmpd. A in different carriers administered at 4.0 mg/kg to dogs.
' ' Treatment Group 1 dogs were treated with a placebo solution. Treatment Group 2 was treated with a formulation comprising 6% (w/v) Cmpd. A in DES; Treatment Group 3 were d with a composition comprising 6% (w/v) Crripd. A in 40% DES/DMI; and Treatment Group 4 were treated with a formulation comprising 6% (w/v) Cmpd. A in DES with 30% Capryol 90. All dogs were treated once topically on Day 0. Topical solutions were applied by parting the hair and applying the solution from a syringe direefly onto the skin in a single spot on the midline of the neck between the base of the skull and the shoulder .
' All dogs Were infested IO with imate‘ly‘ 50 R. sanguiiieuson Days -l_. 7, 14, 2|, 28, 35 and 42. Ticks'were counted upon removal from'dogs on Days 2, 9, 16, 23, 30, 37, and 44. All ticks were counted upon removal at 48 (i3) hours pest treatment or infestation.
The percent efficaeies of the treated groups compared to the untreated control group were determined for the 48 hour reatment/infestation counts. Percent efficacy for each ng time 48 hours after treatment or infestation are listed in Table 8. Treatment Group 3 maintained 3 90% efficacy 48 hours after infestation at every sampling time from Day 9 h Day 44. ent Group 2 was able to maintain at least 90% efficacy 48 hours after infestation throughout the six weeks of the study.
Table 8: y Against Rhipicephalus sanguineus in Dogs Treatment Group Day2 Day9 Day16 Day 23 Day 30 Day37 Day 44 Group2 %Reduction 93.2 100.0 100.0 100.0 97.8 95.3 97.5 Group3 %Rediiction 72.8 100.0 100.0 100.0 100.0 93.5 82.9 Group4 %Rediiction 97.2 100.0 100.0 100.0 98.4 96.1 78.1 Example 7: Efficacy of Spot-on Formulations Comprising Isoxazoline Compound A in ent Carrier Vehicles at 1 mg/kg Against Ctenocephalidesfelis Fleas in Cats The efficacy of several spot-on ations comprising Cmpd. A dosed at 1 mg/kg body weight in different carrier vehicles against fleas in cats was studied. Five eats each were alloeated to 6 Treatment Groups. The six cats per study group were subjected to weekly infestations followed by 24h flea counts for 5 to 8 weeks, according to the following Group allocations: Group 1 —'untreated control; Group 2 - 1.0% (w/v) Cmpd. A in DMI; Group 3 ‘- l.0% (w/v) Cmpd. A in diethyl sebacate (DES); Group 4 - 1.0% (w/v) Cmpd. A in 9% lauryl lactate + DES; Group 5 — 1% (w/v) Cmpd. A in 8% ethyl oleate + DES; and Group 6 - 1% (w/v) Cmpd. A in a vehicle comprising Transeutol'g' + 10% (w/v) ethanol + 5% polyvinylpyrrolidone + % TWEEN 80. Cats were infested with approximately 100 C. fclis on Day -1 and treated on IO Day 0 with the ponding spot-on formulation by application of the formulation directly on the skin in the midline of the neck, between the base of the skull and the shoulder blades'in a single spot using a 1 mL syringe. Twelve hours after treatment, fleas were removed and counted.
The cats were immediately ested with approximately100 fleas. Fleas were removed and counted on Day 1 at approximately 24 hours reatment. Cats were also infested with fleas on Days 7, 21, 38, 35, 42 and 49. Fleas were d and d approximately 24 hours afier infestation on Days 8, 22, 29, 36, 43 and 50. The efficacy for each formulation is ted in Table 9 below.
Table’9i 'Efficacy of Spot-on Formulations Against Ctenocephalides felis Fleas in Cats in Different Formulations at a Dose of 1 mg/kg % Reduction Treatment Group Day0 Day Day Day' Day Day Day Day {12 hr! 1 8 22 29 36 43 50 Group 2 % Reduction 22.3 28.0 99.3 99.5 98.5 94.2 94.3 87.7 Group3 %Redliction 9.6 72.7 99.7 97.4 95.1 79.3 72.2 44.8 Group4 %Red1icti0n 9.2 36.5 99.7 98.5 98.1 89.3 92.7 79.2 Groups % Reduction 65.9 77.2 98.4 96.9 95.0 85.5 79.7 64.0 Group6 % Reduction 17.7 75.6 100_._0 99.3 97.5 93.8 93.9 79.6 As Table 9 trates, all of the spot-on formulations comprising Cmpd. A were highly effective against fleas for at least 29 days. The formulation administered to Group 2 longer lasting efficacy above 90% until at least Day 43 and maintained efficacy above 85% until Day 50. The ation of Group 5 (8% ethyl oleate in DES) exhibited significant efficacy after 12 hours. _ ' ' Example ’8': Efficacy of Spot-on Formulations sing Isoxazoline Compound A in ent Carrier Vehicles at 1 mg/kg t Ctenocepfzalides fie/is Fleas in Cats Protected from Grooming.
In another study, the efficacy of four spot-on formulations comprising Cmpd. A dosed at 1 mg/kg body weight in different carrier vehicles against fleas in cats Was studiedFive eats each were allocated to five Treatment Groups: Group 1 - Untreated; Group 2 — 0.833% (w/v) Cmpd.
IO A in dimethylsulfoxide (DMSO); Group 3 — 0.833% (w/v) Cmpd. A in DMI; Group 4 — 0.833% (w/v) Cmpd. A in Transcutol‘g; and Group 5 — 0.833% (w/v) Cmpd. A in DES. Each cat in the study was fitted with a protective neck collar on Day -1 prior to treatment to t the animals from orally ingesting the topically applied formulation while grooming. Cats were infested with approximately 100 C. felis on Day -1 and treated on Day 0 with the corresponding n formulation by application of the formulation directly on the skin in the e of the neck, between the base of the skull and the shoulder blades in a single spot using a 1 mL syringe.
Infestations with approximately 100 C. felis were conducted weekly on Days 7, 14, 21, 28 and . Fleas were removed and cOunted approximately 24 i 3 hours fellowing treatment on Day 1 and then on Days 8, 15, 22, 29 and 36. The efficacy for each formulation is ted in Table 10 below.
Table 10: Efficacy of Spot-on Formulations Against CIenocep/zalidesfelis Fleas in Cats % Reduction Treatment Group Day Day Day Day" Day Day Day 1‘ 2‘ 8‘ 15 22‘ 29 36 Group 2 % Reduction 43.16 60.54 98.48 95.91 97.90 90.10 74.49 Group3 %Reduction 37.90 88.97 99.62 99.32 98.80 92.66 79.54 % quuquop 76:32 533.12 953.95 99.01 96_.19 95.41 86:61 Group 5 %Reduction 54.40 82.77 98.82 99.26 99.82 92.43 88.11 Example 9: Long lasting Efficacy of Spot-on Composition t Ctenocephalidesfelis Fleas in Cats.
'The efficacy of spot-on compositions comprising Cmpd. A in DMI at different doses against ephalidesfélis fleas in cats was studied. Four treatment groups were formed with five cats per ent group: Group 1 — untreated control; Group 2 —' Compound A at 5.0 % (w/v) in DMI to deliver a dose of 5 {rig/kg; Group 3 — Compound A at a tration of 10.0 % (w/v) in DMI to deliver a dose of 10 mg/kg; and Group 4 — Compound A at a concentration of .0 % (w/v) in DMI to deliver a dose of 15 mg/kg. Treatment was administered once on Day 0.
The cats were each infested with approximately 100 C. fleas at each time point evaluated. .felis IO Cats in all treatment groups were infested 0n Days -1, 0 (approx. 12 h following treatment), 7, 28, 49, 70, 91, 1'05, “1 19 and 133. Cats were also infested ~on Days 126 and 140 (Treatment Groups 1 and 2); Days 147, 154, 155, 161, 168 and 175 (Treatment Groups 1, 3 and 4); Days 182, 189 and 197 (Treatment Groups 1 and 4). After each infestation, fleas were removed and counted imately 48 hours (i3 hours) for most time points.
The results of the study are shown in Tables 11A, 118 and 11C below and in Figure 1.
The study demonstrated surprising long lasting efficacy of the spot-on formulations. The results indicate that formulations sing Cmpd. A at different concentrations were ious compared to Group 1 (untreated control) for extended periods of time. For example Group 2 demonstrated 90% efficacy up to Day 121; Group 3 showed 90% efficacy up to Day 163 and Group 4 exhibited 90% cy up to Day 191. This extremely long lasting tion above 90% from one topical application is unpredictable and remarkable.
Table 1 1A: Efficacy of Against Ctenocephalidesfelis Fleas in Cats % Reduction Fleas Treatment Group Day0 Day Day Day Day Day2 Day9 (12 hr) 30 51 72 93 Group2 % Reduction 61.1 100.0 100.0 100.0 100.0 100.0 100.0 Group3 "/0 Reduction 95.4 100.0 100.0 100.0 100.0 100.0 100.0 Group4 %Re_(_l|iction 85-} 100_.0 100_._0 100_.0 100_.0 100.0 100.0 Table 1 18: Efficacy of Against Ctenocephalidesfelis Fleas in Cats (continued) % Reduction Fleas Treatment Group Day' ' Day Day Day Day Day Day 107 121 128 135 142 149 155 Group2 tion 100.0 92.3 89.1 88.3 80.0 ND ND Group3 %£e_d_u_ction 100.0 100.0 ND 99.8 ND 99.5 50.0 Group4 % Reduction 100.0 100.0 ND 100.0 ND 1000 78.0 Table I IC: Mean Flea Count f% Reduction (continued): Treatment Group % Reduction Fleas Day Day Day Day Day Day Day 157 163 170 177 184 191 199 Group2 %£e_d_lflon ND ND ND ND ND ND ND Group3 °élegfilieflon 98-1 94.5 87.8 7qu ND ND ND Group4 %Reduction 100.0 100.0 96.2 94.8 95.7 90.6 79.2 Example 10: Efficacy of Spot—on Formulations Against Ixodes s Ticks in Cats ‘ The efficacy of spot-on formulations comprising Cmpd.
A were studied against induced infestations of [xodes ricimls ticks in cats. Three ent groups with six cats per group were randomly allocated: Group 1 — Control, untreated; Group 2 —'Cm_pd. A (2.5% w/v_in DMI) at 0.1 ml/kg bedy weight (2.5 mg/kg); and Group 3 — Cmpd. A (5.0% W/v in DMI) at 0.1 ml/kg body weight (5 mg/kg). Treatment Was administered once on Day 0 and efficacy was assessed based on 48-hour tick (1. s) counts following weekly experimental challenge from Day 7 on. As shown in Tables 12A and 12B below, Cmpd. A (2.5% w/v in DMI) at 2.5 rug/kg body weight administered once topically completely prevented the ation of I. s until Day 56 and offered > 90% tion until at least Day 77. In fact, the topical spot-on formulation offered substantial protection against 1. ricinus ticks until the last day of assessment — Day 93. Due to limitations on tick availability 5 mg/kg was tested only up to Day 44 with 100% efficacy. The excellent long-lasting efficacy of the fbrmulation of the invention against 1. ricinus ticks in cats is very surprising and unexpected.
Table 12A: Efficacy Against Ixodes ricinus in Cats % Reduction Ticks Treatment Group Day 2 Day 9 Day 23 Dav 30 Day 37 Day 44 Group 2 ‘Zgiegllctlon 23.71 100.00 99.60 100.00 99.58 100.00 Group 3 % Reduction 70.27 100.00 100.00 100.00 100.00 100.00 Table TZB: Efficacy Against Ixodes ricinus m Cats (continued) % Reduction Ticks Treatment Group Day 51 Dav 58 Day 65 Day 72 Day 79 Day 86 Day 93 Group2 % Reduction 100.00 100.00 99.02 99.21 95.54 84.92 76.65 Group3 % Reduction NDl ND ND ND ND ND ND Example 11: Efficacy of n ation Containing a Combination of Compound A. pyriproxyfen and yram—Against Ctenocephalidesfelis Fleas in Cats.
The efficacy of three spot-on compositions comprising a combination of Compound A, pyriproxyfen and nitenpyram against Ctenocephalides felis fleas in cats was studied and ”compared with an untreated control and with a spot-on composition comprising nitenpyram IO alone. Cats were allocated into five Treatment Groups with 5 cats per group: Group] — cats were untreated (control); Group 2 — cats were d spot—on solution containing 0.83% (w/v) Compound A, 2.08% (w/v) nitenpyram, and 4.17% (w/v) pyriproxyfen in Transcutol'fiw to deliver doses of 1.0 mg/kg Compound A, 2.5 mg/kg yram and 5.0 mg/kg pyriproxyfen; Group 3 — cats were treated a spot-on solution containing 0.83% (w/v) Compound A, 4.17% (w/v) nitenpyram, and 4.17% (w/v) pyriproxyfen in Transcutol® to deliver doses of 1.0 mg/kg nd A, 5.0 mg/kg yram and 5.0 mg/kg pyriproxyfen; Group 4 — cats were d with “a spot-on composition containing 0.83% (WA/VICOmpound A, 8.33% (w/v) nitenpyram and 4.17% (“w/v) pyriproxyfcn in Transcutol'g' to deliver doses of 1.0 mg/kg Compound A, 10.0 mg/kg nitenpyram and 5.0 mg/kg oxyfen; Group 5 — cats were treated 'with a spot-on composition containing 2.08% (w/v) nitenpyram alone in Transcutol® to deliver a dose of 5.0 mg/kg body weight.
PCT/U82012/054719 Treatment was administered once on Day 0. The cats were each infested with approximately 100 C. felis fleas at day -1, on Day 0 approximately 12 hours post treatment and then on Days 1 (approx. 24 hours post treatment), 2, 7, 14, 21, 28 and 35. After each infestation, fleas were removed and counted imately 12 hours (i: 3) on Day 0, and then on Days 1, 2, 8, 15, 22, 29 and 36 (24 3:3 hours after infestation).
The results of the study are shown in Table 13 below. The study demonstrated that a n composition comprising a combination of an isoxazoline compound (Compound A), a neonieotinoid (niténpyra’m) and an insect growth regulator (pyriproxyfen) exhibits extremely fast acting and long-lasting efficacy.
IO Table 13: y of Spot-on Formulation Comprising Three Active Agents Against Ctenocephalidésfelis Fleas in Cats % Reduction Treatment Group Day 0 Day 1 Day 2' Day 8 Day 15 Day 22 gllh) 124h! g24h) 124M 124h) 124M Group 2 % Reduction 99.17 100.00100.00 100.00 100.00 98.76 Group3 ion 9_9_-2L22-£2%JMQ09_0_2251_2171_ Group4 %Rediiction 97.69 100.00100.00 100.00 100.00 98.08 Group 5 %Reduction 99.44 99.79 100.00 100.00 96.76 93.63 Example 12: Efficacy of Spot-on Compositions Comprising Compound A Against 0t0dectes cynotis (ear mites) in Cats.
The efficacy of two spot—on compositions comprising Compound A at doses of 5 mg/kg and 10 mg/kg against Otodectes cynotis in cats was evaluated ed to an untreated control.
Eighteen healthy cats were grouped into three study groups consisting of six cats per group. Cats in the ent groups were infested with tes cynotz's obtained from naturally infested donor eats prior to acclimation on Day -7. Group 1 was an untreated control group. Cats in Groups 2 and 3 were treated once on Day 0 with a n composition comprising Compound A at two different concentrations and doses by application of the formulation directly on the skin in the midline of the neck n the base of’the skull and the shoulder blades with a 1 mL disposable syringe. Cats in Group 2 were treated with a n composition containing 5.0% PCT/U82012/054719 (w/V) Compound A in a carrier containing 40% (v/v) diethyl sebacate (DES) in dimethylisosorbide (DMI) at a dose of 5 mg/kg body ; and cats in Group 3 were treated with a spot-on composition containing 10.0% '(w/v)' Compound A in a carrier—containing 40% (v/v) DES in BM] at a dose of 10 mg/kg body weight. Assessment of the ear mite infestation by otoscopic ation was med on all Cats on Days -7, 3. 7 and 14. Visible live ear mites (adult or immature) were counted and debris/cemmen level was estimated for both ear ducts. A quantitative assessment of ear mites by ear duct flushing, mite collection and live mite count was performed on Day 14. Relative to the untreated control, Group 2 d the infestation of ear mites by 99.0% (only one mite found) and Group 3 reduced the ation of ear mites by IO 100.0%(no live mites found in any cat).
Example 13: Efficacious Plasma Concentration for Topical Compositions.
Plasma concentrations of Compound A from dogs in the studies of Examples 1 and 4 were determined according to the description in Example 1, and the plasma concentration versus % efficacy against A. americamun and D. variabilis were fit to a Sigmoidal Emax model. The EC90 (concentration required to achieve 90% y) against A. anum and D. variabilis ticks were determined to be 92 ng/mL and 70 ng/mL, respectively. Using a similar approach, the EC90 for R. sanguineus ticks from a separate study was found to be 69 ng/mL. For comparison, the ECgo values from an oral dosage form against A. antericanum, "D. variabilis “and R. sanguineus ticks was found to be 158 ng/mL, 110 ng/mL and 101 ng/mL, respectively. Since Compound A is systemically active, the lower concentration of the compound in the plasma required to achieve 90% efficacy from the topical compositions of the invention is surprising and unexpected.
Example 14: Efficacy of Pour-on Formulation Against Haematobia ns (Horn Fly) in Cattle.“ The y of a n formulation of the invention comprising isoxazoline Compound A was tested and“ compared with an untreated control. Two healthy, female Angus crossbread cattle of one year of age weighing between 224 to 330 kg were used in each study group. Cattle in Group 1 were untreated (control) and cattle in Group 2 were treated with a pour- on formulation comprising Compound A at a concentration of 10% (w/v) in DES at a dose of 1 ml/10 kg once on Day 0. The ation was applied by measuring the ed amount of the solution into a marked disposable syringe and applying the material evenly along the mid-line of PCT/U82012/054719 the back of each animal from the withers to the tail head. Each animal was infested with approximately 200 horn flies ed into each of the animal rooms on Day 1, approximately 24 hours post treatment. Approximately 200 horn flies were released again on Days 7, 14, 21, 28 and 36. Horn fly counts were performed at 5 hours and 24 hours after each infestation. Tables 14A and 148 below show the efficacy of the pour-on formulation of the invention.
Table 14A: Efficacy of n Formulation t Horn Fly % Reduction Treatment Groupl Day 1 Day 2 Day 7 Day 8 Day 14 Day 15 5h 24h 5h 24h 5h 24h Group 2 % Reduction 81.2 99.6 84.2 99.7 89.5 99.2 Table 1482 Efficacy of Pour-on Formulation Against Horn Fly (Continued) % Reduction Treatment Groupl Day 21 Day 22 Day 28 Day 29 Day 35 Day 36 (5 h) (24 h) (5 h) (24 h) (5 h) (24 h) Group 2 % Reduction 67.6 97.4 1 1.7 90.4 42.6 90.4 As the tables 14A and 148 show, cant efficacy against horn flies was observed after only 5 hours post infestation. Efficacy of at least 90% was observed 24 hours after infestation through the end of the study (day 36).
Example 15: Efficacy of Pour—0n Formulation Against Rhipicepha/us (Boophilus) microplus ticks The efficacy of two pour-on formulations of the invention comprising Compound A at doses of 2.5 mg/kg and 10 trig/kg were tested against infestations of Rh‘ipicep'halus iBoophz'lus) microplus ticks compared with an untreated control. Five healthy head of cattle of 6 to 15 months of age ng between 100 to 200 kg were used in each study group. Cattle in Group 1 were untreated ol). Cattle in Group 2 were treated on Day 0 with a pour-on formulation comprising Compound A at a concentration of 2.5% (w/v) in DES at a dose of 2.5 mg/kg; and cattle in Group 3 were treated on Day 0 with a pour-on formulation sing nd A at a concentration of 10% (w/v) in DES at a dose of 10 mg/kg. Several weeks before treatment, cattle are infested three times a week with approximately 2500 Rhipz'cephalus (Boophilus) microplus larvae to establish ongoing ations. Cattle in Groups 2 and 3 were treated with the 2012/054719 respective itions on Day 0 by measuring the required amount of the solution into a marked disposable e and applying the material evenly along the ne of the back of each animal from the withers to the tail head.
Each animal was challenged by infestation with approximately 5000 R. microplus larvae on Days 7 and 21 and every 14 days thereafter. Ticks ng from each animal in the previous 24 hotlrs were collected daily and counted from Day 1 until the end of the study. Since the life cycle of the ticks from the point of infestation with larvae until engorged ticks fall off is approximately 21 days (average), the assessment of efficacy for the challenges on Days 7 and 21 and every 14 days thereafter, was done for a range of 7 or 8 days starting approximately 21 days IO after the Challenge. The assessment of y atthe beginning of the study—was done from day 1 until Day 21.
In addition, the ticks collected were weighed as a group to measure the impact of the treatment on the weight gain of the ticks compared to the control to assess the vitality and reproductive capability of the treated ticks. Tables 15A and 153 below shows the total tick count % efficacy of the two pour-on formulations against R. microplus h 139 days post treatment compared with an untreated control group. Tables 16A and 16B show the % efficacy of the two pour-on formulations based on the weight of the ticks collected. Figures 2 and 3 shows plots of the % efficacy of the two formulations ’based on total tick counts and total weight, respectively.
As evidenced from the tables and the figures, the pour-on formulations of the invention at both 2.5 mg/kg and 10 mg/kg provide excellent efficacy against Rhipicephalz/s (Boophilus) microplus ticks for an extended period of time. The pour-on compositions exhibited tick count efficacy above 90% for at least day 139 after administration of the composition. Furthermore, as shown in Tables 16A and 168, the'two pour-on compositions were extremely effective against ticks based on the weight of the ticks collected. This data shows that the itions were highly effective at inhibiting the reproductive capability of the ticks for an extended duration of time. The extremely long lasting efficacy above 90% for pour-on composition t ha‘picepha/us i/us) microplus ticks is remarkable compared with pour-on formulations known in the art.
Table 15A: Tick Count Efficacy Against Rhipicephalus (Boophilus) micmplus Average ‘Vo Efficacy (Tick Count) Treatment Group Day Day Day Day Day Day Day 1-21 28-34 41-48 55-62 69-76 83-90 97-104 mm)—7—Zl—TS—geav-49—63—77— Group 2 0/o Efficacy 58.8 75.6 77.0 91.2 88.3 90.7 79.8 Group 3 0/0 cy 78.1 92.0 98.0 97.8 99.3 98.9 92.4 Talfle 15B: Tick Count Eiiicacy Against halus (Boa/71117115) microplus Average % Efficacy (Tick Count) Treatment Group Day Day Day Day 111-118 132-139 146-153 7 Challenge Day 91 l 12 126 140 Group 2 % Efficacy 79.0 86.2 30.3 74.0 Group 3 % Efficacy 96.6 92.4 72.4 85.8 Table 16A: Tick Weight Efficacy Against Rhipicephalus (Boophilus) microplus e % Efficacy (Tick Weight) Treatment Group Day Day Day Day Day Day Day 1-2'1 28-34 41-48 55-62 69-76 83-90 97-104 Challenge Dav 7 21 35 49 63 77 Group 2 % Efficacy 69.1 81.8 72.9 87.7 84.8 87.4 76.0 Group 3 % Efficacy 85.4 95.2 98.3 96.6 99.2 98.6 90.2 Table 16B: Tick Weight Efficacy Aga1nstR72ipicepha/us (Boophflus) microplus Average % Efficacy (Tick Weight) ent Group Day Day Day Day 111-118 132-139 146-153 160-167 Challenge Day 9] n2 T26 140 Group 2 % Efficacy 74.0 83.2 20.6 63.4 Group 3 % Efficacy 96.0 92.4 61.4 76.3 PCT/U82012/054719 Example 16: Efficacy of n ation Against Linognathus vim/1' (sucking lice) in ' The efficacy of two pour-on formulations of the ion comprising isoxazoline Compound A at doses of 2.5 mg/kg and 10 mg/kg were tested against natural and induced infestations with Linognaz‘hus vitu‘li (sucking lice) in'cattle compared with an untreated control.
Four healthy head of cattle weighing between 100 to 300 kg Were used in each study group.
Cattle in Group 1 were untreated (control). Cattle in Group 2 were treated on Day 0 with a pour- on formulation comprising Compound A at a concentration of 2.5% (w/v) in DES at a dose of 2.5 mg/kg; and cattle in Group 3 were treated on Day 0 with a pour-on formulation comprising IO Compound A at a concentration of 10% (w/v) in DES at a dose of 10 mg/kg. The formulation was applied by measuring the required amount of the solution into a marked disposable syringe and applying the material evenly along the mid-line of the back of each animal from the withers to the tail head.
Live lice s plus nymphs) were counted on days 2, 7, 14, 21, 28, 35, 42, 49 and 56 by counting lice on six selected sites approximately 5 cm x 15 cm on the body surface of the animal by direct examination. In the absence of lice on the selected sites, a thorough body search was conducted. The total louse counts per animal were determined by summation of the live louse s at each site per animal. Tables 17A and 17B below show the efficacy of the two pour—on formulations against Linognathus vim/i over 56 days. As the tables show, both pour-on formulations were ious through at least day 56 of the study with 100% y observed starting day 7. Efficacy on day 2 of the study was greater than 90% in each of the study groups.
The long g efficacy against Linognathus vituli from one topical treatment is unexpected and surprising.
Table 17A: Efficacy of Pour-on Formulation Against Linognathus vitulz' 1 ‘70 Reduction Treatment GrouP Da 2 Da 7 Da 1Dar28 Group 2 % Reddction 92 100 100 100 100 Group 3 % Reduction 98 100 100 100 100 PCT/U82012/054719 Table 178: Efficacy of Pour-on Formulation Against Linognathus vituli (continued) 070 ion Treatment Group Day 35 Day 42 Day 49 Day 56 Group 2 % Reduction 92 100 100 100 Group 3 % Reduction 98 100 100 100 Example [7: Efficacy of Pour-on Formulation Against Sarcoptes scabiez‘ var. bovis (mange mites) in Cattle.
The efficacy of two pour-on formulations of the invention comprising isoxazoline Compound A at doses of 2.5‘ mg/kg and 10 mg/kg were tested against natural and induced infestations with Sarcoptes scabz'ei var. bovis ’mites) in cattle Compared with an untreated control. Four healthy head of cattle weighing between 100 to 300 kg were used in each study group. Cattle in Group 1 were untreated (control). Cattle in Group 2 were treated on Day 0 with a n formulation comprising nd A at a concentration of 2.5% (w/v) in DES at a dose of 2.5 mg/kg; and cattle in Group 3 were treated on Day 0 with a pour-on formulation sing Compound A at a tration of 10% (w/v) in DES at a dose of 10 mg/kg. The ation was; applied by measuring the required amount of the solution into a marked disposable syringe-and applying the material evenly along the ne of the back of each animal from the withers to the tail head.
Live (motile) Sarcoptes scabiei var. how's (mange mites) were d on days 7, 14, 20, 27, 34, 41, 48 and 55 in scrapings collected from the edges of active lesions or, if lesions regressed during the study, from the area where active lesions were at the commencement of the study. Serapings were made from six sites with an area of at least 3 cm x 3 cm in size on each animal. Tables" 18A and 188 below show the efficacy of the two pour-on ations against Sarcoptes scabiei var. bovis over 56 days. As the data shows, both pour-on formulations'were efficacious through at least day 56 of the study with efficacy of higher than 95% starting on day 7. The efficacy of the 10% (w/v) formulation exhibited an efficaey‘of 100% from day 14‘through day 55, while the efficacy of the lower concentration pour—on formulation (Group 2) showed 100% starting from day 27 through the end of the study.“The long lasting efficacy of the pour-on PCT/U82012/054719 formulations of the invention against Sarcopzes scabiei var. how's from one topical ent is unexpected and surprising.
Table 18A: Efficacy of Pbur-on Formulation Against Sarcoptes scabiei var. b0vis 07° ion Treatment Group Day 7 Daxr 14 Day 20 Day 27 Group 2 % Reduction 96.7 98.2 99.6 100 Group 2 % Reduction 96.8 100 100 100 Table 188: Efficacy of Pour-on Formulation Against Sarcoptes scabiei var. bovis (continued) % Reduction Treatment CW" Day 34 Day 41 Day 48 Day 55 Group 2 % Reduction 100 100 100 100 Group 2 % Reduction 100 100 100 100 As the non—limiting examples above demonstrate, the compositions of the invention comprising at least one isoxazoline active agent show superior long lasting efficacy against rasites in a mammal (e.g. dogs, cats and cattle). fl: ’1: ’1: it * * * * * * The tim is r described by the following numbered paragraphs: 1. A topical veterinary composition for treating or preventing a tic infection or infestation in an animal comprising: a) at least one isoxazoline active agent of Formula (I): o—_\I A64 \A4 wherein: PCT/U82012/054719 A' A5 and A6 are independently selected from the group consisting of CR3 , A2, A3, A4, and N, provided that at most 3 of Al, A2, A3, A4, A5 and A6 are N; 3‘, B2 and B3 are independently selected from the group consisting of CR2 and N; W is O or S; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more sUbstituents independently selected from R6: each R2 is independently H, halogen, C1-C6 alkyl, C1-C5 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C 1-C6 alkylthio, C1-C6 haloalkylthio, C 1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C 1- IO C6 alkylsu'lf‘onyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C5 dialkylamino, C7-C4 alkoxycarbonyl, —CN or —NOz; each R3 is independently H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, C3- CO halocycloalkyl, C l-Co alkoxy, C1-C6 haloalkoxy, C 1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C 1-C6 alkylamino, C2-C6 dialkylamino, —CN or —N02; R4 is H, C 1-C6 alkyl, C2-C6 alkenyl, C7-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 carbonyl; ' R5 is H, OR”), NRHR” or Q"; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 lkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each ally tuted with one or more substituents ndently selected from R7; or R4 and R5 are taken er with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N. S and 0, said ring optionally substituted with 1 to 4 tuents independently selected from the group consisting of C1-C2 alkyl, halogen, —CN, —N02 and C1-C2 alkoxy; each R6 is ndently n, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C l-C6 alkylsulfonyl, —CN or —N02; ' each R7 is independently halogen; C1-C6 alkyl, C3-C6 lkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsiilfinyl, C1-C6 alkylsulfonyl, C 1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylearbonyl, C2-C7 halOalkoxycarbonyl, C2-C7 PCT/U82012/054719 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, —NH2, —CN or —N02; or each R8 is ndently halogen, C1-C5 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 earbdnyl, —CN or — ‘ ’ N02; each R9 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 koxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C l-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C 1-C6 haloalkylsulfonyl, C 1-C6 alkylamino, C2-C6 dialkylamino, +CN, —N02, phenyl Or pyridinyl; ‘ ' R10 is H; or C1-C6 alkyl, C2-C6 l, Cg—C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted With one of more halogen; ‘ R” ’ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Cit-C7 alkylcycloalkyl, C4-C7 eyeloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; R12 is H; Q3; or C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally tuted with one or more substituents independently selected from R7; or R11 and R—12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and 0, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, —CN, —N02 and C1-C2 alkoxy; Q' is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or lO-membered fused bicyclic ring system ally containing one to‘three heteroatoms selected from up to l 0, up to l S and up to 3 N, each ring or ring syStem optionally substituted with one or more substituents independently selected from R8; 7 each Q2 is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring ally tuted with one or more substituents independently selected from R9; R Q3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more tuents independently selected from R9; and n is 0, l or 2; and b) a pharmaceutically acceptable carrier that is suitable for application to the skin of an PCT/U82012/054719 animal; and wherein the carrier does not comprise irol and is not a binary mixture of propylene glycol and glycerol formal. 2. The’topical veterinary cemposition of paragraph 1, wherein in the isoxazoline active agent of Formula (I): W is O; R4 is H or C1-C6 alkyl; R5 is -CH2C(O)NHCH2CF3; cach ofA', A2, A3, A4, A5 and A6 is CH; IO R| is C1-C6 alkyl each optionally substituted with one or more substituents independently 7 7 selected from R6; R6 is halogen or C1-C6 alkyl; and 3‘, 32, and B3 are ndently CH, C-halogen, C-Ci-C6 alkyl, o haloalkyl, or C- C1-C6 alkoxy. 3. The topical veterinary composition of paragraph 1, wherein in the isoxazoline active agent of Formula (I): W is O; R' is cry; 132 is CH; B1 is chloro; i33 is CH; each ofA', A2, A3, A“, A5 and A6 is CH; R4 is H; and R5 is -CH2C(O)NHCH2CF3. 4. The topical veterinary ition of paragraph 1, n the pharmaceutically acceptable carder‘comprises a r ota diearboxylic acid, a glycol ester, a glycol ether, a fatty acid ester, a polyethylene glycol, or polyethylene glycol ester, an oil, an alcohol, a glycerol ester, a glycerol ether, propylene glycol, ethylene glycol, a glycol carbonate, dimethyl isOsorbide, N- methylpyrrolidone, or a mixture thereof.
PCT/U82012/054719 . The topical nary composition of paragraph 4, wherein the diester of a dicarboxylic acid is a diester of a C6-C16 dicarboxylic acid. ' 6. The topical veterinary composition of paragraph 5, n the diester of a C6-Cl6 dicarboxylic acid’is diethyl sebaeate or diisopropyl’adipate’. 7. The topical veterinary composition of paragraph 4, wherein the pharmaceutically acceptable carrier comprises mixture of a diester of a oxylic acid and a propylene glycol IO ester, a fatty acid ester, a polyethylene glycol ester, a polyethylene glycol, an oil, a C6-Czoilong- chain aliphatic alcohol, a C1-C8 alcohol,'glycol ether, or a‘combinatit'm thereof. 8. The topical veterinary composition of paragraph 4, wherein the pharmaceutically acceptable carrier comprises a mixture of a diester of a oxylic acid and further ses a mixed ester of sucrose and acetic and isobutyric acid, a low melting wax, a hard fat or a block eo-polymer of ethylene oxide and ene oxide, or a ation thereof. 9. The l veterinary composition of paragraph 4, wherein the pharmaceutically acceptable carrier comprises dimethyl isosorbide, glycerol formal, propylene carbonate, triacetin, diethyleneglyeol monoethyl ether, polyethylene glycol 400 or benzyl alcohol, or a mixture thereof.
. The topical veterinary composition of any one of aph 1 to 9, wherein the composition r comprises at leasta second actiVe agent.” 11. The topical veterinary composition of aph 10, wherein the at least second active agent is an insect growth regulator, a neonicotinoid or an avermectin or milbemycin. 12. The topical veterinary composition of paragraph 11, wherein the isoxazoline active agent is 4-[5—[3-chloro(trifluoromethyl)phenyl]l4,5-dihydro(trifluoromethyl)—3-isoxazolyl]- N-[2-oxo[(2,2,2-trifluoroethyl)amino]ethyl]-l-naphthalaneearboxamide and the neonicotinoid PCT/U82012/054719 is nitenpyram. 13. The topical veterinary composition of paragraph 11, wherein the at least second active agent is an insect growth regulator. 14. The l veterinary composition of paragraph 13, n the insect growth regulator is (S)-methoprene, pyriproxyfen, rene. cyromazine, fluazuron, lufenuron, or novaluron.
IO 15. The topical veterinary composition of paragraph I I, wherein the avermectin or milbemycin is eprinomectin, ivermectin, selamecfin, milbemectin, milbemycin D, ycin oxime, or moxidectin 16. The topical veterinary composition of paragraph 10, wherein the at least second active agent is an anthelmintic active agent selected from thiabendazole, oxibendazole, mcbcndazolc, fcnbcndazolc, oxfcndazolc, albcndazole, triclabcndazolc, fcbantcl, lcvamisolc, pyrantel, morantel, praziquantel, closantel, clorsulon, an amino acetonitrile active agent, or an aryloazolyl cyanoethylamino active agent. 17. The topical veterinary composition of any one of aph 1 to 16, wherein the ition is a spot-on composition. 18. The topical veterinary composition of any one of paragraph 1 to 16, wherein the composition is a pour-on composition. 19. A method for the treatment or prevention of a parasitic infestation or infection in an animal sing stering to the animal an cffcctivc amount of the topical vctcrinary composition of‘ any of paragraph I to 18. 2012/054719 . The method of paragraph 19, wherein the isoxazoline is 4-[5-[3-ehloro (trifluoromethyl)phenyl]—4,5-dihydro(trifluoromethyl)isoxazolyl]-N-[2-oxo[(2,2,2- trifluoroethyl)amino]ethyl]naphthalenecarboxamide. 21. Use of an isoxazoline of formula (I) in paragraph 1 in the preparation of a topical veterinary composition for the treatment or protection of an animal against parasites.
* * * Having thus described in detail s embodiments of the present invention, it is to be understood that the ion defined by the above paragraphs is not to be limited to particular IO details set forth in the above description as many apparent van'ations thereof are possible without departing from the spirit or scope of the present invention. _ _ _ 102

Claims (26)

WHAT IS CLAIMED IS:
1. A topical n or pour-on veterinary composition for treating and/or ting a parasitic infection or infestation in a non-human mammal comprising: a) at least one isoxazoline active agent of Formula (I): wherein: A1, A2, A3, A4, A5 and A6 are independently selected from the group consisting of CR3 and N, provided that at most 3 of A1, A2, A3, A4, A5 and A6 are N; B1, B2 and B3 are independently selected from the group ting of CR2 and N; W is O or S; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently ed from R6; each R2 is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 ulfinyl, C1-C6 haloalkylsulfinyl, C1- C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkoxycarbonyl, —CN or —NO2; each R3 is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 lkyl, C3- C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, —CN or —NO2; R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; R5 is H, OR10, NR11R12 or Q1; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 lkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R4 and R5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one onal atom ed from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, halogen, —CN, —NO2 and C1-C2 alkoxy; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, —CN or —NO2; each R7 is independently n; C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 lamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 dihaloalkylaminocarbonyl, hydroxy, —NH2, —CN or —NO2; or each R8 is independently halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkoxycarbonyl, —CN or — NO2; each R9 is independently n, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cloalkyl, C1-C6 alkoxy, C1-C6 koxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 ulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, —CN, —NO2, phenyl or pyridinyl; R10 is H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one of more halogen; R11 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; R12 is H; Q3; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R7; or R11 and R12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group ting of N, S and O, said ring optionally tuted with 1 to 4 substituents independently selected from the group consisting of C1-C2 alkyl, n, —CN, —NO2 and C1-C2 alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or 10-membered fused bicyclic ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system ally substituted with one or more substituents independently selected from R8; each Q2 is ndently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R9; Q3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R9; and n is 0, 1 or 2; and b) a ceutically acceptable carrier that is suitable for the application to the skin of a non-human , wherein said r comprises a liquid polyethylene glycol.
2. The topical veterinary composition of claim 1, wherein: W is O; R4 is H or C1-C6 alkyl; R5 is -CH2C(O)NHCH2CF3; each of A1, A2, A3, A4, A5 and A6 is CH; R1 is C1-C6 alkyl each optionally substituted with one or more substituents independently selected from R6; R6 is halogen or C1-C6 alkyl; and B1, B2, and B3 are independently CH, C-halogen, C-C1-C6 alkyl, C-C1-C6 haloalkyl, or CC1-C6 alkoxy.
3. The topical veterinary composition of claim 1 or claim 2, wherein: W is O; R1 is CF3; B2 is CH; B1 is C-Cl; B3 is C-CF3; each of A1, A2, A3, A4, A5 and A6 is CH; R4 is H; and R5 is -CH2C(O)NHCH2CF3.
4. The topical veterinary ition of any one of claims 1 to 3, wherein the pharmaceutically acceptable carrier further comprises an alkyl diester of a dicarboxylic acid.
5. The topical veterinary composition of claim 4, wherein the alkyl diester of a dicarboxylic acid is an alkyl diester of a C6-C16 dicarboxylic acid.
6. The topical veterinary ition of claim 5, wherein the alkyl diester of a C6-C16 dicarboxylic acid is diethyl sebacate, dibutyl sebacate, diisopropyl sebacate, diisopropyl adipate, dibutyl adipate or utyl adipate.
7. The topical veterinary composition of any one of claims 1 to 6, wherein the pharmaceutically acceptable carrier comprises polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 600.
8. The topical nary composition of any one of claims 1 to 7, wherein the pharmaceutically acceptable r comprises polyethylene glycol 400.
9. The topical veterinary composition of any of claims 1 to 8, wherein the oline active agent of formula (I) is present in a concentration of about 1 to about 25% (w/v).
10. The topical veterinary composition of any of claims 1 to 9, wherein the isoxazoline active agent of a (I) is present in a concentration of about 1 to about 10% (w/v).
11. The topical veterinary composition of any of claims 1 to 10, wherein the isoxazoline active agent of formula (I) is present in a concentration of about 1 to about 5% (w/v).
12. The topical veterinary composition of any of claims 1 to 8, wherein the isoxazoline active agent of formula (I) is present in a concentration of about 0.5 to about 2.0% (w/v).
13. The topical veterinary ition of any one of claims 1 to 12, further comprising at least a second active agent.
14. The topical veterinary ition of claim 13, wherein the at least second active agent is an insect growth regulator, a neonicotinoid or an ctin or milbemycin.
15. The topical veterinary composition of claim 13 or claim 14, wherein the at least second active agent is an insect growth regulator.
16. The topical veterinary composition of claim 15, wherein the insect growth regulator is thoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron, or novaluron.
17. The topical veterinary ition of claim 14, wherein the avermectin or milbemycin is eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin.
18. The topical veterinary composition of claim 13, wherein the at least second active agent is an anthelmintic active agent selected from thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, uantel, closantel, clorsulon, an amino acetonitrile active agent, or an aryloazol yl cyanoethylamino active agent.
19. The topical veterinary composition of any one of claims 1 to 18, wherein the composition is a spot-on composition.
20. The topical veterinary composition of any one of claims 1 to 18, wherein the composition is a pour-on composition.
21. The l veterinary composition of any one of claims 1 to 18, n the composition is a spot-on composition, and wherein the volume of the composition is between about 0.1 to about 10 ml.
22. The l veterinary composition of claim 21, wherein the volume of the composition is between about 0.1 to about 5 ml.
23. The topical veterinary composition of claim 21 or claim 22, wherein the volume of the composition is between about 0.1 to about 1 ml.
24. The topical veterinary composition of any one of claims 1 to 18, n the composition is a pour-on composition, and wherein the volume of the composition is between about 10 to about 100 ml.
25. The topical veterinary composition of any one of claims 1 to 24, wherein the isoxazoline compound of formula (I) is 4-[5-[3-chloro(trifluoromethyl)phenyl]-4,5-dihydro (trifluoromethyl)isoxazolyl]-N-[2-oxo[(2,2,2-trifluoroethyl)amino]ethyl] naphthalanecarboxamide.
26. A topical spot-on or pour-on nary ition according to claim 1, substantially as hereinbefore described with reference to the examples and excluding, if any, comparative examples. wo
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