US0092.594.17B2

(12) United States Patent (10) Patent No.: US 9.259,417 B2 Soll et al. (45) Date of Patent: Feb. 16, 2016

(54) PARASITICIDAL ORAL VETERINARY USPC ...... 514/378 COMPOSITIONS COMPRISING See application file for complete search history. SYSTEMICALLY-ACTING ACTIVE AGENTS, METHODS AND USES THEREOF (56) References Cited (71) Applicant: MERIAL INC., Duluth, GA (US) U.S. PATENT DOCUMENTS 3,887.964 A 6, 1975 Richards (72) Inventors: Mark David Soll, Alpharetta, GA (US); 4,284,652 A 8, 1981 Christensen Diane Larsen, Buford, GA (US); Susan 4,327,076 A 4/1982 Puglia et al. Mancini Cady, Yardley, PA (US); Peter 4,393,085 A 7/1983 Spradlin et al. Cheifetz, East Windsor, NJ (US); is: A 2. 3. SE, Izabela Galeska, Newtown, PA (US) 4,997,671- - - A 3/1991 SpanierO C. a. 5,236,730 A 8, 1993 Yamada et al. (73) Assignee: MERLAL, INC., Duluth, GA (US) 5,262,167 A 1 1/1993 Vegesna et al. 5,380,535 A 1/1995 Geyer et al. (*) Notice: Subject to any disclaimer, the term of this 5.439,924 A 8, 1995 Miller patent is extended or adjusted under 35 5,578.336 A 1 1/1996 Monte U.S.C. 154(b) by O. davs. 5,605,889 A 2f1997 Curatolo et al. (b) by yS 5,637,313 A 6, 1997 Chau 5,753,255 A 5/1998 Chaukin et al. (21) Appl. No.: 14/627,499 5,824,336 A 10/1998 Janset al. (22) Filed: Feb. 20, 2015 5,827,5655:3. A 10,36 1998 Axelrodin Set al. (65) Prior Publication Data (Continued) US 2015/O164864 A1 Jun. 18, 2015 FOREIGN PATENT DOCUMENTS Related U.S. Application Data AU 2008320992 6, 2010 (63) Continuation of application No. 13/754.969, filed on AU 2010206029 8, 2010 Jan. 31, 2013. (Continued) (60) Provisional application No. 61/595,463, filed on Feb. OTHER PUBLICATIONS 6, 2012. Glossary of medical education terms, Institute of International Medi cal Education. http://www.iime.org/glossary.htm Accessed in Mar. (51) Int. Cl. 2013. A6 IK3I/42 (2006.01) Halos etal. Flea control failure? Mvthsyth and realities. Trends Parasitol A6 IK3I/94 (2006.01) 30:228-233, May 2014. A6 IK9/00 (2006.01) EMEA Report. Committee for Veterinary Medicinal Products: Poly ethylene Glycol Stearates and Polyethylene Glycol 15 Hydroxystear gll, %4. 3:08: ate, Summary Report. EMEAfMRL/392/98-FINAL Rev.1, Jun. 2003. A6 IK3I/4985 (2006.01) Starch 1500 Partially pregelatinized maize starch technical informa A6 IK3I/7048 (2006.01) tion brochure; Colorcon company, 1999. A6 IK3I/365 (2006.01) A6 IK3I/27 (2006.01) (Continued) A6 IK3I/437 (2006.01) Primary Examiner — Mark Shibuya A6 IK 47/10 (2006.01) Assistant Examiner — Yih-Horng Shiao A6 IK 47/12 (2006.01) (74) Attorney, Agent, or Firm — Judy Jarecki-Black; John A6 IK 47/4 (2006.01) Ezcurra; Merial, Inc. A6 IK 47/32 (2006.01) (57) ABSTRACT A6 IK 47/3647/44 (2006.01)2006.O1 This invention relates to veterinary compositions for treating ( .01) and/or preventing fleas or ticks infection or infestation in an (52) U.S. Cl. animal comprising an isoxazoline active agent of Formula CPC ...... A6 IK3I/42 (2013.01); A61 K9/0056 (II): (2013.01); A61 K9/0068 (2013.01); A61 K 31/194 (2013.01); A61 K3I/27 (2013.01); A6 IK3I/365 (2013.01); A61 K3I/437 (II) (2013.01); A61K 31/4985 (2013.01); A61K O-N O 31/7048 (2013.01); A61K 45/06 (2013.01); FC \ A61K47/14A61K47/10 (2013.01); A61K 47/3247/12 (2013.01); C O HN NH A61K47/36 (2013.01); A61K 47/44 (2013.01); O C07D 261/04 (2013.01) C CH (58) Field of Classification Search CPC ... A61K 31/42: A61 K9/0056; A61K 31/194; or a pharmaceutically acceptable salt thereof, and a pharma A61K31/7048. A61K47/44. A61K47/36. ceutically acceptable carrier. A61K 47/14: A61K 47/10; A61K 2300/00 24 Claims, 3 Drawing Sheets US 9,259,417 B2 Page 2

(56) References Cited WO 2008. 144275 11, 2008 WO WO2008, 148027 A1 12/2008 U.S. PATENT DOCUMENTS WO WO2008,154528 A1 12/2008 WO WO2009/002809 A1 12/2008 6,060,078 A 5, 2000 Lee WO 2010/OO3923 1, 2010 6,086,940 A 7/2000 Axelrod WO 2010/056999 5, 2010 6,093.427 A 7/2000 Axelrod WO 2010/07907 7 T 2010 6,093441. A 7/2000 Axelrod WO 2010/084067 T 2010 6,110,521 A 8/2000 Axelrod WO 2011,067272 6, 2011 6,159,516 A 12/2000 Axelrod et al. WO 2011 O92287 8, 2011 6,270,790 B1 8/2001 Robinson et al. WO 2011 104087 9, 2011 6,387.381 B2 5/2002 Christensen WO 2011/154433 12/2011 6,500.463 B1 12/2002 van Lengerich WO 2011/154434 12/2011 7,348,027 B2 3/2008 Rose et al. WO 2011/154494 12/2011 7,662.972 B2 2/2010 Mita et al. WO 2011/157733 12/2011 7,947,715 B2 5, 2011 Mita et al. WO WO2011, 149749 A1 12/2011 7,951,828 B1 5/2011 Mita et al. WO 2012/OO7426 1, 2012 7.955,632 B2 6/2011 Paulsen et al. WO 2012/038851 3, 2012 8,022,089 B2 9/2011 Mita et al. WO 2012/0491.56 4/2012 8.492.311 B2 7, 2013 Mita et al. 8,796.464 B2 8/2014 Moriyama et al. OTHER PUBLICATIONS 38 1993 A. 58: his “Understanding and optimizing the dual excipient functionality of 2003,7958OOO 1/2003 Chen sodium lauryl sulfate in tablet formulation of poorly water soluble 2004/0037869 A1 2/2004 Cleverly et al. drug: wetting and lubrication.” Aljaberi et al., Pharmaceutical Devel 2004.0043925 A1 3, 2004 Kolbe et al. opment and Technology, 2013; 18(2): 490-503. 2004/0234579 A1 11, 2004 Finke “Parasites of domestic owned cats in Europe: co-infestations and risk 2005/0O3.2718 A1 2/2005 Burke et al. factors.” Beugnet et al., Parasites & Vectors, 2014, 7:291. 2005/0226908 A1* 10, 2005 Huron et al...... 424/442 "Pharmacokinetics of fluralaner in dogs following a single oral or 2006/014 1009 A1 6/2006 Cady et al. intravenous administration.” Kilp et al., Parasites & Vectors, 2014, 2006/0222684 A1 10, 2006 ISele 7:85. 2009,028O159 A1 11, 2009 Paulsen et al. "A randomized, blinded, controlled USA field study to assess the use 3988: A. g388 Mia et 514,378 offluralaner tablets in controlling canine flea infestations.” Meadows Ita et al...... et al., Parasites & Vectors, 2014, 7: 375. 2010/01791.94 A1 7, 2010 Mihara et al. European Medicines Agency Committee for Medicinal Products for 3888 . 2. A. 6.588 th st al Veterinary Use (CVMP) Assessment Report for Bravecto, Dec. 12, Ong et al. 2014. 2011 OOO9438 A1 1/2011 Mita et al. "A randomized, blinded, controlled and multi-centered field study 2011/0059988 A1 3/2011 Heckeroth et al. comparing the efficacy and safety of BravectoM (fluralaner) against 33; 8. s: : A. 38: if Elois etal FrontlineTM (fipronil) in flea- and tick-infested dogs.” Rohdich et al., 2011/O159107 A1 6, 2011 Koerber et al. Easy R EPAR Product Information for 2011/O166193 A1 7, 2011 Renold et al. Eri Nishi S. 54 38885A. A. 1933; Rial “Onset of activity of fluralaner (BRAVECTOTM) against 2012, 0035122 A1 2/2012 Vaillancourt et al. Stephalides felis on dogs.” Taenzler et al., Parasites & Vectors, 5858. A. 33. St.it al. U.S. Freedom of Information Summary for NADA 141-426 BRAVECTO, May 15, 2014. 2015,0057239 A1 2/2015 Freehaufetal. “Comparative efficacy of two oral treatments for dogs containing either afoxolaner or fluralaner against Rhipicephalus Sanguineus FOREIGN PATENT DOCUMENTS sensulato and Dermacentor reticulatus.” Beugnet et al., Veterinary Parasitology, 209 (2015), 142-145. EP O273OO1 6, 1988 “Comparative speed of efficacy against Ctenocephalides felis of two EP 492235 7, 1992 oral treatments for dogs containing either afoxolaner or fluralaner.” EP O75443 3, 1993 Beugnet et al., Veterinary Parasitology, 207 (2015), 297-301. EP 1023841 8, 2000 “Safety of fluralaner, a novel systemic antiparasitic drug, in EP 1247456 10, 2002 MDR1(--) Collies after oral administration.” Walther et al., Para GB 2300 103 10, 1996 sites & Vectors, 2014, 7:86. NZ 286545 11, 1998 “Safety of the concurrent treatment of dogs with BravectoM NZ 568.394 6, 2010 (fluralaner) and ScaliborTM protectorband (deltamethrin).” Walther et WO 99.48372 9, 1999 al., Parasites & Vectors, 2014, 7:105. W. 85.835 383 “Safety of concurrent treatment of dogs with fluralaner (BravectoM) WO O3/030653 4/2003 and milbemycin Oxime praziquantel.” Walther et al., Parasites & WO WO2005/O137142005/O13714 A1 2, 2005 E.e effect of E.food on the pharmacokinetics of oral fluralaner in WO 2005/O16356 3, 2005 dogs.” Walther et al., Parasites & Vectors, 2014, 7:84. WO WO2005/062782 A1 7/2005 “The speed of kill of fluralaner (BravectoM) against Ixodes ricinus WO 2005/099.453 10/2005 tickson dogs.” Wengenmayer et al., Parasites & Vectors, 2014, 7:525. WO WO2005/0996.92 A1 10, 2005 Fluralaner, al novel isoxazoline, prevents flea (Ctenocephalides WO 2007/07O606 6, 2007 felis) reproduction in vitro and in a simulated home environment.” WO 2007/075459 7/2007 Williams et al., Parasites & Vectors, 2014, 7:275. WO 2007/079162 7/2007 “Safety of fluralaner chewable tablets (Bravecto"), a novel systemic WO 2007/123855 11, 2007 antiparasitic drug, in dogs after oral administration.” Walther et al. WO 2008/030469 3, 2008 Parasites & Vectors, 2014, 7:87. WO 2008, 1348.19 11, 2008 WO 2008/136791 11, 2008 * cited by examiner U.S. Patent Feb. 16, 2016 Sheet 1 of 3 US 9.259,417 B2

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------: 3. 4. s 3. ise bay Figure 5: Plasma Concentration of Compound A from Chewable Compositions" US 9,259,417 B2 1. 2 PARASITICIDAL ORAL VETERINARY Toxascaris, Trichuris, Enterobius, Haemonchus, Trichos COMPOSITIONS COMPRISING trongylus, Ostertagia, Cooperia, Oesophagostomum, Bunos SYSTEMICALLY-ACTING ACTIVE AGENTS, tomum, Strongylus, Cyathostomum, and Parascaris among METHODS AND USES THEREOF others, and those that are found in the blood vessels or other tissues and organs include Onchocerca, Dirofilaria, Wuchere CROSS REFERENCE TO RELATED ria and the extra intestinal stages of Strongyloides, Toxocara APPLICATIONS and Trichinella. Therapeutic agents are administered to ani mals by a variety of routes. This application is a continuation of and claims benefit of These routes include, for example, oral ingestion, topical co-pending U.S. patent application Ser. No. 13/754.969, filed 10 application or parenteral administration. The particular route Jan. 31, 2013, which claims the benefit of U.S. Provisional selected by the practitioner depends upon factors such as the Application Ser. No. 61/595,463, filed Feb. 6, 2012, which are physicochemical properties of the pharmaceutical or thera incorporated herein by reference in their entirety. peutic agent, the condition of the host and economics. In certain cases, it is convenient and efficient to administer vet FIELD OF THE INVENTION 15 erinary medicines orally by placing the therapeutic agent in a solid or liquid matrix that is suitable for oral delivery. These The present invention provides oral Veterinary composi methods include chewable drug-delivery formulations. The tions comprising at least one systemically-acting active agent problem associated with administering oral formulations to for controlling ectoparasites and/or endoparasites in animals; animals is that the therapeutic agent often provides an the use of these compositions to control ectoparasites and/or unpleasant taste, aroma, or texture, which causes the animals endoparasites, and methods for preventing or treating para to reject the composition. This is further exacerbated by com sitic infections and infestations in animals. positions that are hard and difficult to swallow. Oral veterinary compositions in the form of soft chewable BACKGROUND OF THE INVENTION compositions (“soft chews'), or chewable tablets that are 25 palatable are usually convenient to administer to certain ani Animals including mammals and birds are often suscep mals, particularly cats and dogs, and may be used effectively tible to parasite infestations/infections. These parasites may to dose veterinary medicine to these animals. However, many be ectoparasites or endoparasites. Domesticated animals, oral compositions comprising active agents with a bitter or Such as cats and dogs, are often infested with one or more of unpleasant taste are not well accepted by cats and dogs. the following ectoparasites: 30 Furthermore, when the bioavailability of an active agent from fleas (e.g. Ctenocephalides spp., Such as Ctenocephalides an oral dosage form is not sufficientoris variable, the required fells and the like): exposure of the animal to the active ingredient may not be ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor sufficient to provide the desired efficacy. Problems such as spp., Amblyoma spp., Haemaphysalis spp., and the like); these often lead to low or sub-optimal efficacy and control of mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., 35 parasites. Cheyletiella spp., and the like); Chewable dosage forms for drug delivery are well known lice (e.g. Trichodectes spp., Felicola spp., Linognathus to pharmaceutical technology. It is known in the pharmaceu spp., and the like); tical industry that the act of chewing increases the Surface mosquitoes (Aedes spp., Culex spp., Anopheles spp. and area of the available active ingredient and may increase the the like); and 40 rate of absorption by the digestive tract. Chewable systems flies (Musca spp., Stomoxys spp., Dermatobia spp., and the are also advantageous where it is desirable to make an active like). ingredient available topically to the mouth or throat areas for Fleas are a problem because not only do they adversely both local effects and/or systemic absorption. Further, chew affect the health of the animal or human, but they also cause able dosage forms are also utilized to ease drug administra a great deal of psychological stress. Moreover, fleas may also 45 tion in pediatric and geriatric patients. Examples of chewable transmit pathogenic agents to animals and humans, such as dosage forms may be found in U.S. Pat. Nos. 6,387.381: tapeworm (Dipylidium caninum). 4,284,652; 4,327,076; 4,935,243; 6,270,790; 6,060,078: Similarly, ticks are also harmful to the physical and/or 4,609.543; and, 5,753,255, all incorporated herein by refer psychological health of the animal or human. However, the CCC. most serious problem associated with ticks is that they are 50 Palatability and “mouth feel” are important characteristics vectors of pathogenic agents affecting both humans and ani to be considered in providing a dosage form, or matrix, for an mals. Major diseases which may be transmitted by ticks active pharmaceutical or medicinal. Unfortunately, many include borreliosis (Lyme disease caused by Borrelia burg pharmaceuticals and other active ingredients have a bitter or dorferi), babesiosis (or piroplasmosis caused by Babesia otherwise unpalatable taste, or an unacceptable mouth feel, spp.) and rickettsioses (e.g. Rocky Mountain spotted fever). 55 due to the grittiness or chalkiness of the compound, or both. Ticks also release toxins which cause inflammation or paraly These characteristics make it difficult to incorporate such sis in the host. Occasionally, these toxins may be fatal to the active ingredients into the current state of the art for chewable host. dosage forms because the objectionable taste and/or mouth Animals and humans also suffer from endoparasitic infec feel make it less likely to obtain compliance by the user. Oral tions caused by parasitic worms categorized as cestodes 60 Veterinary dosage forms that are not palatable to the animal (tapeworms), nematodes (roundworms) and trematodes (flat treated result in low acceptance of the medicament by the worms or flukes). These parasites cause a variety of patho animal and a low level of compliance. Thus, there is a need for logic conditions in domestic animals including dogs, cats, improved oral veterinary dosage forms that are palatable and pigs, sheep, horses, cattle and poultry. Nematode parasites well accepted by the treated animal. which occur in the gastrointestinal tract of animals and 65 Another challenge with oral Veterinary compositions, par humans include those of the genera Ancylostoma, Necator, ticularly soft chewable compositions, is that the release and Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, dissolution of the active agent from the composition after it is US 9,259,417 B2 3 4 ingested by the animal can be variable and incomplete. This ing parasiticidal active agent and their use to control external leads to variability in the amount of the drug that is absorbed and/or internal parasites in or on warm-blooded animals and from the digestive tract of the animal. birds. In accordance with this invention, it has been discov U.S. Pat. No. 7,955,632 (incorporated herein by reference) ered that these oral compositions Surprisingly provide excep describes palatable, edible soft chewable medication vehicles for the delivery of pharmaceutically acceptable active ingre tionally high bioavailability of the active agent resulting in dients to an animal and processes of making the same. plasma levels sufficient to provide excellent protection US 2004/0037869 A1 and WO 2004/016252 to Cleverly et against parasites for an extended period of time, unmatched al. (incorporated herein by reference) describe non-animal by known oral veterinary compositions. The oral composi product containing veterinary formulations, including chew tions of the invention are exceptionally palatable and provide able veterinary formulations and tablets, that contain at least 10 desirable safety profiles for warm-blooded animals and birds, one pharmaceutical active agent and do not contain animal while providing excellent protection against parasites. In products. addition, it has been discovered that a single administration of US 2004/0151759 A1 and WO 2005/062782 to Cleverly et the inventive compositions generally provides potent activity al. (incorporated herein by reference) describe non-animal against one or more ectoparasites and/or endoparasites with a product containing veterinary formulations comprising a) at 15 least one nodulisporamide or a nodulisporic acid derivative; fast onset of activity and at the same time providing a long or b) a combination comprisingi) at least one avermectin or duration of efficacy. milbemycin derivative; and ii) at least one of praziquantel or In certain embodiments, the Veterinary compositions of the pyrantel. invention are advantageously in the form of soft chewable WO 2009/02451A2 and US 2011/0059988 to Heckerothet formulations that are palatable for animals, including cats and al. describe various parasiticidal compositions comprising dogs. In another embodiment, the oral Veterinary composi isoxazoline active agents for the control of parasites on ani tions of the invention are in the form of a chewable tablet. mals. The compositions include compositions for oral admin The invention encompasses uses of the soft chewable vet istration. erinary compositions for the treatment and/or prophylaxis of Traditionally, in veterinary formulations, palatability had 25 been achieved by the inclusion of animal byproducts or fla parasitic infections and infestations of animals (either wild or Vors derived from animal sources into the formulation. For domesticated), including livestock and companion animals example, it is customary to include excipients, such as with the aim of ridding these hosts of parasites commonly chicken powder, liver powder, beef, ham, fish, or rawhide encountered by Such animals. Animals that may benefit from derived products in dog chews to make the chew attractive the inventive oral compositions include, but are not limited to, and palatable to the dog. See, e.g., U.S. Pat. No. 6,086,940; 30 cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and U.S. Pat. No. 6093441; U.S. Pat. No. 6,159,516; U.S. Pat. cattle, among others. No. 6,110,521; U.S. Pat. No. 5,827,565; U.S. Pat. No. 6,093, The invention also provides methods for the treatment 427, all to Axelrod et at. (all incorporated herein by refer and/or prevention of parasitic infections and infestations in ence). Notwithstanding the compositions comprising parasiti 35 animals, comprising administering an effective amount of a cidal active agents described in the documents above, there is composition of the invention comprising at least one systemi a need for palatable oral veterinary compositions that are well cally-acting parasiticide to the animal. Surprisingly, it has accepted by the animals treated and methods with improved been found that the inventive compositions and formulations duration of efficacy, bioavailability, and spectrum of coverage described herein exhibit superior broad spectrum efficacy to protect animals against endoparasites and/or ectoparasites. 40 against harmful ectoparasites and/or endoparasites more rap Optimal compositions should be palatable and well accepted idly, and over a longer duration compared to oral Veterinary by the animals, provide good oral bioavailability, be effica compositions known in the art. cious against external and/or internal parasites, have a quick In one embodiment, the invention provides soft chewable onset of activity, have a long duration of activity, and be safe Veterinary compositions comprising effective amounts of a) to the animal recipients and/or their human owners. This 45 (i) at least one isoxazoline active agent; or invention addresses this need. (ii) at least one systemically-acting active agent that is active against internal parasites, wherein the systemically INCORPORATION BY REFERENCE acting active agent that is active against internal parasites is Any foregoing applications, and all documents cited one or more macrocyclic lactones, one or more benzimida therein or during their prosecution (“application cited docu 50 Zoles, levamisole, pyrantel, morantel, praziquantel, closantel, ments') and all documents cited or referenced in the applica clorSulon, one or more amino acetonitrile active agents or one tion cited documents, and all documents cited or referenced or more aryloazol-2-yl cyanoethylamino active agents, or a herein (“herein cited documents'), and all documents cited or combination of thereof; or referenced in herein cited documents, together with any (iii) a combination of at least one isoxazoline active agent manufacturers instructions, descriptions, product specifica 55 of formula (I) and at least one additional systemically-acting tions, and product sheets for any products mentioned herein active agent, wherein the systemically active agent is one or or in any document incorporated by reference herein, are more macrocyclic lactones, one or more spinosyn com hereby incorporated herein by reference, and may be pounds, one or more spinosoid compounds, one or more employed in the practice of the invention. benzimidazoles, levamisole, pyrantel, morantel, praziquan Citation or identification of any document in this applica 60 tel, closantel, clorSulon, one or more amino acetonitrile active tion is not an admission that such document is available as agents, one or more arylpyrazoles, one or more insect growth prior art to the present invention. regulators, one or more neonicotinoids or one or more ary loazol-2-ylcyanoethylamino active agents, or a combination SUMMARY OF THE INVENTION of thereof, and b) a pharmaceutically acceptable carrier. 65 In one embodiment, the isoxazoline active agent has the The present invention is directed to soft chewable veteri formula (I) below where variables A, A, A, A, A, A, B, nary compositions comprising at least one systemically-act B. B. R. R. R. R. W. and n are defined herein: US 9,259,417 B2 6 specific embodiments described, may best be understood in

(I) conjunction with the accompanying drawings, in which: FIG. 1 is a plot showing the average dissolution of 2 gram size soft chewable compositions of the invention containing about 2.3% (w/w) of Compound A which have been stored at 25° and 60% relative humidity (RH). FIG. 2 is a plot showing the average dissolution of 2 gram size soft chewable compositions of the invention containing about 2.3% (w/w) of Compound A which have been stored at 10 40° and 75% relative humidity (RH). FIG. 3 is a plot showing the average dissolution of 4 gram In another embodiment, the compositions of the invention size soft chewable compositions of the invention containing comprise an isoxazoline compound of formula (II), (III) or about 2.3% (w/w) of Compound A which have been stored at 25° and 60% relative humidity (RH). (IV) described herein. 15 FIG. 4 is a plot showing the average dissolution of 4 gram In one embodiment, the invention provides soft chewable size soft chewable compositions of the invention containing compositions comprising an isoxazoline active agent of for about 2.3% (w/w) of Compound A which have been stored at mula (I) wherein Wis O, R' is CF B is CH, B is C Cl, B 40° and 75% relative humidity (RH). is C CF, each of A, A, A, A, A and A is CH; R is H FIG. 5 shows the plasma concentration of Compound A in and R is —CHC(O)NHCHCF. In some embodiments, the dogs over time after administration of soft chewable compo Soft chewable veterinary compositions and methods com sitions at doses of 20 mg/kg and 40 mg/kg compared with prise 4-5-3-chloro-5-(trifluoromethyl)phenyl-4,5-dihy administration of Compound A in a polyethyleneglycol/alco dro-5-(trifluoromethyl)-3-isoxazolyl-N-(2-oxo-2-(2.2.2- hol based solution. trifluoroethyl)aminoethyl-1-naphthalenecarboxamide (Compound A) as the isoxazoline active agent. 25 DETAILED DESCRIPTION In still another embodiment of the invention, the composi tions comprise an isoxazoline Compound B or Compound The present invention provides novel and inventive oral 1.001-1.025 or Compound 2.001-2018 described below. Veterinary compositions comprising at least one systemi In another embodiment, the compositions of the invention cally-acting parasiticide together with a pharmaceutically may include at least one isoxazoline active agent in combi 30 acceptable carrier or diluent. nation with one or more additional active agents. In one In one embodiment of the invention, the veterinary com embodiment, the composition may comprise at least one isox positions are in the form of a soft chewable composition. In aZoline active agent in combination with at least one macro another embodiment of the invention, the oral veterinary cyclic lactone active agent, including, but not limited to, an compositions are in the form of a chewable tablet. Each of the 35 compositions of the invention is palatable to the animal and avermectin or milbemycin compound. In some embodiments, provides for easy administration of the composition to the the avermectin or milbemycin active agent is eprinomectin, animal. These compositions provide Surprisingly effective ivermectin, Selamectin, abamectin, emamectin, latidectin, protection of the animals against parasites for an extended lepimectin, milbemectin, milbemycin D. milbemycin oxime, period of time, while also providing a fast onset of action. The or moxidectin, or a combination thereof. 40 compositions of the invention have been Surprisingly found to In one embodiment, the soft chewable compositions of the have an exceptionally high bioavailability with rapid absorp invention comprise one or more fillers, one or more flavoring tion of the active into the blood stream of the animal. The agents, one or more binders, one or more solvents, one or exceptional bioavailability of the compositions is the result of more Surfactants, one or more humectants and optionally an the combination of the non-active components of the compo antioxidant or a preservative. 45 sitions together with the properties of the active agent. In one It is an object of the invention to not encompass within the embodiment of the invention, the exceptionally high bioavail invention any previously known product, process of making ability of an isoxazoline active ingredient from the oral vet the product, or method of using the product such that the erinary compositions along with the intrinsic half-life of the Applicants reserve the right and hereby disclose a disclaimer active agent in the body and its potency provide for unparal of any previously known product, process, or method. It is 50 leled long lasting efficacy against ectoparasites from an oral further noted that the invention does not intend to encompass dosage form. This effect is quite Surprising and unexpected. within the scope of the invention any product, process, or Also provided are methods for the treatment and/or pro making of the product or method of using the product, which phylaxis of parasitic infections and infestations of animals, does not meet the written description and enablement require comprising administering an effective amount of an oral vet ments of the USPTO (35 U.S.C. S112, first paragraph) or the 55 erinary composition of the invention to the animal. The inven EPO (Article 83 of the EPC), such that Applicants reserve the tion also provides uses of the inventive compositions in the right and hereby disclose a disclaimer of any previously treatment and/or prophylaxis of parasitic infections and/in described product, process of making the product, or method festations and in the manufacture of a medicament for the of using the product. treatment and/or prophylaxis of parasitic infections and/or These and other embodiments are disclosed or are obvious 60 infestations in animals. from and encompassed by, the following Detailed Descrip The oral veterinary compositions of the invention include, tion. but are not limited to, soft chewable and chewable tablet compositions. The invention includes at least the following BRIEF DESCRIPTION OF THE DRAWINGS features: 65 (a) palatable oral veterinary compositions, including soft The following detailed description, given by way of chewable and chewable tablet compositions, that provide example, but not intended to limit the invention solely to the Superior efficacy against parasites comprising an effective US 9,259,417 B2 7 8 amount of at least one isoxazoline active agent together with tering an effective amount of an oral veterinary composition a pharmaceutically acceptable carrier or diluent; of the invention comprising at least one isoxazoline com (b) palatable oral veterinary compositions comprising an pound together with a pharmaceutically acceptable carrier or effective amount at least one isoxazoline active agent formula diluent; (I), formula (II), formula (III) or formula (IV) that provide (1) methods for the treatment and/or prevention of parasitic Surprisingly high plasma concentrations and bioavailability infections and infestations in an animal comprising adminis of the isoxazoline active agent; tering an effective amount of an oral veterinary composition (c) palatable oral veterinary compositions that exhibit of the invention comprising at least one isoxazoline of for Superior fast-acting efficacy that comprise an effective mula (I), formula (II), formula (III) or formula (IV), alone or amount of at least one isoxazoline compound of formula (I), 10 formula (II), formula (III) or formula (IV) described herein in combination with one or more macrocyclic lactones, one or together with a pharmaceutically acceptable carrier or dilu more spinosyn compounds, one or more spinosoid com ent; pounds, a benzimidazole, levamisole, pyrantel, morantel, (d) palatable oral veterinary compositions that exhibit praziquantel, closantel, clorSulon, one or more amino aceto Superior fast acting and long lasting efficacy that comprise an 15 nitrile active agent, one or more insect growth regulators, one effective amount of at least one isoxazoline Compound A. or more neonicotinoids, one or more arylpyrazoles, or one or Compound B, Compound 1.001-1.025 or Compound 2.001 more aryloazol-2-yl cyanoethylamino active agents, or a 2.018 described herein together with a pharmaceutically combination of thereof, together with a pharmaceutically acceptable carrier or diluent; acceptable carrier or diluent; (e) palatable oral Veterinary compositions comprising an (m) methods for the treatment and/or prevention of para effective amount of at least one isoxazoline active agent in sitic infections and infestations in an animal comprising combination with one or more macrocyclic lactones, one or administering to an animal an effective amount of an oral more spinosyn compounds, one or more spinosoid com Veterinary composition of the invention comprising at least pounds, a benzimidazole, levamisole, pyrantel, morantel, one isoxazoline Compound A. Compound B. Compound praziquantel, closantel, clorSulon, one or more amino aceto 25 1.001-1.025 or Compound 2.001-2018 described herein in nitrile active agent, one or more insect growth regulators, one combination with one or more macrocyclic lactone active or more neonicotinoids, one or more arylpyrazoles, or one or agents, together with a pharmaceutically acceptable carrier or more aryloazol-2-yl cyanoethylamino active agents, or a diluent; combination of thereof, in combination with a pharmaceuti (n) methods for the treatment and/or prevention of parasitic cally acceptable carrier or diluent; 30 infections and infestations in an animal comprising adminis (f) palatable oral veterinary compositions that exhibit tering an effective amount of an oral veterinary composition superior fast acting and long lasting efficacy that comprise an of the invention comprising at least one isoxazoline Com effective amount of at least one isoxazoline Compound A. pound A. Compound B, Compound 1.001-1.025 or Com Compound B, Compound 1.001-1.025 or Compound 2.001 pound 2.001-2.018, alone or in combination with one or more 2.018 described herein in combination with one or more 35 macrocyclic lactones, one or more spinosyn compounds, one macrocyclic lactone active agent, together with a pharmaceu or more spinosoid compounds, a benzimidazole, levamisole, tically acceptable carrier or diluent; pyrantel, morantel, praziquantel, closantel, clorSulon, one or (g) palatable oral Veterinary compositions, including soft more amino acetonitrile active agent, one or more insect chewable and chewable tablet compositions, comprising an growth regulators, one or more neonicotinoids, one or more effective amount of at least one systemically-active parasiti 40 arylpyrazoles, or one or more aryloazol-2-yl cyanoethy cide that is active against internal parasites together with a lamino active agents, or a combination of thereof, together pharmaceutically acceptable carrier or diluent. with a pharmaceutically acceptable carrier or diluent; (h) palatable oral Veterinary compositions, including soft (o) methods for the treatment and/or prevention of chewable and chewable tablet compositions, comprising an endoparasitic infections in an animal comprising administer effective amount of at least one systemically-active parasiti 45 ing an effective amount of an oral veterinary compositions, cide active agent that is active against internal parasites including soft chewable and chewable tablet compositions, selected from the group consisting of one or more macrocy comprising an effective amount of at least one systemically clic lactones, a benzimidazole, levamisole, pyrantel, moran active parasiticide active agent that is active against internal tel, praziquantel, closantel, clorSulon, one or more amino parasites selected from the group consisting of one or more acetonitrile active agent, and one or more aryloazol-2-yl cya 50 macrocyclic lactones, one or more benzimidazoles, levami noethylamino active agents, or a combination of thereof; sole, pyrantel, morantel, praziquantel, closantel, clorSulon, (i) a chewable oral composition comprising an isoxazoline one or more amino acetonitrile active agent and one or more active agent of formulae (I), (II), (III) or formula (IV) for use aryloazol-2-yl cyanoethylamino active agents, or a combina in the treatment or prophylaxis of a parasitic infection or tion of thereof infestation in an animal; 55 (p) use of oral veterinary compositions of the invention () a chewable oral composition comprising an effective comprising at least one isoxazoline compound of formula (I), amount of at least one systemically-acting active agent that is formula (II), formula (III) or formula (IV), alone or in com active against internal parasites selected from the group con bination with one or more macrocyclic lactones, one or more sisting of one or more macrocyclic lactones, one or more spinosyn compounds, one or more spinosoid compounds, a benzimidazoles, levamisole, pyrantel, morantel, praziquan 60 benzimidazole, levamisole, pyrantel, morantel, praziquantel, tel, closantel, clorSulon, one or more amino acetonitrile active closantel, clorSulon, one or more amino acetonitrile active agents and one or more aryloazol-2-yl cyanoethylamino agent, one or more insect growth regulators, one or more active agents, or a combination of thereof, for use in the neonicotinoids, one or more arylpyrazoles, or one or more treatment or prophylaxis of a parasitic infection or infestation aryloazol-2-yl cyanoethylamino active agents, or a combina in an animal; 65 tion of thereof, together with a pharmaceutically acceptable (k) methods for the treatment and/or prevention of parasitic carrier or diluent in the prevention or treatment of animal infections and infestations in an animal comprising adminis parasites: US 9,259,417 B2 9 10 (q) use of the oral veterinary compositions of the invention to elicit the desired biological response to the target comprising at least one of Compound A. Compound B, Com parasite(s) after administration of the composition to the ani pound 1.001 to 1.025 or Compound 2.001 to 2.018, alone or mal, as measured by methods known in the art and/or in combination with one or more macrocyclic lactones, one or described in the examples herein. In some embodiments, an more spinosyn compounds, one or more spinosoid com 5 “effective amount of the active agent in the composition will pounds, a benzimidazole, levamisole, pyrantel, morantel, provide an efficacy of at least 70% against the target parasite praziquantel, closantel, clorSulon, one or more amino aceto compared to an untreated control. In other embodiments, “an nitrile active agent, one or more insect growth regulators, one effective amount of the active agent will provide an efficacy or more neonicotinoids, one or more arylpyrazoles, or one or of at least 80%, or at least 85% compared to untreated con more aryloazol-2-yl cyanoethylamino active agents, or a 10 trols. More typically, “an effective amount of the active combination of thereof, together with a pharmaceutically agent will provide an efficacy of at least 90%, at least 93%, at acceptable carrier or diluent in the treatment and/or preven least 95% or at least 97% against the target parasite. In certain tion of a parasitic infestation and infections in an animal; embodiments, including the prevention of Dirofilaria immi (r) the use of an isoxazoline active agent of formulae (I), tis, the term “effective amount’ may provide efficacy as high (II), (III) or (IV) in the preparation of a chewable oral veteri 15 as 100%. nary composition for the treatment of a parasitic infection or As used herein, the terms "systemically-acting or “sys infestation in an animal; temically active' will be understood to mean that the active (s) use of the oral veterinary compositions of the invention compounds are active when administered orally and may be comprising at least one systemically-acting active agent that distributed through the plasma and/or tissues of the animal is active against internal parasites selected from the group treated and act on the parasite when a blood meal is taken or consisting of one or more macrocyclic lactones, one or more when the parasite comes in contact with the active agent. benzimidazoles, levamisole, pyrantel, morantel, praziquan As used herein, the term "amylaceous ingredients' is tel, closantel, clorSulon, one or more amino acetonitrile active meant those food-stuffs containing a preponderance of starch agent, and one or more aryloazol-2-yl cyanoethylamino and/or starch-like material. Examples of amylaceous ingre active agents, or a combination of thereof, together with a 25 dients are cereal grains and meals or flours obtained upon pharmaceutically acceptable carrier or diluent in the treat grinding cereal grains such as corn, oats, wheat, milo, barley, ment and/or prevention of a parasitic infection in an animal; rice, and the various milling by-products of these cereal or a combination thereof, and grains such as wheat feed flour, wheat middlings, mixed feed, (t) the use of at least one systemically-active parasiticide wheat shorts, wheat red dog, oat groats, hominy feed, and active agent that is active against internal parasites selected 30 other Such material. Also included as sources of amylaceous from the group consisting of one or more macrocyclic lac ingredients are the tuberous food stuffs such as potatoes, tones, one or more benzimidazoles, levamisole, pyrantel, tapioca, and the like. morantel, praziquantel, closantel, clorSulon, one or more As used herein the term “palatable' means an oral veteri amino acetonitrile active agents, and one or more aryloazol nary composition that is readily accepted by dogs without any 2-yl cyanoethylamino active agents, or a combination of 35 coaxing or with limited coaxing. Palatable compositions are thereof, in the in the preparation of a chewable oral veterinary compositions that are consumed by at least 75% of dogs composition for the treatment of a parasitic infection or infes without manual administration of the composition. tation in an animal. The term “alkyl refers to saturated straight, branched, In this disclosure and in the claims, terms such as "com cyclic, primary, secondary or tertiary hydrocarbons, includ prises.” “comprising.” “containing and “having and the like 40 ing those having 1 to 20 atoms. In some embodiments, alkyl can have the meaning ascribed to them in U.S. Patent law and groups will include C1-C12, C1-Co C-Cs. C-C or C1-C4 can mean “includes.” “including, and the like; 'consisting alkyl groups. Examples of C-C alkyl include, but are not essentially of or “consists essentially” likewise has the limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-me meaning ascribed in U.S. patent law and the term is open thylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-me ended, allowing for the presence of more than that which is 45 thylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpro recited so long as basic or novel characteristics of that which pyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1.2- is recited is not changed by the presence of more than that dimethylpropyl. 1-methylpentyl, 2-methylpentyl, which is recited, but excludes prior art embodiments. 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1.2- dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2.3- DEFINITIONS 50 dimethylbutyl, 3.3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1.1.2-trimethylpropyl, 1.2.2-trimethylpropyl. 1-ethyl-1-me Terms used herein will have their customary meaning in thylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethyl the art unless specified otherwise. The organic moieties men hexyl, nonyl and decyl and their isomers. C-C-alkyl means tioned in the definitions of the variables of formula (I) are— for example methyl, ethyl, propyl, 1-methylethyl, butyl, like the term halogen—collective terms for individual listings 55 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. of the individual group members. The prefix C-C, indicates Cyclic alkyl groups or “cycloalkyl, which are encom in each case the possible number of carbon atoms in the passed by alkyl include those with 3 to 10 carbon atoms group. having single or multiple condensed rings. In some embodi The term “animal' is used herein to include all mammals, ments, cycloalkyl groups include C-C, or C-C cyclic alkyl birds and fish and also include all vertebrate animals. Animals 60 groups. Non-limiting examples of cycloalkyl groups include include, but are not limited to, cats, dogs, cattle, chickens, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, turkeys, deer, goats, horses, llamas, pigs, sheep, yaks, rodents cycloheptyl, cyclooctyl and the like. and birds. It also includes an individual animal in all stages of The alkyl groups described herein can be unsubstituted or development, including embryonic and fetal stages. In some substituted with one or more moieties selected from the group embodiments, the animal will be a non-human animal. 65 consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, The expression “effective amount’ as used herein means a acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, concentration of the active agent in the composition Sufficient alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, Sulfonic US 9,259,417 B2 11 12 acid, Sulfate, Sulfonyl, Sulfanyl, Sulfinyl, Sulfamonyl, ester, 10 carbon atoms and containing at least one triple bond. Such phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl. n-but-1-yn-1-yl, thioether, acid halide, anhydride, oxime, hydrazine, carbam n-but-1-yn-3-yl. n-but-1-yn-4-yl. n-but-2-yn-1-yl, n-pent-1- ate, phosphonic acid, phosphate, phosphonate, or any other yn-1-yl. n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5- viable functional group that does not inhibit the biological yl. n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, activity of the compounds of the invention, either unpro 3-methylbut-1-yn-3-yl 3-methylbut-1-yn-4-yl, n-hex-1-yn tected, or protected as necessary, as known to those skilled in 1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, the art, for example, as taught in Greene, et al., Protective n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2- Groups in Organic Synthesis, John Wiley and Sons. Third yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, Edition, 1999, hereby incorporated by reference. 10 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl 3-methyl Terms including the term “alkyl such as “alkylcy cloalkyl.” “cycloalkylalkyl.” “alkylamino,” or “dialky pent-1-yn-4-yl, 3-methylpent-1-yn-5-yl 4-methylpent-1-yn lamino” will be understood to comprise an alkyl group as 1-yl 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and defined above linked to the other functional group, where the the like. group is linked to the compound through the last group listed, 15 The term “haloalkyl refers to an alkyl group, as defined as understood by those of skill in the art. herein, which is Substituted by one or more halogen atoms. The term “alkenyl refers to both straight and branched For example C-C-haloalkyl includes, but is not limited to, carbon chains which have at least one carbon-carbon double chloromethyl, bromomethyl, dichloromethyl, trichlorom bond. In some embodiments, alkenyl groups may include ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorof C-C alkenyl groups. In other embodiments, alkenyl luoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, includes C-C, C-Co C-Cs. C-C or C-C alkenyl 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl 2-fluoroethyl, groups. In one embodiment of alkenyl, the number of double 2,2-difluoroethyl, 2.2.2-trifluoroethyl, 2-chloro-2-fluoroet bonds is 1-3, in another embodiment of alkenyl, the number hyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, of double bonds is one or two. Other ranges of carbon-carbon 2.2.2-trichloroethyl, pentafluoroethyl and the like. double bonds and carbon numbers are also contemplated 25 The term “haloalkenyl refers to an alkenyl group, as depending on the location of the alkenyl moiety on the mol defined herein, which is substituted by one or more halogen ecule. "C-Co-alkenyl groups may include more than one atOmS. double bond in the chain. Examples include, but are not The term “haloalkynyl refers to an alkynyl group, as limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethe defined herein, which is substituted by one or more halogen nyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 30 atOmS. 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-pro “Alkoxy' refers to alkyl-O , wherein alkyl is as defined penyl: 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-me above. Similarly, the terms “alkenyloxy.” “alkynyloxy.” thyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, “haloalkoxy.” “haloalkenyloxy.” “haloalkynyloxy.” 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-bute “cycloalkoxy.” “cycloalkenyloxy.” “halocycloalkoxy.” and nyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3- 35 “halocycloalkenyloxy' refer to the groups alkenyl-O , alky butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, nyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, 1.2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-pro cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and penyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hex halocycloalkenyl-O-, respectively, wherein alkenyl, alky enyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl nyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, 1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 40 cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pen defined above. Examples of C-C-alkoxy include, but are not tenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl limited to, methoxy, ethoxy, CH, CHO—, (CH) 3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, CHO n-butoxy, CH, CH(CH)O (CH) CH 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pen CHO—, (CH)CO—, n-pentoxy, 1-methylbutoxy, 2-meth tenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1.2- 45 ylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dim dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl ethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, 3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpen 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dim toxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbu ethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3- toxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimeth butenyl, 3.3-dimethyl-1-butenyl, 3.3-dimethyl-2-butenyl, 50 ylbutoxy, 3.3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1.1.2-trimethylpropoxy, 1.2.2-trimethylpropoxy, 1-ethyl-1- 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1.1, methylpropoxy, 1-ethyl-2-methylpropoxy and the like. 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, The term “alkylthio’ refers to alkyl-S , wherein alkyl is 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-prope as defined above. Similarly, the terms “haloalkylthio.” nyl. 55 “cycloalkylthio.” and the like, refer to haloalkyl-S and Alkynyl refers to both straight and branched carbon cycloalkyl-S where haloalkyl and cycloalkyl areas defined chains which have at least one carbon-carbon triple bond. In above. one embodiment of alkynyl, the number of triple bonds is 1-3: The term “alkylsulfinyl refers to alkyl-S(O)—, wherein in another embodiment of alkynyl, the number of triple bonds alkyl is as defined above. Similarly, the term “haloalkylsulfi is one or two. In some embodiments, alkynyl groups include 60 nyl refers to haloalkyl-S(O)— where haloalkyl is as defined from C-C alkynyl groups. In other embodiments, alkynyl above. groups may include C2-C2, C-Co., C2-Cs. C-C or C-Ca The term “alkylsulfonyl refers to alkyl-S(O)—, wherein alkynyl groups. Other ranges of carbon-carbon triple bonds alkyl is as defined above. Similarly, the term “haloalkylsul and carbon numbers are also contemplated depending on the fonyl refers to haloalkyl-S(O) where haloalkyl is as location of the alkenyl moiety on the molecule. For example, 65 defined above. the term "C-Co-alkynyl as used herein refers to a straight The term alkylamino and dialkylamino refer to alkyl chain or branched unsaturated hydrocarbon group having 2 to NH and (alkyl)-N where alkyl is as defined above. Simi US 9,259,417 B2 13 14 larly, the terms “haloalkylamino” refers to haloalkyl-NH thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, where haloalkyl is as defined above. furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, pip The terms “alkylcarbonyl.” “alkoxycarbonyl.” “alkylami erazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyr nocarbonyl, and “dialkylaminocarbonyl refer to alkyl-C rolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, (O)—, alkoxy-C(O)—, alkylamino-C(O)— and dialky pyrazinyl, pyrimidinyl, pyridaZinyl, tetrahydropyranyl, mor lamino-C(O)— where alkyl, alkoxy, alkylamino and pholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thia dialkylamino are as defined above. Similarly, the terms morpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-di “haloalkylcarbonyl.” “haloalkoxycarbonyl. “haloalkylami oXothienyl, triazolyl, triazinyl, and the like. nocarbonyl, and “dihaloalkylaminocarbonyl refer to the Exemplary bicyclic heterocyclic groups include, but are groups haloalkyl-C(O)—, haloalkoxy-C(O)—, haloalky 10 not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzo lamino-C(O)— and dihaloalkylamino-C(O)— where dioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hy haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino droisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyra are as defined above. nyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, Aryl refers to a monovalent aromatic carbocyclic group benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl pyrrol of from 6 to 14 carbonatoms having a single ring or multiple 15 condensed rings. In some embodiments, aryl groups include opyridyl, furopyridinyl (such as furo2.3-cpyridinyl, furo3, Co-Co aryl groups. Aryl groups include, but are not limited 2-bipyridinyl or furoI2,3-bipyridinyl), dihydroisoindolyl, to, phenyl, biphenyl, naphthyl, tetrahydronaphtyl, phenylcy dihydroquinazolinyl (Such as 3,4-dihydro-4-oxo-quinazoli clopropyl and indanyl. Aryl groups may be unsubstituted or nyl), tetrahydroquinolinyl and the like. Substituted by one or more moieties selected from halogen, Exemplary tricyclic heterocyclic groups include carba cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alky Zolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridi nyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, nyl, Xanthenyl, and the like. haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alk Halogen means the atoms fluorine, chlorine, bromine and enyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalky iodine. The designation of “halo' (e.g. as illustrated in the nyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, 25 term haloalkyl) refers to all degrees of substitutions from a halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalky single Substitution to a perhalo Substitution (e.g. as illustrated lthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alky with methyl as chloromethyl ( CHCl), dichloromethyl nyl-sulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalky (—CHCl), trichloromethyl ( CC1)). nylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, Stereoisomers and Polymorphic Forms haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfo 30 nyl, alkylamino, alkenylamino, alkynylamino, di(alkyl) It will be appreciated by those of skill in the art that certain amino, di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl. compounds within the compositions of the invention may The term “aralkyl refers to an aryl group that is bonded to exist and be isolated as optically active and racemic forms. the parent compound through a diradical alkylene bridge, Compounds having one or more chiral centers, including at a (—CH ), where n is 1-12 and where “aryl” is as defined 35 Sulfur atom, may be present as single enantiomers or diaste above. reomers or as mixtures of enantiomers and/or diastereomers. “Heteroaryl” refers to a monovalent aromatic group of For example, it is well known in the art that compounds from 1 to 15 carbon atoms, preferably from 1 to 10 carbon containing a Sulfoxide functional group may be optically atoms, having one or more oxygen, nitrogen, and Sulfur het active and may exist as single enantiomers or racemic mix eroatoms within the ring, preferably 1 to 4 heteroatoms, or 1 40 tures. In addition, compounds within the compositions of the to 3 heteroatoms. The nitrogen and Sulfur heteroatoms may invention may include one or more chiral centers, which optionally be oxidized. Such heteroaryl groups can have a results in a theoretical number of optically active isomers. single ring (e.g., pyridyl or furyl) or multiple condensed rings Where compounds within the compositions of the invention provided that the point of attachment is through a heteroaryl include n chiral centers, the compounds may comprise up to ring atom. Preferred heteroaryls include pyridyl, piridazinyl, 45 2'' optical isomers. The present invention encompasses the pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinoli specific enantiomers or diastereomers of each compound as nyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl. well as mixtures of different enantiomers and/or diastere thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, omers of the compounds of the invention that possess the isothiazolyl pyrazolyl benzofuranyl, and benzothiophenyl. useful properties described herein. The optically active forms Heteroaryl rings may be unsubstituted or substituted by one 50 can be prepared by, for example, resolution of the racemic or more moieties as described for aryl above. forms by selective crystallization techniques, by synthesis “Heterocyclyl,” “heterocyclic” or "heterocyclo” refer to from optically active precursors, by chiral synthesis, by chro fully Saturated or unsaturated, cyclic groups, for example, 3 to matographic separation using a chiral stationary phase or by 7 membered monocyclic or 4 to 7 membered monocyclic; 7 to enzymatic resolution. 11 membered bicyclic, or 10 to 15 membered tricyclic ring 55 systems, which have one or more oxygen, Sulfur or nitrogen The compounds within the compositions of present inven heteroatoms in ring, preferably 1 to 4 or 1 to 3 heteroatoms. tion may also be present in different solid forms such as The nitrogen and Sulfur heteroatoms may optionally be oxi different crystalline forms or in the form of an amorphous dized and the nitrogen heteroatoms may optionally be quat Solid. The present invention encompasses different crystal ernized. The heterocyclic group may be attached at any het 60 line forms as well as amorphous forms of the inventive com eroatom or carbonatom of the ring or ring system and may be pounds. unsubstituted or substituted by one or more moieties as In addition, the compounds within the compositions of the described for aryl groups above. invention may exist as hydrates or Solvates, in which a certain Exemplary monocyclic heterocyclic groups include, but Stoichiometric amount of water or a solvent is associated with are not limited to, pyrrolidinyl, pyrrolyl pyrazolyl, oxetanyl. 65 the molecule in the crystalline form. The compositions of the pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, invention may include hydrates and Solvates of the active oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, agents. US 9,259,417 B2 15 16 Salts R" is alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkylor Also contemplated within the scope of the invention are cycloalkylalkyl, each optionally substituted with one or more acid or base salts, where applicable, of the compounds of the substituents independently selected from R: invention provided for herein. each R is independently H, halogen, alkyl, haloalkyl, The term “acid contemplates all pharmaceutically accept alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, able inorganic or organic acids. Inorganic acids include min haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alky eral acids such as hydrohalic acids such as hydrobromic acid lamino, dialkylamino, alkoxycarbonyl. —CN or —NO; and hydrochloric acid, Sulfuric acid, phosphoric acids and each R is independently H, halogen, alkyl, haloalkyl, nitric acid. Organic acids include all pharmaceutically cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio. acceptable aliphatic, alicyclic and aromatic carboxylic acids, 10 haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, dicarboxylic acids, tricarboxylic acids, fatty acids and Sul haloalkylsulfonyl, alkylamino, dialkylamino, —CN or fonic acids. In one embodiment of the acids, the acids are —NO; straight chain or branched, saturated or unsaturated C-Co R" is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcy aliphatic carboxylic acids, which are optionally Substituted cloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl: by halogen or by hydroxyl groups, or C-C aromatic car 15 R is H, OR', NR'R' or Q"; or alkyl, alkenyl, alkynyl, boxylic acids. Examples of Such acids are carbonic acid, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each option formic acid, acetic acid, propionic acid, isopropionic acid, ally substituted with one or more substituents independently Valeric acid, C-hydroxy acids such as glycolic acid and lactic selected from R'; or acid, chloroacetic acid, benzoic acid, and salicylic acid. R" and Rare taken together with the nitrogen to which Examples of dicarboxylic acids include oxalic acid, malic they are attached to form a ring containing 2 to 6 atoms of acid, Succinic acid, tartaric acid, fumaric acid, and maleic carbon and optionally one additional atom selected from the acid. An example of a tricarboxylic acid is citric acid. Fatty group consisting of N, S and O, said ring optionally Substi acids include all pharmaceutically acceptable Saturated or tuted with 1 to 4 substituents independently selected from the unsaturated aliphatic or aromatic carboxylic acids having 4 to 25 group consisting of alkyl, halogen, —CN.—NO and alkoxy; 24 carbon atoms. Examples include butyric acid, isobutyric each R is independently halogen, alkyl, alkoxy, alkylthio. acid, sec-butyric acid, lauric acid, palmitic acid, Stearic acid, alkylsulfinyl, alkylsulfonyl, —CN or - NO; oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. each R is independently halogen; alkyl, cycloalkyl, Other acids include gluconic acid, glycoheptonic acid and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, 30 dialkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbo lactobionic acid. Sulfonic acids include alkyl or haloalkylsul nyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkyl fonic acids and arylsulfonic acids including, but not limited to carbonyl, halo alkoxycarbonyl, haloalkylaminocarbonyl, methane Sulfonic acid, ethane Sulfonic acid, benzenesulfonic dihaloalkylaminocarbonyl, hydroxy, NH, —CN or acid and naphthalenesulfonic acid, among others. - NO; or Q: The term “base' contemplates all pharmaceutically accept 35 each R is independently halogen, alkoxy, haloalkoxy, able inorganic or organic bases, including hydroxides, car alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, bonates or bicarbonates of alkali metal or alkaline earth met alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, als. Salts formed with such bases include, for example, the alkoxycarbonyl, —CN or - NO; alkali metal and alkaline earth metal salts, including, but not each R is independently halogen, alkyl, haloalkyl, limited to, as the lithium, Sodium, potassium, magnesium or 40 cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio. calcium salts. Salts formed with organic bases include the haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, common hydrocarbon and heterocyclic amine salts, which haloalkylsulfonyl, alkylamino, dialkylamino. —CN. —NO. include, for example, ammonium salts (NH4), alkyl- and phenyl or pyridinyl; dialkylammonium salts, and salts of cyclic amines such as the R" is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcy morpholine and piperidine salts. 45 cloalkyl or cycloalkylalkyl, each optionally substituted with In one embodiment, the invention provides a soft chewable one of more halogen; Veterinary composition comprising an effective amount of at R'' is H. alkyl, alkenyl, alkynyl, cycloalkyl, alkylcy least one isoxazoline compound of formula (I) below in com cloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl: bination with a pharmaceutically or veterinarily acceptable R'' is H; Q; or alkyl, alkenyl, alkynyl, cycloalkyl, alkyl carrier: 50 cycloalkyl or cycloalkylalkyl, each optionally Substituted with one or more substituents independently selected from R7; or (I) R'' and R'' are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of 55 carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally Substi tuted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, —CN.—NO and alkoxy; Q" is a phenyl ring, a 5- or 6-membered heterocyclic ring, 60 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 wherein optionally substituted with one or more substituents indepen A, A, A, A, A and A are independently CR or N, dently selected from R: provided that at most 3 of A, A, A, A, A and Aare N: 65 each Q is independently a phenyl ring or a 5- or 6-mem B', B and Bare independently CR or N: bered heterocyclic ring, each ring optionally Substituted with W is O or S; one or more substituents independently selected from R: US 9,259,417 B2 17 18 Q is a phenyl ring or a 5- or 6-membered heterocyclic ring, haloalkoxycarbonyl, C-C, haloalkylaminocarbonyl, C-Co each ring optionally Substituted with one or more Substituents dihaloalkylaminocarbonyl, hydroxy, NH, —CN or independently selected from R; and - NO; or Q: n is 0, 1 or 2. each R is independently halogen, C-C alkoxy, C-C, In another embodiment, the invention provides soft chew haloalkoxy, C-C alkylthio, C-C haloalkylthio, C-C, able veterinary compositions comprising an effective amount alkylsulfinyl, C-C haloalkylsulfinyl, C-C alkylsulfonyl, of at least one isoxazoline of formula (I) in combination with C-C haloalkylsulfonyl, C-C alkylamino, C-C dialky lamino, C-C alkoxycarbonyl, —CN or NO; a pharmaceutically or veterinarily acceptable carrier: each R is independently halogen, C-C alkyl, C-C, 10 haloalkyl, C-C cycloalkyl, C-C halocycloalkyl, C-C, alkoxy, C-C haloalkoxy, C-C alkylthio, C-C haloalky (I) lthio, C-C alkylsulfinyl, C-C haloalkylsulfinyl, C-C, alkylsulfonyl, C-C haloalkylsulfonyl, C-C alkylamino, C-C dialkylamino. —CN. —NO phenyl or pyridinyl: 15 R" is H; or C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, C-C, alkylcycloalkyl or C-C, cycloalky lalkyl, each optionally substituted with one of more halogen; R'' is H. C-C alkyl, C-C alkenyl, C-C alkynyl, C-C, cycloalkyl, Ca-C, alkylcycloalkyl, C-C, cycloalkylalkyl, C-C, alkylcarbonyl or C-C, alkoxycarbonyl: R'' is H; Q; or C-C alkyl, C-C alkenyl, C-C alkynyl, wherein: C-C cycloalkyl, Ca-C, alkylcycloalkyl or C-C, cycloalky A, A, A, A, A and A are independently CR or N, lalkyl, each optionally substituted with one or more substitu provided that at most 3 of A, A, A, A, A and Aare N: ents independently selected from R'; or B', B and Bare independently CR or N: 25 R'' and R'' are taken together with the nitrogen to which W is O or S; they are attached to form a ring containing 2 to 6 atoms of R" is C-C alkyl, C-C alkenyl, C-C alkynyl, Cs-Co carbon and optionally one additional atom selected from the cycloalkyl, C-C, alkylcycloalkyl or C-C, cycloalkylalkyl, group consisting of N, S and O, said ring optionally Substi each optionally substituted with one or more substituents tuted with 1 to 4 substituents independently selected from the independently selected from R: 30 group consisting of C-C alkyl, halogen, —CN. —NO and each R is independently H, halogen, C-C alkyl, C-C, C-Calkoxy; haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkylthio. Q" is a phenyl ring, a 5- or 6-membered heterocyclic ring, C-C haloalkylthio, C-C alkylsulfinyl, C-C haloalkyl or an 8-, 9- or 10-membered fused bicyclic ring system sulfinyl, C-C alkylsulfonyl, C-Chaloalkylsulfonyl, C-C, optionally containing one to three heteroatoms selected from alkylamino, C-C dialkylamino, C-C alkoxycarbonyl, 35 up to 1 O. up to 1 S and up to 3 N, each ring or ring system —CN or - NO; optionally substituted with one or more substituents indepen each R is independently H, halogen, C-C alkyl, C-C, dently selected from R: haloalkyl, C-C cycloalkyl, C-C halocycloalkyl, C-C, each Q is independently a phenyl ring or a 5- or 6-mem alkoxy, C-C haloalkoxy, C-C alkylthio, C-C haloalky bered heterocyclic ring, each ring optionally Substituted with 40 one or more substituents independently selected from R: lthio, C-C alkylsulfinyl, C-C haloalkylsulfinyl, C-C, Q is a phenyl ring or a 5- or 6-membered heterocyclic ring, alkylsulfonyl, C-C haloalkylsulfonyl, C-C alkylamino, each ring optionally Substituted with one or more Substituents C-C dialkylamino, —CN or - NO; independently selected from R. and R" is H. C-C alkyl, C-C alkenyl, C-C alkynyl, C-C, n is 0, 1 or 2. cycloalkyl, Ca-C, alkylcycloalkyl, C-C, cycloalkylalkyl, 45 In one embodiment of formula (I), W is O. In another C-C, alkylcarbonyl or C-C, alkoxycarbonyl: embodiment, W is S. R is H, OR, NR'R' or Q'; or C-C alkyl, C-C, In another embodiment of formula (I), A', A, A, A, A alkenyl, C-C alkynyl, C-C cycloalkyl, Ca-C, alkylcy and Aare each CR. cloalkyl or C-C, cycloalkylalkyl, each optionally substituted In another embodiment of formula (I), B, B and B are with one or more substituents independently selected from 50 each CR. R"; or In still another embodiment of formula (I), W is O and A', R and R are taken together with the nitrogen to which A, A, A, A and Aare each CR. they are attached to form a ring containing 2 to 6 atoms of In yet another embodiment of formula (I), W is O; A', A, carbon and optionally one additional atom selected from the A, A, A and Aare each CR; and B, B and B are each group consisting of N, S and O, said ring optionally Substi 55 CR2. tuted with 1 to 4 substituents independently selected from the In another embodiment of formula (I), A', A, A, A, A group consisting of C-C alkyl, halogen, —CN, —NO and and Aare each CH. C-C alkoxy; In another embodiment of formula (I), B, B and B are each R is independently halogen, C-C alkyl, C-C, each CR; and R is H. halogen, C-C alkyl or C-C, alkoxy, C-C alkylthio, C-C alkylsulfinyl, C-C alkylsul 60 haloalkyl. fonyl, —CN or - NO; In still another embodiment of formula (I), R is C-C, each R" is independently halogen; C1-C alkyl, Cs-Co alkyl optionally substituted by one or more of R: cycloalkyl, C-C alkoxy, C-C alkylthio. C-C alkylsulfi R is independently H, halogen, C-C haloalkyl, nyl, C-C alkylsulfonyl, C-C alkylamino, C-Cs dialky C-Chaloalkoxy or —CN; and lamino, C-C cycloalkylamino, C-C, alkylcarbonyl, C-C, 65 each R is independently H, halogen, C-C alkyl, C-C, alkoxycarbonyl, C-C, alkylaminocarbonyl, C-Co dialky haloalkyl, C-C cycloalkyl, C-C halocycloalkyl, laminocarbonyl, C-C, haloalkylcarbonyl, C-C, C-Calkoxy, C-Chaloalkoxy, —CN or —NO. US 9,259,417 B2 19 20 In still another embodiment, the invention provides a soft R is C-C alkyl optionally substituted with one or more chewable veterinary composition comprising an isoxazoline R"; and of formula (I) wherein: R’ is C-C, alkylaminocarbonyl, Cs-Co dialkylaminocar W is O or S.; R is H or C-C alkyl; R is —CHC(O) bonyl, C-C, haloalkylaminocarbonyl or C-C dihaloalky NHCHCF.: each of A =A=A=A=A=A is CH: laminocarbonyl. R" is C-C alkyl each optionally substituted with one or more substituents independently selected from R: In a preferred embodiment, a soft chewable veterinary com R is halogen or C-C alkyl; and position comprising an isoxazoline active agent of formula (I) B', B, and B are independently CH, C-halogen, C. C is provided, wherein: Calkyl, C-C-Chaloalkyl, or C-C-C alkoxy. 10 R is CF; In another embodiment of formula (I), B, B and B are independently CR; W is O: W is O: A, A, A, A, A and Aare each CH: R is H. C-C alkyl, C-C, alkylcarbonyl or C-C, alkoxy B is CH: carbonyl; and 15 B' is chloro; R is H, NR'R' or Q"; or C-C alkyl, C-C alkenyl, B is CF3; C-C alkynyl, C-C cycloalkyl, C-C, alkylcycloalkyl or C-C cycloalkylalkyl, each optionally Substituted with one R is H: or more of R7. R is CHC(O)NHCHCF; and In still another embodiment of formula (I), R is C-C, n is 2. alkyl optionally substituted with halogen; In one embodiment, the invention provides soft chewable each R is independently H, CFs, OCF, halogen or—CN: Veterinary compositions comprising an effective amount of each R is independently H, C-C alkyl, C-Chaloalkyl, the isoxazoline compound 1-4-5-3-chloro-5-(trifluorom C-C cycloalkyl, C-C alkoxy or —CN; and 25 ethyl)phenyl-4,5-dihydro-5-(trifluoromethyl)-3-isox each R" is independently halogen, C-C alkyl, C-C, azolyl-N-(2-oxo-2-(2.2.2-trifluoroethyl)aminoethyl-1- alkoxy, C-C alkylthio, C-C alkylsulfinyl, C-C alkylsul naphthalenecarboxamide (Compound A). This compound fonyl, C-C alkylcarbonyl, C-C alkoxycarbonyl, C-Cs alkylaminocarbonyl, C-Cs haloalkylcarbonyl, C-Cs has the following structure: haloalkoxycarbonyl, C-Cs haloalkylaminocarbonyl, 30 —NH, —CN or NO2; or Q. Compound A In yet another embodiment of formula (I), R is H: R is C-C alkyl optionally substituted with one or more C O-N O R7; FC \ /NCF, each R" is independently halogen or Q; and 35 each Q is independently phenyl, pyridinyl orthiazolyl. In still another embodiment of formula (I), R is CF; O A, A, A, A, A and Aare each CR; FC B is CR; and 40 each R is independently H, C-C alkyl or CN. In another embodiment, B is CH: In other embodiments, the invention provides soft chew B' and B are each CR where each R is independently able veterinary compositions comprising an effective amount halogen or C-C haloalkyl, of an isoxazoline active agent described in WO 2009/ A, A, A, A, A and Aare each CR; 45 02451A2 and US 2011/0059988, both incorporated herein by R is H; and reference in their entirety, in combination with a pharmaceu n is 2. tically acceptable carrier or diluent. The compounds of gen In still another embodiment of formula (I), R is CF; eral formula (II) shown below are described in US 2011/ A, A, A, A, A and Aare each CR: O059988 and WO 2009/O2451 A2. B is CH: 50 each of B' and B are CR; each R is independently H or C-C alkyl; Formula (II) each R is independently halogen or C-Chaloalkyl; R is H: R is C-C alkyl optionally substituted with one or more 55 R7; and R’ is C-C, alkylcarbonyl, C-C, alkoxycarbonyl, C-C, alkylaminocarbonyl, C-C dialkylaminocarbonyl, C-C, haloalkylcarbonyl, C-C, haloalkoxycarbonyl, C-C, 60 haloalkylaminocarbonyl, C-Co dihaloalkylaminocarbonyl. In yet another embodiment of formula (I), R' is CF; A, A, A, A, A and Aare each CH: In still another embodiment, the invention provides soft B is CH: chewable veterinary compositions comprising an effective each of B' and B are CR: 65 amount of compound 11-1 described in US 2011/0059988, each R is independently halogen or C-Chaloalkyl; which is referred to as Compound Bherein and has the struc R is H: ture:

US 9,259,417 B2 23 24 of administration. Furthermore, in some embodiments the

Formula (IV) compositions of the invention provide extremely long-lasting efficacy against ectoparasites and/or endoparasites that is unexpected and Surprising from an immediate release oral dosage form. In one embodiment, the soft chewable compositions of the invention provide exceptionally high bioavailability for sys temically-acting isoxazoline active agents. The Surprisingly high bioavailability of the isoxazoline active agents achieved 10 from the compositions of the invention is a key factor in achieving the fast onset of action and the very long lasting efficacy against ectoparasites observed. R In order for the compositions of the invention to be effica O cious against ectoparasites such as ticks and fleas for an R 16 15 extended period of time, the isoxazoline active agent must be present at a minimally effective concentration in the plasma and/or tissues of the animal for the desired period of time. The TABLE 2

Compounds 2.001 to 2.018

Compound MS RT LCMS No. (Z), B3 B4 B3 B2 BI RIS R 16 MH' (min) Method 2001 3,5-C1, C-H C-H N C H C H H CHC(O)NHCHCF 2002 3,5-C1, C-H C-H N C H C H H CHCF 2003 3,5-C1, C-H C-H N C H C H H CHCH-SCH 2.004 3,5-(CF), C-H C-H N C H C H H CHC(O)NHCHCF, 650 1.85 1 2.005 3.5-(CF), C H C-H N C H C H H CHCF 2.006 3.5-(CF), C H C-H N C H C H H CHCH-SCH 2.007 3-Cl, 5-CF C H C-H N C H C H H CHC(O)NHCHCF 2.008 3-C1, 5-CF, C-H C-H N C H C H H CHCF 2.009 3-Cl, 5-CF C H C-H N C H C H H CHCH-SCH 2010 3,5-C1, C-H C H C H C H C H H CHC(O)NHCHCF, 2011 3,5-C1, C-H C H C H C H C H H CHCF 2012 3,5-C1, C-H C H C H C H C-H H CHCH-SCH, 2.013 3,5-(CF), C H C H C H C H C H H CHC(O)NHCHCF 2.014 3,5-(CF), C H C H C H C H C H H CHCF 2.015 3.5-(CF), C H C H C H C H C H H CHCH-SCH 2.016 3-Cl, 5-CF C H C H C H C H C H H CHC(O)NHCHCF 2.017 3-Cl, 5-CF C H C H C H C H C H H CHCF 2.018 3-Cl, 5-CF C H C H C H C H C H H CHCH-SCH

40 In another embodiment, the soft chewable veterinary com- time that the active agent remains in the systemic circulation positions of the invention may include one or more com- (measured as half-life or T, the period of time it takes for pounds of the isoxazolines disclosed in US 2010/0254960 the amount of active agent undergoing decay to decrease by A1, US2011/0159107, US2012/0309620, US2012/0030841, 45 half) is based on the intrinsic structure of the compound and US2010/0069247, WO 2007/125984, WO 2012/08.6462, how it behaves in vivo. However, the amount of the active U.S. Pat. No. 8,318,757, US 2011/0144349, U.S. Pat. No. agent that is absorbed into the systemic circulation from an 8,053,452: US 2010/0137612, US 2010/0254959, US 2011/ oral dosage form may be significantly affected by the non 152081, WO 2012/089623, WO 2012/089622, U.S. Pat. No. active excipients of the composition. As such, the specific 8,119,671; U.S. Pat. No. 7,947,715; WO 2102/120135, WO so combination of non-active excipients in a composition can 2012/107533, WO 2011/157748, US 2011/0245274, US have a major effect on the bioavailability of a given active 2011/0245239, US 2012/0232026, US 2012/0077765, US agent. 2012/0035122, US 2011/0251247, WO 2011/154433, WO In order for an active ingredient to be readily bioavailable 2011/154434, US 2012/0238517, US 2011/0166193, WO and absorbed from the gastrointestinal lumen into the blood 2011/104088, WO 2011/104087, WO 2011/104089, US 55 stream of the animal, the active agent must first be effectively 2012/015946, US 2009/0143410, WO 2007/123855A2, US released from the Solid composition after ingestion. Sec 2011/01 18212, U.S. Pat. No. 7,951,828 & U.S. Pat. No. ondly, in the case of active agents with low water solubility, 7,662,972, US 2010/0137372A1, US 2010/01791.94 A2, US the active agent must be maintained in solution at the appro 2011/0086886A2, US 2011/0059988 A1, US 2010/01791.95 priate location in the gastrointestinal lumen to be absorbed A1, U.S. Pat. No. 7,897,630, U.S. Pat. No. 7,951,828 and U.S. 60 across the intestinal epithelium and into the bloodstream. Pat. No. 7,662.972, all of which are incorporated herein by Both of these factors can be significantly affected by the reference in their entirety. combination of non-active excipients in the oral dosage Bioavailability of Active Agents forms. It has been Surprisingly found that the compositions of the It is well known that one of the drawbacks of oral dosage invention provide exceptionally high bioavailability for the 65 forms is that the amount of the drug that can be absorbed from systemically-acting active agents in the blood of the animal to the digestive tract into the systemic circulation is limited. In which the compositions are administered within a few hours fact, it is well established in the literature that low bioavail US 9,259,417 B2 25 26 ability is one of the leading causes of new drug candidate isoxazoline active agent relative to intravenous dosing. In failures in pre-clinical and clinical development, especially other embodiments of the invention, the soft chewable com for compounds with low aqueous solubility. Compounds that positions provide at least about 85% or at least about 95% achieve poor bioavailability tend to have low plasma expo bioavailability of the isoxazoline active agent after adminis sure and high variability between subjects, limiting their tration. In some embodiments, the bioavailability of the isox therapeutic usefulness (see V. Hayden et al. The RoadMap to aZoline active agent from the inventive chewable composi Oral Bioavailability: an Industrial Perspective, Expert Opin. tions is even up to about 100% relative to intravenous Drug Metab. Toxicol. 2006, 204):591-608). Poor bioavailabil administration of the active agent. ity limits the choice of drugs for oral administration, and in These levels of bioavailability of an isoxazoline active other cases significant allowances must be made to account 10 agent having low water solubility from a soft chewable vet for the low absorption of the active agent. This is reflected in erinary composition are surprisingly high and unexpected. the established minimal acceptable oral bioavailability of Although the extremely high bioavailability of the chewable only 30% for typical oral dosage drug development programs compositions is in part due to the physicochemical properties (V. Hayden et al., Ibid.). Further, a number of well-known of the isoxazoline active agents, the high levels observed from human drugs are known to have bioavailabilities of s20% 15 the chewable compositions of the invention are made possible (see Fasinu et al., Biopharm. Drug Dispos. 2011, 32, 1185 by the presence and combination of the non-active excipients, 209). which ensure complete and predictable dissolution of the In one embodiment, the compositions of the invention composition and maintain the active agents in Solution in the comprising at least one isoxazoline active agent have excep digestive tract of the animal. The significant effect of the tionally consistent and predictable dissolution profiles in non-active excipients of the compositions of the invention on vitro over a range of dosage form sizes, releasing a high the bioavailability of the isoxazoline active agent is demon percentage of the isoxazoline active ingredient. In an embodi strated by FIG. 5. This plot compares the plasma concentra ment, the compositions of the invention release at least about tion of an isoxazoline active agent (Compound A) delivered 70% (w/w) of the available isoxazoline active ingredient from soft chewable compositions of the invention designed to within 60 minutes, as measured by a standard dissolution test. 25 deliver 20 mg/kg and 40 mg/kg of body weight with admin In other embodiments, the compositions of the invention istration of a polyethylene glycol/alcohol solution of the release at least about 80% (w/w) of the available isoxazoline active agent at 25 mg/kg body weight. The figure shows that active agent within about 60 minutes. In still another embodi the Soft chewable compositions of the invention provide sig ment, the compositions of the invention release at least about nificantly higher plasma levels even when dosed at lower 85% (w/w) or about 90% (w/w) of the available isoxazoline 30 levels compared to a solution of the active agent (20 mg/kg active agent within about 60 minutes. The predictable and chewable composition vs. 25 mg/kg Solution). This is particu consistent dissolution profiles exhibited by the compositions larly surprising since the chewable compositions are in the of the invention are unusual for chewable compositions and form of a solid that must disintegrate and completely release are indicative of the excellent bioavailability in vivo. and solubilize the active agent for efficient absorption during FIGS. 1 and 2 show the dissolution profiles of 2 gram soft 35 digestion. One would expect the Solution to provide higher chewable compositions of the invention that have been stored bioavailability because the active agent is completely dis at 25°C. and 60% relative humidity (RH) and 40° C. and 75% solved when administered. The significantly higher bioavail RH, respectively, taken at 1, 2, 3, 6 and 12 months. FIGS. 3 ability achieved from the chewable compositions of the and 4 show the dissolution profiles of 4 gram soft chewable invention is clearly the result of the non-active excipients in compositions of the invention that have been stored at 25°C. 40 the composition rather than the natural permeability of the and 60% relative humidity (RH) and 40° C. and 75% RH, active agent since the same active is used. respectively, taken at 0, 2 and 6 months. As the figures show, The surprisingly high bioavailability of the isoxazoline both the 2 gram and 4 gram size soft chewable compositions active agents in the oral Veterinary compositions of the inven exhibit extremely reproducible dissolution profiles, even tion significantly contributes to the fast onset of action and the after storage at accelerated Stability conditions. This demon 45 extremely long lasting efficacy against fleas and ticks. Thus, strates the predictable and consistent release profile of the in Some embodiments, the ability of the compositions to compositions of the invention, which is an important factor in safely and predictably achieve a desired concentration of the obtaining the Surprising and unexpected bioavailability isoxazoline active agent in the blood stream without having to observed. dose very high levels of the compound to the animal coupled Consistent with the predictable and efficient dissolution 50 with the residence time of the active agent in the blood stream profile exhibited in vitro, animals treated with the composi results in Superior control of ectoparasites, including for up to tions of the invention absorb a very high proportion of the about 90 days or longer against fleas. This length of efficacy isoxazoline active agent in vivo after administration. Thus in from a once-dosed immediate release oral dosage form is one embodiment, the compositions of the invention provide a unparalleled and very Surprising. maximum drug concentration in plasma after as little as about 55 In another embodiment, the soft chewable compositions of 3 hours after administration. In other embodiments, the com the invention may provide exceptionally high and unexpected positions of the invention provide a maximum concentration bioavailability of parasiticidal active agents that are active of the drug after about 3 and a halfhours or after about 4 hours against endoparasites. Thus, in one embodiment, the soft after administration. In still other embodiments, the compo chewable compositions of the invention may provide a bio sitions of the invention provide a maximum concentration of 60 availability of at least about 70% relative to intravenous dos the isoxazoline in the plasma after about 4 and a half or about ing of a parasiticide selected from the group consisting of a 5 hours after administration. macrocyclic lactone active agent, a benzimidazole agent The compositions of the invention comprising at least one including thiabendazole, oxibendazole, mebendazole, fen isoxazoline active agent exhibit surprisingly high bioavail bendazole, Oxfendazole, albendazole, triclabendazole and ability of the isoxazoline active agent in vivo. Thus, in one 65 febantel; levamisole, pyrantel, morantel, closantel, clorSulon, embodiment, the soft chewable veterinary compositions of an amino acetonitrile active agent and an aryloazol-2-ylcya the invention provide at least about 70% bioavailability of the noethylamino active agent. In another embodiment, the soft US 9,259,417 B2 27 28 chewable compositions of the invention may provide a bio In some embodiments, the very long lasting oral veterinary availability of at least about 80%, at least about 85% or at least compositions of the invention comprising at least one isox about 90% relative to intravenous dosing of a parasiticide aZoline active provide an efficacy against certain species of selected from a macrocyclic lactone active agent, a benzimi ticks of at least about 90% for at least about 44 days, at least dazole agent including thiabendazole, oxibendazole, about 58 days, or at least about 72 days. In other embodi mebendazole, fenbendazole, oxfendazole, albendazole, tri ments, the oral veterinary compositions of the invention pro clabendazole and febantel; levamisole, pyrantel, morantel, vide an efficacy against certain species of ticks of at least closantel, clorSulon, an amino acetonitrile active agent and an about 90% for at least about 79 days, at least about 86 days, at aryloazol-2-yl cyanoethylamino active agent. least about 93 days, at least about 100 days or even at least Ectoparasiticidal Compositions 10 about 107 days. In some embodiments, the oral compositions of the invention provide an efficacy of at least about 95% The soft chewable veterinary compositions of the inven against ticks for at least about 44 days, at least about 58 days, tion, which include at least one isoxazoline active agent and a at least about 72 days or at least about 79 days. In certain other pharmaceutically acceptable carrier that is suitable for oral embodiments, the compositions of the invention will provide administration to an animal, have been Surprisingly discov 15 an efficacy of at least 95% for at least about 100 days or even ered to be safe and effective against a broad spectrum of at least about 107 days against certain species of ticks (e.g. D. ectoparasites for an extended period of time. For example, in variabilis). In other embodiments, the compositions of the one embodiment of the invention, the soft chewable compo invention will even provide an efficacy of about 100% against sitions of the invention provide protection of at least 90% certain species of ticks for at least about 93 days, at least about efficacy against fleas (C. felis) for at least30days or at least 36 100 days or even at least about 107 days. This very high level days as measured against untreated controls according to the of efficacy against ticks for Such extended periods of time methods described in the examples. In another embodiment, from an oral dosage form is striking and without precedence the soft chewable compositions of the invention provide at in immediate release oral dosage forms. Furthermore, the oral least 90% efficacy against fleas for at least 44 days or for at compositions of the invention are surprisingly effective least 58 days. 25 against hard to control ticks including Amblyomma ameri In some embodiments of the invention, the compositions of canum and others. the invention comprising at least one isoxazoline active pro The softchewable veterinary compositions of the invention vide a high level of efficacy against fleas for periods of time in comprising at least one isoxazoline active agent have been excess of 60 days. For example, in one embodiment, the found to exhibit a very fast onset of action against parasites compositions of the invention provide an efficacy of at least 30 that harm animals. For example, in Some embodiments of the 90% against fleas for at least 72 days. In other embodiments, invention, the soft chewable veterinary compositions of the the compositions of the invention provide an efficacy of at invention provide an efficacy of at least about 15%, at least least 90% against fleas for at least 79 days, at least 86 days or about 20% or at least about 30% against fleas (C. felis) only even at least 93 days. In still other embodiments, the very long about 30 minutes after administration to the animal compared lasting oral compositions of the invention provide an efficacy 35 with untreated controls, as measured according to the meth of at least 90% against fleas for at least about 100 days, at least ods described in the examples. about 107 days or even at least about 114 days. In other embodiments, the soft chewable compositions of In yet another embodiment, the soft chewable veterinary the invention provide an efficacy of at least about 30%, at least compositions of the invention comprising at least one isox about 40% or at least about 50% against fleas only about 4 azoline active provide an efficacy of at least about 95% 40 hours after administration. In still other embodiments, the against fleas (C. felis) for at least about 30 days or at least compositions of the invention provide an efficacy of at least about 36 days. In yet another embodiment, the soft chewable about 50%, at least about 60% or at least about 70% against Veterinary compositions of the invention provide an efficacy fleas about 8 hours after administration to the animal. In yet of at least about 95% for at least about 44 days, at least about other embodiments, the compositions of the invention pro 58 days or at least about 72 days. In still other embodiments, 45 vide an efficacy of at least about 85%, at least about 90%, at the very long lasting oral compositions of the invention pro least about 95% or at least about 98% about 12 hours after vide an efficacy of at least about 95% for at least about 79 administration of the composition to the animal. This Surpris days, at least about 86 days or even about 93 days. ingly fast onset of efficacy is very important for effectively In yet another embodiment of the invention, the soft chew treating animals with established severe ectoparasitic infes able compositions comprising an effective amount of at least 50 tations. one isoxazoline active agent provide about 100% efficacy Typically, the isoxazoline(s) active agents may be present against fleas for at least about 23 days, at least about 30 days in the composition at a concentration of about 0.1 to about or at least about 36 days. In still other embodiments, the 40% (w/w). In another embodiment, the concentration of the compositions of the invention provide an efficacy of about isoxazoline(s) active agents is about 0.1 to about 30% (w/w). 100% against fleas for at least about 44 days, at least about 58 55 In some embodiments of the invention, the isoxazoline active days or at least about 72 days. agents are present in the composition at a concentration from In another embodiment of the invention, the soft chewable about 1 to about 25% (w/w), about 1 to about 20% (w/w), Veterinary compositions comprising an isoxazoline active about 1 to about 10% (w/w), about 1 to about 5% (w/w), or agent provide an efficacy of at least about 90% against ticks about 1 to about 3% (w/w). In still other embodiments, the (including, but not limited to, Dermacentor variabilis, Ixodes 60 isoxazoline(s) active agents are present in a concentration of scapularis, Amblyomma americanum, Rhipicephalus san about 0.1 to about 5% (w/w), about 0.5 to about 5% (w/w), guineus, Ixodes ricinus, Dermacentor reticulatus and Ixodes about 0.5 to about 3% (w/w) or about 1 to about 3% (w/w) in holocyclus) for at least about 30 days or at least about 36 days. the composition. In yet other embodiments, the In still another embodiment, the soft chewable veterinary isoxazoline(s) active agents are present in a concentration of compositions of the invention will provide an efficacy of at 65 about 3 to about 6% (w/w), or about 5 to 10% (w/w). In other least about 95% for at least about 23 days, at least about 30 embodiments, the isoxazoline active agent is present in a days or at least about 36 days. relatively higher concentration in the dosage form, including US 9,259,417 B2 29 30 about 5% (w/w) to about 15% (w/w), about 10% (w/w) to acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, about 20% (w/w), about 10% (w/w) to about 15% (w/w) or albendazole, albuterol sulfate, alfentanil, allopurinol, alpra about 15% (w/w) to about 20% (w.fw) in the composition. Zolam, altrenogest, amantadine, amikacin Sulfate, aminocap Some dosage units may contain from about 0.5 mg to about roic acid, aminopentamide hydrogen Sulfate, aminophylline/ 2000 mg of at least one isoxazoline active agent or a combi theophylline, amiodarone, amitriptyline, amlodipine nation of isoxazoline active agents. In one embodiment, the besylate, ammonium chloride, ammonium molybdenate, isoxazoline active is present in an amount of from about 1 mg amoxicillin, clavulanate potassium, amphotericin B desoxy to about 200 mg in the composition. More typically, the cholate, amphotericin B lipid-based, amplicillin, amprolium, isoxazoline active agent is present in an amount of about 1 mg antacids (oral), antivenin, apomorphione, apramycin Sulfate, to about 150 mg or about 10 mg to about 150 mg per chewable 10 ascorbic acid, asparaginase, aspiring, atenolol, atipamezole, unit. In some embodiments, the amount of at least one isox atracurium besylate, atropine Sulfate, aurnofin, aurothioglu aZoline active agent in a dosage unit is about 5 mg to about 50 cose, azaperone, azathioprine, azithromycin, baclofen, bar mg, bout 1 mg to about 30 mg, or about 5 mg to about 30 mg. bituates, benazepril, betamethasone, bethanechol chloride, In other embodiments, the amount of at least one isoxazoline bisacodyl, bismuth subsalicylate, bleomycin sulfate, bold active agent in a dosage unit of the invention is about 1 mg to 15 enone undecylenate, bromides, bromocriptine mesylate, about 20 mg or about 1 mg to about 15 mg. In other embodi budenoside, buprenorphine, buspirone, buSulfan, butorpha ments, the dosage units will contain about 50 mg to about 150 nol tartrate, cabergoline, calcitonin salmon, calcitrol, calcium mg, about 50 mg to about 100 mg. or about 75 mg to about 140 salts, captopril, carbenicillin indanyl Sodium, carbimazole, mg of at least one isoxazoline active agent. carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefa In other embodiments, the amount of at least one isoxazo Zolin sodium, cefixime, clorSulon, cefoperaZone sodium, line active agent will be about 100 mg to about 2000 mg per cefotaxime sodium, cefotetan disodium, cefoxitin Sodium, dosage unit. More typically, the amount of at least one isox ce?podoxime proxetil, ceftazidime, ceftiofur sodium, ceftio aZoline active agent in a dosage unit will be about 100 mg to fur, ceftiaxone sodium, cephalexin, cephalosporins, cephapi about 1500 mg, about 100 mg to about 1000 mg or about 500 rin, charcoal (activated), chlorambucil, chloramphenicol, mg to about 1200 mg per dosage unit. 25 chlordiazepoxide, chlordiazepoxide--/- clidinium bromide, Additional Active Agents chlorothiazide, chlorpheniramine maleate, chlorpromazine, In another aspect of the invention, oral veterinary compo chlorpropamide, chlortetracycline, chorionic gonadotropin sitions, including Soft chewable compositions and chewable (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cis tablet compositions, that comprise one or more additional platin, citrate salts, clarithromycin, clemastine fumarate, systemically-acting parasiticidal active agents are provided. 30 clenbuterol, clindamycin, clofazimine, clomipramine, claon The active agents that may be included in the composition can azepam, clonidine, cloprostenol Sodium, cloraZepate dipotas be from various classes of systemically-acting parasiticides sium, clorsulon, cloxacillin, codeine phosphate, colchicine, and may be included in the oral veterinary compositions of corticotropin (ACTH), coSyntropin, cyclophosphamide, the invention alone or in combination with an isoxazoline cyclosporine, cyproheptadine, cytarabine, dacarbazine, dac active agent and/or other systemically-acting ectoparasiti 35 tinomycin/actinomycin D, dalteparin Sodium, danazol, dant cides including, but not limited to, one or more spinosyn or rolene Sodium, dapsone, decoquinate, deferoxamine mesy spinosoid, one or more insect growth regulators, one or more late, deracoxib, deslorelin acetate, desmopressin acetate, arylpyrazoles and one or more neonicotinoids. When the desoxycorticosterone pivalate, detomidine, dexamethasone, compositions comprise a combination of a systemically-act dexpanthenol, dexraaZOxane, dextran, diazepam, diaZoxide ing endoparasiticidal agent in combination with an ectopara 40 (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, siticidal agent including, but not limited to, an isoxazoline diethylcarbamazine citrate, diethylstilbestrol (DES), difloxa active agent, the compositions will be effective against both cin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhy endoparasitic and ectoparasitic infections and infestations. drinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost In one embodiment, the invention provides a soft chewable tromethamine, diphenylhydramine, disopyramide phosphate, Veterinary composition comprising at least one isoxazoline 45 dobutamine, docusate/DSS. dolasetron mesylate, domperi active agent in combination with at least one other systemi done, dopamine, doramectin, doxapram, doxepin, doxorubi cally-acting active agent that is active against endoparasites, cin, doxycycline, edetate calcium disodium.calcium EDTA, and a pharmaceutically acceptable carrier or diluent. In edrophonium chloride, enalapril/enalaprilat, enoxaparin another embodiment, the invention provides a soft chewable Sodium, enrofloxacin, ephedrine Sulfate, epinephrine, epo Veterinary composition comprising at least one isoxazoline 50 etin/erythropoietin, eprinomectin, epsiprantel, erythromycin, active agent in combination with at least one systemically esmolol, estradiol cypionate, ethacrynic acid/ethacrynate acting active agent that is active against ectoparasites, Sodium, ethanol (alcohol), etidronate sodium, etodolac, eto together with a pharmaceutically acceptable carrier or dilu midate, euthanasia agents w/pentobarbital, famotidine, fatty ent. acids (essential/omega), felbamate, fentanyl, ferrous Sulfate, In some embodiments, the additional active agents com 55 filgrastim, finasteride, fipronil, florfenicol, fluconazole, bined with an isoxazoline active agent may include, but are flucytosine, fludrocortisone acetate, flumazenil, flumetha not limited to, acaricides, anthelmintics, insecticides and sone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, other parasiticides of various classes presented herein. fluticasone propionate, fluvoxamine maleate, fomepizole In another embodiment, the soft chewable compositions (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, may also include Veterinary therapeutic agents. Veterinary 60 gentamicin Sulfate, glimepiride, glipizide, glucagon, gluco pharmaceutical agents that may be included in the composi corticoid agents, glucosamine/chondroitin Sulfate, tions of the invention are well-known in the art (see e.g. glutamine, glyburide, glycerine (oral), glycopyrrolate, gona Plumb' Veterinary Drug Handbook, 5' Edition, ed. Donald dorelin, grisseofulvin, guaifenesin, halothane, hemoglobin C. Plumb, Blackwell Publishing, (2005) or The Merck Veteri glutamer-200 (OXYGLOBINR(R), heparin, hetastarch, nary Manual, 9th Edition, (January 2005)) and includebut are 65 hyaluronate sodium, hydrazaline, hydrochlorothiazide, not limited to acarbose, acepromazine maleate, acetami hydrocodone bitartrate, hydrocortisone, hydromorphone, nophen, acetazolamide, acetazolamide Sodium, acetic acid, hydroxyurea, hydroxy Zine, ifosfamide, imidacloprid, imi US 9,259,417 B2 31 32 docarb dipropinate, impenemi-cilastatin Sodium, imipramine, In one embodiment of the invention, arylpyrazole com inamrinone lactate, insulin, interferon alfa-2a (human recom pounds such as phenylpyrazoles may be included in the oral binant), iodide (sodium/potassium), ipecac (syrup), ipodate Veterinary compositions of the invention. The arylpyrazoles Sodium, iron dextran, isoflurane, isoproterenol, isotretinoin, are known in the art and are suitable for combination with the isoXSuprine, itraconazole, ivermectin, kaolin?pectin, ket isoxazoline compounds in the soft chewable compositions of amine, ketoconazole, ketoprofen, ketorolac tromethamine, the invention. Examples of Such arylpyrazole compounds lactulose, leuprolide, levamisole, levetiracetam, levothyroX include but are not limited to those described in U.S. Pat. Nos. ine Sodium, lidocaine, lincomycin, liothyronine Sodium, lisi 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540: nopril, lomustine (CCNU), lufenuron, lysine, magnesium, 6,685,954, 6,998,131 and 7,759,381 (all of which are incor mannitol, marbofloxacin, mechlorethamine, meclizine, 10 porated herein by reference). A particularly preferred meclofenamic acid, medetomidine, medium chain triglycer arylpyrazole active agent is fipronil. In one embodiment, the ides, medroxyprogesterone acetate, megestrol acetate, melar arylpyrazole may be included in the soft chewable composi Somine, melatonin, meloxican, melphalan, meperidine, mer tions in combination with one or more isoxazoline active captopurine, meropenem, metformin, methadone, agents, one or more macrocyclic lactones, one or more spi methazolamide, methenamine mandelate/hippurate, methi 15 nosyn compounds, one or more spinosoid compounds, a ben mazole, methionine, methocarbamol, methohexital Sodium, Zimidazole, levamisole, pyrantel, morantel, praziquantel, methotrexate, methoxyflurane, methylene blue, meth closantel, clorSulon, one or more amino acetonitrile active ylphenidate, methylprednisolone, metoclopramide, meto agent, one or more insect growth regulators, one or more prolol, metronidaxole, mexiletine, mibolerlone, midazolam neonicotinoids or one or more aryloazol-2-yl cyanoethy milbemycin Oxime, mineral oil, minocycline, misoprostol, lamino active agents, or a combination of thereof. mitotane, mitoxantrone, morphine Sulfate, moxidectin, In another embodiment of the invention, one or more mac naloxone, mandrolone decanoate, naproxen, narcotic (opiate) rocyclic lactones or lactams, which act as an acaricide, an agonist analgesics, neomycin Sulfate, neostigmine, niacina anthelmintic agent and/or an insecticide, can be included in mide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglyc the compositions of the invention. The macrocyclic lactone erin, nitroprusside Sodium, nizatidine, novobiocin Sodium, 25 active agents are very potent and may be included alone in the nystatin, octreotide acetate, olSalazine sodium, omeproZole, compositions or in combination with one or more isoxazoline ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin active agents, one or more spinosyn compounds, one or more Sodium, oxazepam, oxibutynin chloride, oxymorphone, spinosoid compounds, a benzimidazole, levamisole, pyran oxytretracycline, oxytocin, pamidronate disodium, pancrep tel, morantel, praziquantel, closantel, clorSulon, one or more lipase, pancuronium bromide, paromomycin Sulfate, parozet 30 amino acetonitrile active agent, one or more insect growth ine, pencillamine, general information penicillins, penicillin regulators, one or more neonicotinoids or one or more ary G, penicillin V potassium, pentazocine, pentobarbital loazol-2-yl cyanoethylamino active agents, or a combination Sodium, pentosan polysulfate Sodium, pentoxifylline, per of thereof. Furthermore, in one embodiment, the oral veteri golide mesylate, phenobarbital, phenoxybenzamine, pheylb nary compositions of the invention may comprise a combi utaZone, phenylephrine, pheny propanolamine, phenytoin 35 nation of two or more macrocyclic lactone active agents, Sodium, pheromones, parenteral phosphate, phytonadione/ alone or in combination with other systemically-acting active Vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, agents. For the avoidance of doubt, the term “macrocyclic polysulfated glycosaminoglycan, ponazuril, potassium chlo lactone' as used herein includes both naturally occurring and ride, pralidoxime chloride, prazosin, prednisolone/pred synthetic or semi-synthetic avermectin and milbemycin com nisone, primidone, procainamide, procarbazine, prochlor 40 pounds. perazine, propantheline bromide, propionibacterium acnes The macrocyclic lactones that may be used in the compo injection, propofol, propranolol, protamine Sulfate, pseu sitions of the invention include, but are not limited to, the doephedrine, psyllium hydrophilic mucilloid, pyridostig naturally produced avermectins (e.g. including the compo mine bromide, pyrilamine maleate, pyrimethamine, quina nents designated as Aa, Ab, Aa, Ab, Ba, Bb. Ba and crine, quinidine, ranitidine, rifampin, S-adenosyl-methionine 45 Bb) and milbemycin compounds, semisynthetic avermec (SAMe), Saline/hyperosmotic laxative, Selamectin, sel tins and milbemycins, avermectin monosaccharide com egiline/l-deprenyl, Sertraline, sevelamer, sevoflurane, sily pounds and avermectin aglycone compounds. Examples of marin/milk thistle, sodium bicarbonate, sodium polystyrene macrocyclic lactone compounds that may be used in the com Sulfonate, Sodium Stibogluconate, Sodium sulfate, sodium positions include, but are not limited to, abamectin, dimadec thiosulfate, Somatotropin, Sotalol, spectinomycin, spirono 50 tin, doramectin, emamectin, eprinomectin, ivermectin, lati lactone, stanozolol, Streptokinase, Streptozocin, Succimer, dectin, lepimectin, selamectin, ML-1.694,554 and Succinylcholine chloride, Sucralfate, Sufentanil citrate, Sul milbemycins including, but not limited to, milbemectin, mil fachlorpyridazine Sodium, Sulfadiazine/trimethroprim, Sul bemycin D. milbemycin A, milbemycin A, milbemycin famethoxazole/trimethoprim, Sulfadimentoxine, Sul Oxime, moxidectin and nemadectin. Also included are the fadimethoxineformetoprim, Sulfasalazine, taurine, 55 5-oxo and 5-oxime derivatives of said avermectins and mil tepoxaline, terbinafline, terbutaline sulfate, testosterone, tet bemycins. racycline, thiacetarsamide Sodium, thiamine, thioguanine, The macrocyclic lactone compounds are known in the art thiopental Sodium, thiotepa, thyrotropin, tiamulin, ticarcilin and can easily be obtained commercially or through synthesis disodium, tiletamine/Zolazepam, tilmocsin, tiopronin, tobra techniques known in the art. Reference is made to the widely mycin Sulfate, tocainide, tolazoline, telfenamic acid, topira 60 available technical and commercial literature. For avermec mate, tramadol, trimcinolone acetonide, trientine, triloStane, tins, ivermectin and abamectin, reference may be made, for trimepraxine tartrate w/prednisolone, tripelennamine, example, to the work "Ivermectin and Abamectin', 1989, by tylosin, urdosiol, Valproic acid, Vanadium, Vancomycin, vaso M. H. Fischer and H. Mrozik, William C. Campbell, pub pressin, vecuronium bromide, Verapamil, vinblastine Sulfate, lished by Springer Verlag., or Albers-Schonberg etal. (1981), Vincristine Sulfate, vitamin E/selenium, warfarin Sodium, 65 'Avermectins Structure Determination, J. Am. Chem. Soc., Xylazine, yohimbine, Zafirlukast, Zidovudine (AZT), Zinc 103,4216-4221. For doramectin, “Veterinary Parasitology', acetate/zinc sulfate, Zonisamide and mixtures thereof. vol. 49, No. 1, July 1993, 5-15 may be consulted. For milbe US 9,259,417 B2 33 34 mycins, reference may be made, interalia, to Davies H. G. et mycin A, milbemycin A, milbemycin oxime, moxidectin or al., 1986, “Avermectins and Milbemycins, Nat. Prod. Rep. nemadectin, or a combination thereof. In another embodi 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins ment, the invention provides a soft chewable veterinary com from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. position comprising an effective amount of at least one of Pat. No. 4,134,973 and EP 0 677 054, both incorporated Compound A. Compound B, Compound 1.001 to 1.025 or herein by reference. Compound 2.001 to 2.018 in combination with an effective The structure of the avermectins and milbemycins are amount of abamectin, emamectin, eprinomectin, ivermectin, closely related, e.g., by sharing a complex 16-membered doramectin or Selamectin, or a combination thereof. In still macrocyclic lactone ring. The natural product avermectins another embodiment, the invention provides a soft chewable are disclosed in U.S. Pat. No. 4,310,519 and the 22,23-dihy 10 Veterinary composition comprising an effective amount of at dro avermectin compounds are disclosed in U.S. Pat. No. least one of Compound A. Compound B, Compound 1.001 to 4,199,569. Mention is also made of U.S. Pat. Nos. 4,468.390, 1.025 or Compound 2.001 to 2.018 in combination with an 5,824,653, EP0007812 A1, U.K. Patent Specification 1390 effective amount of at least one of ivermectin, milbemectin, 336, EP 0002916, and New Zealand Patent No. 237 086, milbemycin D. milbemycin A, milbemycin A, milbemycin interalia. Naturally occurring milbemycins are described in 15 Oxime, moxidectin or nemadectin, or a combination thereof. U.S. Pat. No. 3,950,360 as well as in the various references In some embodiments, the chewable veterinary composi cited in “The Merck Index" 12" ed., S. Budavari, Ed., Merck tions may comprise a combination of at least one isoxazoline & Co., Inc. Whitehouse Station, N.J. (1996). Latidectin is active agent with two different macrocyclic lactone active described in the “International Nonproprietary Names for agents. Pharmaceutical Substances (INN), WHO Drug Information, In still another embodiment, the invention provides a soft vol. 17, no. 4, pp. 263-286, (2003). Semisynthetic derivatives chewable veterinary composition comprising an effective of these classes of compounds are well known in the art and amount of Compound A in combination with an effective are described, for example, in U.S. Pat. Nos. 5,077.308, amount of abamectin, emamectin, eprinomectin, ivermectin 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, or Selamectin, or a combination thereof. In yet another 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 25 embodiment, the invention provides a soft chewable veteri 4,978,677, 4,920,148 and EP 0 667 054, all incorporated nary composition comprising an effective amount of Com herein by reference. pound A in combination with an effective amount of ivermec In one embodiment, the oral Veterinary compositions of the tin, milbemycin Oxime or moxidectin, or a combination invention, including soft chewable compositions and chew thereof. able tablet compositions, comprise an effective amount of at 30 In another embodiment of the invention, a composition least one of abamectin, dimadectin, doramectin, emamectin, comprising a class of acaricides or insecticides known as eprinomectin, ivermectin, latidectin, lepimectin, selamectin, insect growth regulators (IGRs) are provided. The IGRactive milbemectin, milbemycin D. milbemycin A, milbemycin agents may be included in the oral Veterinary compositions of A milbemycin Oxime, moxidectin or nemadectin, or a com the invention. The IGR active agents may be included in the bination thereof. In another embodiment, the invention pro 35 composition alone, or in combination with at least one isox vides a soft chewable veterinary composition comprising an aZoline active agent or another systemically-acting active effective amount of at least one of abamectin, emamectin, agent described herein including, but not limited to, one or eprinomectin, ivermectin, doramectin or Selamectin, or a more macrocyclic lactones, one or more spinosyn com combination thereof. In still another embodiment, the soft pounds, one or more spinosoid compounds, a benzimidazole, chewable veterinary compositions of the invention comprise 40 levamisole, pyrantel, morantel, praziquantel, closantel, clor an effective amount of at least one of ivermectin, milbemec Sulon, one or more amino acetonitrile active agent, one or tin, milbemycin oxime or moxidectin, or a combination more insect growth regulators, one or more neonicotinoids or thereof. one or more aryloazol-2-ylcyanoethylamino active agents, or In another embodiment, oral veterinary compositions com a combination of thereof. Compounds belonging to this group prising at least one isoxazoline active agent in combination 45 are well known to the practitioner and represent a wide range with abamectin, dimadectin, doramectin, emamectin, epri of different chemical classes. These compounds all act by nomectin, ivermectin, latidectin, lepimectin, Selamectin, mil interfering with the development or growth of the insect pests. bemectin, milbemycin D. milbemycin A milbemycin A, Insect growth regulators are described, for example, in U.S. milbemycin oxime, moxidectin or nemadectin, or a combi Pat. Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751, nation thereof, are provided. Instill another embodiment, oral 50 225, EPO 179 022 or U.K. 2 140010 as well as U.S. Pat. Nos. Veterinary compositions comprising at least one isoxazoline 6,096,329 and 6,685,954 (all incorporated herein by refer active agent in combination with abamectin, emamectin, epri ence). nomectin, ivermectin, doramectin or Selamectin, or a combi In one embodiment the compositions of the invention may nation thereof, are provided. include an IGR compound that mimics juvenile hormone or In yet another embodiment, soft chewable veterinary com 55 that modulates levels of juvenile hormones in insects. positions comprising at least one isoxazoline active agent of Examples of juvenile hormone mimics include azadirachtin, formula (I), formula (II), formula (III) or formula (IV) in diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, combination with an effective amount of ivermectin, milbe pyriproxyfen, tetrahydroazadirachtin and 4-chloro-2(2- mectin, milbemycin oxime or moxidectin, or a combination chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)py thereof, are provided. 60 ridazine-3 (2H)-one. In another embodiment, the composi In another embodiment, the invention provides a soft tions of the invention comprise an isoxazoline compound in chewable veterinary composition comprising an effective combination with methoprene or pyriproxyfen and a pharma amount of at least one of Compound A. Compound B, Com ceutically acceptable carrier. pound 1.001 to 1.025 or Compound 2.001 to 2.018 in com In another embodiment, the compositions of the invention bination with an effective amount of abamectin, dimadectin, 65 include an IGR compound that is a chitin synthesis inhibitor. doramectin, emamectin, eprinomectin, ivermectin, latidectin, Chitin synthesis inhibitors include chlorofluaZuron, cyro lepimectin, Selamectin, milbemectin, milbemycin D. milbe mazine, diflubenZuron, fluaZuron, flucycloxuron, flufenoXu US 9,259,417 B2 35 36 ron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, mycin B, C-santonin and kainic acid. These antinematodal triflumoron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluo active agents may be included in the compositions alone or in romethyl)phenylurea, 1-(2,6-difluoro-benzoyl)-3-(2-fluoro combination one or more of the systemically-acting parasiti 4-(1,1,2,2-tetrafluoroethoxy)-phenylurea and 1-(2,6-difluo cides described herein. robenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea. In other embodiments, the compositions of the invention In some embodiments, the compositions of the invention may include antitrematodal agents. Suitable antitrematodal may include one or more antinematodal agents including, but agents include, but are not limited to, the miracils such as not limited to, active agents in the benzimidazoles, imida miracil D and mirasan; praziquantel, clonazepam and its Zothiazoles, tetrahydropyrimidines and the organophosphate 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxam class of compounds. In some embodiments, benzimidazoles 10 niquine, amoscanate, niridazole, nitroxynil, various bisphe including, but not limited to, thiabendazole, cambendazole, nol compounds known in the art including hexachlorophene, parbendazole, oxibendazole, mebendazole, flubendazole, bithionol, bithionol sulfoxide and menichlopholan; various fenbendazole, oxfendazole, albendazole, cyclobendazole, salicylanilide compounds including tribromsalan, oxycloza febantel, thiophanate and its o.o-dimethyl analogue may be nide, clioxanide, rafoxanide, nitroxynil, brotianide, bromox included in the compositions. The aforementioned active 15 anide and closantel; triclabendazole, diamfenetide, clorSulon, agents may be included in the compositions alone or in com hetolin and emetime. bination with other systemically-acting parasiticides Anticestodal compounds may also be advantageously used described herein including, but not limited to, one or more in the compositions of the invention including, but not limited isoxazoline active agents, one or more macrocyclic lactone to, arecoline in various salt forms, bunamidine, niclosamide, active agents, one or more spinosyn or spinosoid compounds, nitroscanate, paromomycin, paromomycin II, praziquantel levamisole, pyrantel, morantel, praziquantel, closantel, clor and epsiprantel. Sulon, one or more amino acetonitrile active agents, one or The antinematodal, antitrematodal and anticestodal active more insect growth regulators, one or more neonicotinoids or agents described above may be included in the compositions one or more aryloazol-2-ylcyanoethylamino active agents, or alone or in combination with one or more of the systemically a combination thereof. 25 acting active agents described herein including, but not lim In other embodiments, the compositions may include an ited to, one or more isoxazoline active agents, one or more imidazothiazole compounds including, but not limited to, macrocyclic lactone active agents, one or more spinosyn or tetramisole, levamisole and butamisole, alone or in combina spinosoid active agents, one or more benzimidazole agents tion with one or more systemically-active active agents including thiabendazole, oxibendazole, mebendazole, fen described herein including, but not limited to, one or more 30 bendazole, Oxfendazole, albendazole and febantel; levami isoxazoline active agents, one or more macrocyclic lactone sole, pyrantel, morantel, one or more amino acetonitrile active agents, one or more spinosyn or spinosoid compounds, active agent, one or more insect growth regulators, one or one or more benzimidazole agents including thiabendazole, more neonicotinoids and one or more aryloazol-2-yl cyano oxibendazole, mebendazole, fenbendazole, oxfendazole, ethylamino active agents, or a combination thereof. albendazole, triclabendazole and febantel; pyrantel, moran 35 In yet other embodiments, the compositions of the inven tel, praziquantel, closantel, clorSulon, one or more amino tion may include other active agents that are effective against acetonitrile active agents, one or more insect growth regula arthropod parasites. Suitable active agents include, but are not tors, one or more neonicotinoids and one or more aryloazol limited to, bromocyclen, chlordane, DDT, endosulfan, lin 2-yl cyanoethylamino active agents, or a combination dane, methoxychlor, toxaphene, bromophos, bromophos thereof. 40 ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, cro In still other embodiments, the compositions of the inven toxyphos, cythioate, diazinon, dichlorenthion, diemthoate, tion may include tetrahydropyrimidine active agents includ dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate, ing, but not limited to, pyrantel, oxantel, and morantel, alone iodofenphos, malathion, naled, phosalone, phosmet, phoxim, or in combination with one or more systemically-acting propetamphos, ronnel, Stirofos, allethrin, cyhalothrin, cyper active agents including, but not limited to, one or more isox 45 methrin, deltamethrin, fenvalerate, flucythrinate, permethrin, aZoline active agents, one or more macrocyclic lactone active phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon agents, one or more spinosynor spinosoid compounds, one or disulfide, crotamiton, diflubenZuron, diphenylamine, disul more benzimidazole agents including thiabendazole, oxi firam, isobornyl thiocyanato acetate, methoprene, monosul bendazole, mebendazole, fenbendazole, oxfendazole, firam, piremonylbutoxide, rotenone, triphenyltin acetate, albendazole, triclabendazole and febantel; levamisole, prazi 50 triphenyltin hydroxide, deet, dimethyl phthalate, and the quantel, closantel, clorSulon, one or more amino acetonitrile compounds 1.5a,6,9.9a,9b-hexahydro-4a(4H)-dibenzo active agents, one or more insect growth regulators, one or furancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7, more neonicotinoids and one or more aryloazol-2-yl cyano 7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione ethylamino active agents, or a combination thereof. (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK Suitable organophosphate active agents include, but are not 55 326) and 2-(octylthio)ethanol (MGK-874). limited to, coumaphos, trichlorfon, haloxon, naftalofos and In another embodiment, an antiparasitic agent that can be dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP. included in the soft chewable veterinary composition can be a and tetrachlorvinphos. biologically active peptide or protein including, but not lim In other embodiments, the compositions may include the ited to, depsipeptides, which act at the neuromuscular junc antinematodal compounds phenothiazine, piperazine as the 60 tion by stimulating presynaptic receptors belonging to the neutral compound and in various salt forms, diethylcarbam secretin receptor family resulting in the paralysis and death of azine, phenols such as disophenol, arsenicals such as arsena parasites. In one embodiment of the depsipeptide, the dep mide, ethanolamines such as bephenium, thenium closylate, sipeptide is emodepside (see Wilson et al., Parasitology, and methyridine; cyanine dyes including pyrvinium chloride, January 2003, 126(Pt 1):79-86). pyrvinium pamoate and dithiazanine iodide; isothiocyanates 65 In another embodiment, the compositions of the invention including bitoscanate, Suramin Sodium, phthalofyne, and may comprise an active agent from the neonicotinoid class of various natural products including, but not limited to, hygro parasiticides. The neonicotinoids bind and inhibit insect spe US 9,259,417 B2 37 38 cific nicotinic acetylcholine receptors. In one embodiment, porated herein by reference); Sager et al., Veterinary Parasi the neonicotinoid insecticidal agent that can be combined tology, 2009, 159,49-54; Kaminsky et al., Nature vol. 452, 13 with an isoxazoline compound to form a topical composition Mar. 2008, 176-181. The AAD class of compounds may be of the invention is imidacloprid. Agents of this class are included in the oral veterinary compositions of the invention described, for example, in U.S. Pat. No. 4,742,060 or in EP 0 5 alone or in combination with one or more of the systemically 892 060 (both incorporated herein by reference). In another acting parasiticides described herein including, but not lim embodiment, the compositions of the invention may com ited to, one or more isoxazoline active agents, one or more prise nitenpyram, another active agent of the neonicotinoid macrocyclic lactone active agents, one or more spinosyn or class of pesticides. The use ofnitenpyram for controlling fleas spinosoid active agents, one or more benzimidazole agents is described in U.S. Pat. No. 5,750,548, which is incorporated 10 including thiabendazole, oxibendazole, mebendazole, fen herein by reference in its entirety. The neonicotinoid active bendazole, Oxfendazole, albendazole, triclabendazole and agents may be included in the compositions alone, or in febantel; levamisole, pyrantel, morantel, praziquantel, clos combination with one or more of the other systemically antel, clorSulon, one or more insect growth regulators, one or acting active agents described herein including, but not lim more neonicotinoid active agents and one or more aryloazol ited to, one or more isoxazoline active agents, one or more 15 2-yl cyanoethylamino active agents, or a combination macrocyclic lactone active agents, one or more spinosyn or thereof. spinosoid active agents, one or more benzimidazole agents The compositions of the invention may also include ary including thiabendazole, OXibendazole, mebendazole, fen loazol-2-yl cyanoethylamino compounds such as those bendazole, Oxfendazole, albendazole, triclabendazole and described in U.S. Pat. No. 8,088,801 to Soll et al., which is febantel; levamisole, pyrantel, morantel, praziquantel, clos incorporated herein by reference, and thioamide derivatives antel, clorSulon, one or more amino acetonitrile active agents, of these compounds, as described in U.S. Pat. No. 7.964,621 one or more insect growth regulators and one or more aryloa to Le Hir de Fallois, which is also incorporated herein by Zol-2-yl cyanoethylamino active agents, or a combination reference. Aryloazol-2-yl cyanoethylamino active agents, thereof. In another embodiment, the soft chewable composi which are systemically-acting against endoparasites may be tions of the invention comprise the isoxazoline Compound A 25 used alone in the oral Veterinary compositions of the inven in combination with nitenpyram and/or imidacloprid. tion or in some embodiments in combination with one or In other certain embodiments of the invention, an insecti more systemically-acting active agents described herein cidal agent that can be combined with the compositions of the including, but not limited to, one or more isoxazoline active invention is a semicarbazone. Such as metaflumizone. agents, one or more macrocyclic lactone active agents, one or In another embodiment, the compositions of the invention 30 more spinosyn or spinosoid active agents, one or more ben may advantageously include a mixture of one or more other Zimidazole agents including thiabendazole, oxibendazole, isoxazoline compounds known in the art, in addition to or in mebendazole, fenbendazole, oxfendazole, albendazole, tri place of the isoxazoline active agents described above. These clabendazole and febantel, or anthelmintics of other classes active agents are described in US 2010/0254960A1, US2011/ including levamisole, pyrantel, morantel, praziquantel, clos 0159107, US2012/0309620, US2012/0030841, US2010/ 35 antel, clorSulon, one or more insect growth regulators, one or 0069247, WO 2007/125984, WO 2012/08.6462, U.S. Pat. No. more neonicotinoid active agents and one or more amino 8,318,757, US 2011/0144349, U.S. Pat. No. 8,053,452; US acetonitrile active agents (AAD), or a combination thereof. 2010/0137612, US 2010/0254959, US 2011/152081, WO The compositions of the invention may also include para 2012/089623, WO 2012/089622, U.S. Pat. No. 8,119,671; herquamide compounds and derivatives of these compounds, U.S. Pat. No. 7,947,715; WO 2102/120135, WO 2012/ 40 including derquantel (see Ostlind et al., Research in Veteri 107533, WO 2011/157748, US 2011/0245274, US 2011/ nary Science, 1990, 48, 260-61; and Ostlind et al., Medical 0245239, US 2012/0232026, US 2012/0077765, US 2012/ and Veterinary Entomology, 1997, 11, 407-408). The para 0035122, US 2011/0251247, WO 2011/154433, WO 2011/ herquamide family of compounds is a known class of com 154434, US 2012/0238517, US 2011/0166193, WO 2011/ pounds that include a spirodioxepino indole core with activity 104088, WO 2011/104087, WO 2011/104089, US 2012/ 45 against certain parasites (see Tett. Lett. 1981, 22, 135, J. 015946, US 2009/0143410, WO 2007/123855A2, US 2011/ Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). 01 18212, U.S. Pat. No. 7,951,828 & U.S. Pat. No. 7,662,972, In addition, the structurally related marcfortine family of US 2010/0137372 A1, US 2010/01791.94 A2, US 2011/ compounds, Such as marcfortines A-C, are also known and 0086886 A2, US 2011/0059988 A1, US 2010/01791.95 A1, may be combined with the formulations of the invention (see U.S. Pat. No. 7,897,630, U.S. Pat. No. 7,951,828 and U.S. 50 J. Chem. Soc.—Chem. Comm. 1980, 601 and Tet. Lett. 1981, Pat. No. 7,662.972, all of which are incorporated herein by 22, 1977). Further references to the paraherquamide deriva reference in their entirety. tives can be found, for example, in WO 91/09961, WO In another embodiment of the invention, nodulisporic acid 92/22555, WO 97/03988, WO 01/076370, WO 09/004.432 and its derivatives may be added to the compositions of the and US 2010/0197624, U.S. Pat. No. 5,703,078 and U.S. Pat. invention. These compounds are used to treat or prevent 55 No. 5,750,695, all of which are hereby incorporated by ref infections in humans and animals and are described, for erence in their entirety. In one embodiment, the paraherqua example, in U.S. Pat. Nos. 5,399.582, 5,962,499, 6,221,894 mide and/or marcfortine active agents may be included in the and 6.399,786, all of which are hereby incorporated by ref oral veterinary compositions of the invention alone. In other erence in their entirety. The compositions may include one or embodiments, the paraherquamide and/or marcfortine active more of the known nodulisporic acid derivatives in the art, 60 agents may be combined with at least one additional systemi including all stereoisomers, such as those described in the cally-acting active agents described herein including, but not literature cited above. limited to, one or more isoxazoline active agents, one or more In another embodiment, anthelmintic compounds of the macrocyclic lactone active agents, one or more spinosyn or amino acetonitrile class (AAD) of compounds such as mon spinosoid compounds, one or more benzimidazole agents epantel (ZOLVIX) and the like may be added to the compo 65 including thiabendazole, oxibendazole, mebendazole, fen sitions of the invention. These compounds are described, for bendazole, Oxfendazole, albendazole, triclabendazole and example, in U.S. Pat. No. 7,084.280 to Ducray et al. (incor febantel, or anthelmintics of other classes including levami US 9,259,417 B2 39 40 sole, pyrantel, morantel, praziquantel, closantel, clorSulon, (III) or (IV) described above) in the soft chewable composi one or more amino acetonitrile active agents, one or more tions of the invention will typically be from about 0.01% to insect growth regulators, one or more neonicotinoid active about 30% (w/w) depending on the potency of the active agents or one or more aryloazol-2-yl cyanoethylamino active agent. In certain embodiments for very potent active agents agents, or a combination thereof. 5 including, but not limited to a macrocyclic lactone active In another embodiment of the invention, the compositions agent, the concentration of the active agent will typically be may include a spinosyn active agent produced by the soil from about 0.01% to about 10% (w/w), from about 0.01 to actinomycete Saccharopolyspora spinosa (see, for example about 1% (w/w), from about 0.01% to about 0.5% (w/w), Salgado V. L. and Sparks T. C., “The Spinosyns: Chemistry, from about 0.1% to about 0.5% (w/w) or from about 0.01% to Biochemistry, Mode of Action, and Resistance.” in Compre 10 about 0.1% (w/w). In other embodiments, the concentration hensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) of the active agent will typically be from about 0.1% to about or a semi-synthetic spinosoid active agent. The spinosyns are 2% (w/w) or about 0.1% to about 1% (w/w). typically referred to as factors or components A, B, C, D, E, F, In other embodiments, the systemically-acting active agent G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of (other than an isoxazoline active agent of formula (I), (II), these components, or a combination thereof, may be used in 15 (III) or (IV) described above) will typically be present at the compositions of the invention. The spinosyn compound higher concentrations to achieve the desired efficacy. In some may be a 5.6,5-tricylic ring system, fused to a 12-membered embodiments, the active agent will be present in a concentra macro cyclic lactone, a neutral Sugar (rhamnose), and an tion of about 1% to about 30% (w/w), about 1% to about 20% amino Sugar (forosamine). These and other natural spinosyn (w/w) or about 1% to about 15% (w/w). In still other embodi compounds, including 21-butenyl spinosyn produced by Sac ments, the active agent will be present in a concentration of charopolyspora pagona, which may be used in the composi about 5% to about 20% (w/w) or about 5% to about 15% tions of the invention, may be produced via fermentation by (w/w) in the composition. conventional techniques known in the art. Other spinosyn In various embodiments of the invention, a systemically compounds that may be used in the compositions of the acting active agent (other than an isoxazoline active agent of invention are disclosed in U.S. Pat. Nos. 5,496,931; 5,670, 25 formula (I), (II), (III) or (IV) described above) may be 364; 5,591,606:5,571,901:5,202,242; 5,767,253; 5,840,861; included in the composition to deliver a dose of about 0.001 5,670,486; 5,631,155 and 6,001,981, all incorporated by ref. mg/kg to about 50 mg/kg or about 0.5 mg/kg to about 50 erence herein in their entirety. The spinosyn compounds may mg/kg of body weight of the animal. In other embodiments, include, but are not limited to, spinosyn A, spinosyn D. Spi the active agent will typically be present in an amount Suffi nosad, spinetoram, or combinations thereof. Spinosad is a 30 cient to deliver a dose of about 0.05 mg/kg to about 30 mg/kg, combination of spinosyn A and spinosyn D, and spinetoram is about 0.1 mg/kg to about 20 mg/kg. In other embodiments, a combination of 3'-ethoxy-5,6-dihydro spinosyn J and the active agent will be present in an amount sufficient to 3'-ethoxy spinosyn L. deliver a dose of about 0.1 mg/kg to about 10 mg/kg, about 0.1 In one embodiment, oral Veterinary compositions, includ mg/kg to about 1 mg/kg or about 0.5 mg/kg to about 50 mg/kg ing soft chewable compositions and chewable tablet compo 35 per body weight of the animal. sitions, comprising a spinosyn and/or a spinosoid active In certain embodiments of the invention where the systemi agent, are provided. In some embodiments, the compositions cally-acting active agent is a very potent compound such as a may contain a combination of two or more spinosyn and/or macrocyclic lactone or other potent compounds, the active spinosoid active agents. For example, in one embodiment, the agent will be present in a concentration to provide a dose of compositions may include spinosad, which is a combination 40 about 0.001 mg/kg to about 5 mg/kg, about 0.001 mg/kg to of spinosyn A and spinosyn D. Other combinations are also about 0.1 mg/kg or about 0.001 mg/kg to about 0.01 mg/kg. In contemplated. In another embodiment, the compositions may still other embodiments, the active agent is present in an include a spinosyn and/or a spinosoid active agent, or a com amount sufficient to deliver a dose of about 0.01 mg/kg to bination thereof, in combination with one or more additional about 2 mg/kg or about 0.1 mg/kg to about 1 mg/kg per body systemically-acting active agents described herein including, 45 weight of the animal. In still other embodiments, the addi but not limited to, one or more isoxazoline active agents, one tional active agent may be present in an amount to deliver a or more macrocyclic lactone active agents, one or more ben dose of about 1 ug/kg to about 200 ug/kg or about 0.1 mg/kg Zimidazole agents including thiabendazole, oxibendazole, to about 1 mg/kg of weight of animal. mebendazole, fenbendazole, oxfendazole, albendazole, tri Endoparasiticidal Compositions clabendazole and febantel, or anthelmintics of other classes 50 In one embodiment of the invention, soft chewable veteri including levamisole, pyrantel, morantel, praziquantel, clos nary compositions comprising one or more systemically-act antel, clorSulon, one or more amino acetonitrile active agents, ing active agents that are active against internal parasites are one or more insect growth regulators, one or more neonico provided. In this embodiment, the compositions will provide tinoid active agents or an aryloazol-2-yl cyanoethylamino a high level of efficacy against roundworms, whipworms and active agent, or a combination thereof 55 hookworms while also preventing development of heart In general, the systemically-acting active agent (other than worm. In one embodiment, the active agent is a macrocyclic an isoxazoline active agent of formula (I), (II), (III) or (IV) lactone active agent or a combination of two or more macro described above) is included in the dosage units of the inven cyclic lactones. In another embodiment, the active agent is tion in an amount of between about 0.1 ugandabout 1000 mg. one or more benzimidazole active agents including, but not Typically, the active agent may be included in an amount of 60 limited to, thiabendazole, cambendazole, parbendazole, oxi about 10 ug to about 500 mg, about 10 ug to about 400 mg. bendazole, mebendazole, flubendazole, fenbendazole, about 1 mg to about 300 mg, about 10 mg to about 200 mg or oxfendazole, albendazole, cyclobendazole, febantel, about 10 mg to about 100 mg. More typically the active agent thiophanate and its o.o-dimethyl analogue; levamisole, pyr will be present in an amount of about 5 mg to about 50 mg in antel, morantel, praziquantel, closantel, clorSulon, one or the compositions of the invention. 65 more amino acetonitrile active agents or one or more aryloa The concentration of systemically-acting active agents Zol-2-yl cyanoethylamino active agents, or a combination of (other than an isoxazoline active agent of formula (I), (II), thereof. US 9,259,417 B2 41 42 In another embodiment, the invention provides soft chew 2.001-2.018 incombination withabamectin, dimadectin, dor able compositions comprising one or more macrocyclic lac amectin, emamectin, eprinomectin, ivermectin, latidectin, tones in combination with one or more benzimidazole active lepimectin, Selamectin, milbemectin, milbemycin D. milbe agents, levamisole, pyrantel, morantel, praziquantel, closan mycin A, milbemycin A, milbemycin oxime, moxidectin or tel, clorSulon, one or more amino acetonitrile active agents or 5 nemadectin, or a combination thereof. In still another one or more aryloazol-2-ylcyanoethylamino active agents, or embodiment, the invention provides soft chewable composi a combination of thereof. In still another embodiment, the tions comprising Compound A in combination with ivermec invention provides soft chewable compositions comprising tin, milbemycin Oxime or moxidectin, or a combination abamectin, dimadectin, doramectin, emamectin, eprinomec thereof. In yet another embodiment, the invention provides tin, ivermectin, latidectin, lepimectin, Selamectin, milbemec 10 tin, milbemycin D. milbemycin A, milbemycin A, milbe Soft chewable compositions comprising Compound A in mycin oxime, moxidectin or nemadectin, or a combination combination with ivermectin, milbemycin oxime or mox thereof. In another embodiment, the invention provides soft idectin, or a combination thereof, and with one or more ben chewable compositions comprising abamectin, emamectin, Zimidazole active agents, levamisole, pyrantel, morantel, eprinomectin, ivermectin, doramectin or Selamectin, or a 15 praziquantel, closantel, clorSulon, one or more amino aceto combination thereof. In still another embodiment, soft chew nitrile active agents or one or more aryloazol-2-yl cyanoet able compositions comprising iVermectin, milbemycin hylamino active agents, or a combination of thereof. In Oxime or moxidectin, or a combination thereof, are provided. another embodiment, the invention provides soft chewable In another embodiment, Soft chewable compositions com compositions comprising Compound A in combination with prising a combination of abamectin, dimadectin, doramectin, ivermectin, milbemycin Oxime or moxidectin, or a combina emamectin, eprinomectin, ivermectin, latidectin, lepimectin, tion thereof, and with pyrantel, praziquantel, febantel, or a Selamectin, milbemectin, milbemycin D. milbemycin A, combination of thereof. milbemycin A, milbemycin oxime, moxidectin or nemadec In some embodiments, the endoparasiticidal compositions tin, or a combination thereof, with one or more benzimidazole comprising one or more macrocyclic lactones alone or in active agents, levamisole, pyrantel, morantel, praziquantel, 25 combination with an isoxazoline active agent will provide an closantel, clorSulon, one or more amino acetonitrile active efficacy of at least about 90% against roundworm (Toxocara agents or one or more aryloazol-2-yl cyanoethylamino active canis), whipworm (Trichuris vulpis) or hookworm (Ancylos agents, or a combination of thereof, are provided. In another toma Caninum) while also preventing development of heart embodiment, the invention provides soft chewable composi worms and controllingectoparasites (e.g. fleas and ticks) with tions comprisingivermectin, milbemycin Oxime or moxidec 30 a high level of efficacy, as described above. In another tin, or a combination thereof, in combination with one or embodiment, the compositions of the invention comprising more benzimidazole active agents, levamisole, pyrantel, mor one or more macrocyclic lactone active agents alone or in antel, praziquantel, closantel, clorSulon, one or more amino combination with an isoxazoline active agent will provide an acetonitrile active agents or one or more aryloazol-2-yl cya efficacy of at least about 95% against roundworm (Toxocara noethylamino active agents, or a combination of thereof. 35 canis), whipworm (Trichuris vulpis) or hookworm (Ancylos In yet another embodiment, the invention provides soft toma caninum). In still another embodiment, the soft chew chewable compositions comprising ivermectin, milbemycin able compositions of the invention may provide an efficacy of Oxime or moxidectin, or a combination thereof, with praZi up to 100% against Dirofilaria immitis (heartworm) while quantel, pyrantel, febantel or levamisole. In yet another also controlling fleas and ticks with a high level of efficacy embodiment, soft chewable compositions comprising iver 40 (see above). Thus, administration of the soft chewable com mectin, milbemycin oxime or moxidectin, or a combination positions of the invention comprising one or more macrocy thereof, in combination with praziquantel, one or more ben clic lactones in combination with an isoxazoline active agent Zimidazole active agents or pyrantel, or a combination will prevent heartworm disease and control endoparasite thereof. infections while also controlling ectoparasites (e.g. fleas and In another embodiment, the endoparasiticidal composi 45 ticks). tions may include a combination of an isoxazoline active Formulations agent in combination with one or more macrocyclic lactone In one embodiment of the invention, the soft chewable active agents, a benzimidazole, levamisole, pyrantel, moran veterinary compositions are in the form of a soft chewable tel, praziquantel, closantel, clorSulon, one or more amino formulation (“soft chew') which is palatable and acceptable acetonitrile active agents, or one or more aryloazol-2-yl cya 50 to the animal. In addition to the active ingredient(s), the soft noethylamino active agents, or a combination of thereof. chews of the invention may include one or more of the fol In another embodiment, the invention provides composi lowing components: a solvent or mixture of Solvents, one or tions active against both endoparasites and ectoparasites more fillers, one or more binders, one or more surfactants, one comprising at least one isoxazoline compound of formula (I), or more humectants, one or more lubricants, one or more (II), (III) or (IV) in combination with abamectin, dimadectin, 55 disintegrants, one or more colorants, one or more antimicro doramectin, emamectin, eprinomectin, ivermectin, latidectin, bial agents, one or more antioxidants, one or more pH modi lepimectin, Selamectin, milbemectin, milbemycin D. milbe fiers and one or more flavoring agents. mycin A, milbemycin A, milbemycin oxime, moxidectin or Preferably, the components of the oral veterinary compo nemadectin, or a combination thereof, and optionally with a sitions will be classified as food grade quality or higher (e.g. further systemically-active endoparasiticide selected from 60 USP or NF grade). The term “food grade” is used to refer to one or more benzimidazole active agents, levamisole, pyran material that is Suitable for consumption by animals and will tel, morantel, praziquantel, closantel, clorSulon, one or more not contain chemical or other agents that are hazardous to the amino acetonitrile active agents and one or more aryloazol health of the animal. Thus, a food grade component, if of 2-yl cyanoethylamino active agents, or a combination of animal origin, will be prepared to Substantially reduce or thereof. In another embodiment, the invention provides com 65 eliminate the presence of infectious agents or contaminants positions comprising at least one isoxazoline compound of by processes known in the art Such as pasteurization, filtra formula (A), (B), Compound 1.001-1.025 or Compound tion, pressurization or irradiation. More preferably, the com US 9,259,417 B2 43 44 ponents of the soft chewable veterinary compositions of the corn syrup, honey, maple syrup and Sugars of various types; or invention will not be of animal origin to avoid transmission of a combination of two or more binders. In one embodiment, infective agents. the composition comprises the binders Povidone K30 LP and Solvents that may be used in the compositions of the inven PEG 3350 or PEG 4000, or a combination thereof. Binders tion include, but are not limited to, various grades of liquid are typically present in the compositions at a concentration of polyethylene glycol (PEG) including PEG 200, PEG 300, about 1% to about 30% (w/w). More typically, the composi PEG 400 and PEG 540; propylene carbonate; propylene gly tions will include binders at a concentration of about 1% to col; triglycerides including, but not limited to caprylic/capric about 20% (w/w), about 1 to about 15% (w/w), about 1% to triglyceride, caprylic/capric/linoleic triglyceride (e.g. MIG about 10% (w/w), about 5% to about 15% (w/w) or about 5% LYOLR 810 and 812, caprylic/capric/succinic triglyceride, 10 to about 10% (w/w). propylene glycol dicaprylate/dicaprate, and the like; water, Humectants that may be used in the compositions include, Sorbitol Solution, glycerol caprylate/caprate and polygly but are not limited to, glycerol (also referred to herein as colized glycerides (GELUCIRE(R), or a combination thereof. glycerin), propylene glycol, cetyl alcohol and glycerol Solvents may be included in the compositions in concen monostearate, and the like. Polyethylene glycols of various trations of about 1 to about 50% (w/w). In other embodi 15 grades may also be used as humectants. ments, the concentration of the solvents will be from about 1 In some embodiments, the humectant may comprise more to about 40% (w/w), about 1 to about 30% (w/w) or about 1 to than one oil including, but not limited to, fat or fats, both about 20% (w/w). More typically, the solvents will be in the natural and synthetic. Oil employed as an ingredient in the compositions at concentrations of about 5% to about 20% Soft chew may be a saturated or unsaturated liquid fatty acid, (w/w) or about 5% to about 15% (w/w). its glyceride derivatives or fatty acid derivatives of plant or Various fillers known in the art may be used in the soft animal origin or a mixture thereof. A source for typical animal chewable compositions of the invention. Fillers include, but fats or oils are fish oil, chicken fat, tallow, choice white are not limited to, corn starch, pre-gelatinized corn starch, Soy grease, prime steam lard and mixtures thereof. However, protein fines, corn cob, and corn gluten meal, and the like. In other animal fats are also suitable for use in the soft chew. Some embodiments, a combination of two or more fillers may 25 Suitable sources for vegetable fats or oils can be derived palm be used in the compositions. oil, palm hydrogenated oil, corn germ hydrogenated oil, cas The starch component may comprise starch from any tor hydrogenated oil, cotton-seed oil, soybean oil, olive oil, Source and may act as a binder in the soft chew. In one peanut oil, palm olein oil, Cacao fat, margarine, butter, short embodiment, the starch component used in the compositions ening and palm Stearin oil, and mixtures thereof. Addition is unmodified. In another embodiment, the starch component 30 ally, a mixture of animal or vegetable oils or fats is suitable for is derivatized and/or pregelatinized. In another embodiment, use in the matrix. the starch component is highly derivatized. Some starches Humectants may typically present in the compositions at a that can serve as a base starch for derivatization include concentration of about 1% to about 25% (w/w). Typically, the regular corn, waxy corn, potato, tapioca, rice, etc. Suitable concentration of the humectant in the composition of the types of derivatizing agents for the starch include, but are not 35 invention will be 1% to about 20% (w/w), about 1% to about limited to, ethylene oxide, propylene oxide, acetic anhydride, 15% (w/w) or about 5% to about 15% (w/w). More typically, and Succinic anhydride, and other food approved esters or the compositions of the invention will contain about 1% to ethers, introducing such chemicals alone or in combination about 10% (w/w) humectant. with one another. Surfactants may be present in the composition at concen In various embodiments, prior cross-linking of the starch in 40 trations of about 0.1% to about 10% (w/w), about 1% to about the starch component may or may not be necessary, based on 10% (w/w) or about 5% to about 10% (w/w). More typically, the pH of the system and the temperature used to form the surfactants may be presentat concentrations of about 0.1% to product. about 5% (w/w) or about 1 to about 5% (w/w). Examples of The starch component may also include amylaceous ingre Surfactants that may be used in the compositions include, but dients. The amylaceous ingredients can be gelatinized or 45 are not limited to, glyceryl monooleate, polyoxyethylene Sor cooked before or during the forming step to achieve the bitan fatty acid esters, Sorbitan esters including Sorbitan desired matrix characteristics. If gelatinized starch is used, it monooleate (SpanR 20), polyvinyl alcohol, polysorbates may be possible to prepare the product of the subject inven including polysorbate 20 and polysorbate 80, d-C-tocopheryl tion or perform the process of the subject invention without polyethylene glycol 1000 succinate (TPGS), sodium lauryl heating or cooking. However, ungelatinized (ungelled) or 50 Sulfate, co-polymers of ethylene oxide and propylene oxide uncooked Starch may also be used. (e.g. poloxomers such as LUTROL(R) F87 and the like), poly Fillers are typically present in the compositions at a con ethylene glycol castor oil derivatives including polyoxyl 35 centration of about 5% to about 80% (w/w), about 10% to castor oil (Cremophor(REL), polyoxyl 40 hydrogenated cas about 70% (w/w), about 10% to about 60%, about 10% to tor oil (Cremophor(R) RH 40), polyoxyl hydrogenated castor about 50% (w/w), or about 10% to about 40% (w/w). More 55 oil (Cremophor R. RH60); propylene glycol monolaurate typically, the fillers may be present at concentrations of about (LAUROGLYCOLR); glyceride esters including glycerol 30% to about 70%, about 30% to about 60%, about 30% to caprylate/caprate (CAPMUL(R) MCM), polyglycolized glyc about 50% or about 35% to about 55%. erides (GELUCIRE(R), PEG 300 caprylic/capric glycerides Binders that may be used in the compositions of the inven (SoftigenR 767), PEG 400 caprylic/capric glycerides (Labra tion include, but are not limited to, polyvinylpyrrolidone (e.g. 60 solR), PEG 300 oleic glycerides (Labrafil.R M-1944CS), Povidone), cross-linked polyvinylpyrrolidone (Crospovi PEG 300 linoleic glycerides (Labrafil.R M-2125CS); poly done), polyethylene glycols of various grades including PEG ethylene glycol Stearates and polyethylene glycol hydroxy 3350, PEG 4000, PEG 6000, PEG 8000 and even PEG stearates including polyoxyl 8 stearate (PEG 400 monostear 20,000, and the like; co-polymers of vinylpyrrolidone and ate), polyoxyl 40 stearate (PEG 1750 monostearate, and the vinyl acetate (e.g. Copovidone) Such as the product sold by 65 like. Polyethylene glycol Stearates (synonyms include mac BASF by the tradename Kollidon RVA 64 and the like; starch rogol Stearates, polyoxylstearates, polyoxyethylene Stearates, Such as potato starch, tapioca starch or corn starch; molasses, ethoxylated stearates; CAS No. 9004-99-3, 9005-08-7) are US 9,259,417 B2 45 46 mixtures of mono- and distearate esters of mixed polyoxy ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, ethylene polymers. Polyethylene glycol hydroxy Stearate is a Sodium ascorbate, Sodium metabisulfate, n-propyl gallate, mixture of mono- and diesters of hydroxystearic acid with BHA (butylated hydroxy anisole), BHT (butylated hydroxy polyethylene glycols. One polyethylene glycol hydroxy Stear toluene) monothioglycerol and the like. The antioxidants are ate that may be used in the compositions is polyethylene generally added to the formulation in amounts of from about glycol 12-hydroxyStearate. In another embodiment, the com 0.01 to about 2.0% (w/w), based upon total weight of the positions may include the Surfactant polyethylene glycol 15 formulation, with about 0.05 to about 1.0% or about 0.1% to 12-hydroxystearate (Solutol R HS 15 from BASF), a mixture about 0.2% (w/w) being especially preferred. of mono- and diesters of 12-hydroxystearic acid with 15 The compositions of the invention may also include one or moles of ethylene oxide. Again, these compounds, as well as 10 more lubricants/processing aids. In some cases, the lubricant/ their amounts are well known in the art. In another embodi processing aid may also behave as a solvent, and accordingly, ment of the invention, the compositions may include poly there some of the components of the inventive compositions oxyl 35 castor oil (Cremophor REL) as a surfactant. In other may have dual functions. Lubricants/processing aids include, embodiments, the chewable compositions may include poly but are not limited to polyethylene glycols of various molecu oxyl 40 hydrogenated castor oil (Cremophor(R) RH 40) or 15 lar weight ranges including PEG 3350 (Dow Chemical) and polyoxyl 60 hydrogenated castor oil (Cremophor R. RH60) as PEG 4000, corn oil, mineral oil, hydrogenated vegetable oils Surfactants. The compositions of the invention may also (STEROTEX or LUBRITAB), peanut oil and/or castor oil. In include a combination of Surfactants. certain embodiments, the lubricant/processing aid is a neutral The type and nature of the surfactant has been found to be oil comprising a medium chain triglyceride or propylene very important in keeping the active agent(s) in Solution after glycol fatty acid esters including caprylic/capric triglycer ingestion and dissolution of the oral compositions. This is ides. Non-limiting examples of neutral oils are known by the particularly important for obtaining the very high bioavail trademark MIGLYOL(R) including MIGLYOLR 810, MIG ability observed from the inventive oral compositions. How LYOLOR 812, MIGLYOLOR 818, MIGLYOLOR. 829 and MIG ever, it has been found that inclusion of certain Surfactants LYOLR 840. If present, the lubricant/processing aid may be with the veterinary dosage forms adversely affect the palat 25 in the composition at a concentration of about 1% to about ability of the dosage form, resulting in low acceptance by the 20% (w/w). Typically, the lubricant/processing aid will be animals treated. In one embodiment, polyethylene glycol 15 presentata concentration of about 1% to about 15% (w/w) or hydroxy Stearate, polyoxyl 40 hydrogenated castor oil or about 1% to about 10% (w/w). Preferably, the lubricant/ polyoxyl 60 hydrogenated castor oil, are effective for solubi processing aid will be present in the compositionata concen lizing active agents with low water Solubility including, but 30 tration of about 1% to about 5% (w/w). not limited to, isoxazoline active agents and the like, after The compositions may also include anti-microbial agents ingestion by the animal while also maintaining the palatabil or preservatives. Suitable preservatives include, but are not ity of the oral dosage form. Thus, in one embodiment of the limited to, the parabens (methylparaben and/or propylpara invention, the oral Veterinary compositions comprise Poly ben), benzalkonium chloride, benzethonium chloride, ben ethylene glycol 15 hydroxyStearate, polyoxyl 40 hydroge 35 Zoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, nated castor oil or polyoxyl 60 hydrogenated castor oil. In chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylpa another embodiment of the invention, the veterinary soft raben, imidurea, methylparaben, phenol, phenoxyethanol, chewable compositions of the invention comprise Polyethyl phenylethyl alcohol, phenylmercuric acetate, phenylmercu ene glycol 15 hydroxy Stearate, polyoxyl 40 hydrogenated ric borate, phenylmercuric nitrate, potassium Sorbate, sodium castor oil or polyoxyl 60 hydrogenated castor oil at a concen 40 benzoate, Sodium propionate, Sorbic acid, thimerosal, and the tration of about 1 to about 5% (w/w). like. The concentration of the preservatives in the composi In some embodiments, the compositions of the invention tions of the invention are typically from about 0.01 to about may contain one or more disintegrants. Examples of disinte 5.0% (w/w), about 0.01 to about 2% (w/w) or about 0.05 to grants that may be used in the compositions of the invention about 1.0% (w/w). In one embodiment, the compositions of include, but are not limited to, cellulose, carboxymethyl cel 45 the invention will contain about 0.1% to about 0.5% (w/w) of lulose calcium, carboxymethyl cellulose sodium, polacrilin the preservative. potassium, starch, hydroxypropyl starch, corn Starch, prege In an embodiment, the oral Veterinary compositions of the latinized starch, modified Starch, lactose monohydrate, cros invention may contain one or more stabilizers to stabilize carmellose sodium, hydroxypropyl cellulose, glycine, active ingredients that are susceptible. Suitable stabilizer Crospovidone, magnesium aluminum silicate, Sodium starch 50 components include, but are not limited to, magnesium Stear glycolate, guar gum, colloidal silicon dioxide, polyvinylpyr ate, citric acid, Sodium citrate, and the like. However, stabi rolidone (Povidone), alginic acid, Sodium alginate, calcium lizer components are common in the art and any Suitable one alginate, methylcellulose, chitosan, and the like, or a combi or mixture of more than one may be used. In an embodiment, nation thereof. a stabilizer component comprises about 0.0 percent to about In certain embodiments, the oral veterinary compositions 55 3.0 percent of the soft chew. In an alternate embodiment, a of the invention will include up to about 10% (w/w) of one or stabilizer component comprises about 0.5 percent to about more disintegrants. In one embodiment, the compositions 1.5 percent of the soft chew. may include about 1% (w/w) to about 7% (w/w) of one or Compounds which stabilize the pH of the formulation are more disintegrants. In another embodiment, the compositions also contemplated in the compositions of the invention. may include about 1% (w/w) to about 5% (w/w) or about 2% 60 Again, such compounds are well known to a practitioner in (w/w) to about 4% (w/w) of one or more disintegrants. the art as well as how to use these compounds. Buffering The inventive formulations may contain other inert ingre systems include, for example, systems selected from the dients such as antioxidants, preservatives, or pH stabilizers. group consisting of acetic acid/acetate, malic acid/malate, These compounds are well known in the formulation art. citric acid/citrate, tartaric acid/tartrate, lactic acid/lactate, Antioxidants may be added to the compositions of the inven 65 phosphoric acid/phosphate, glycine/glycimate, tris, glutamic tion to inhibit degradation of the active agents. Suitable anti acid/glutamates and Sodium carbonate. In one embodiment, oxidants include, but are not limited to, alpha tocopherol, the compositions may include the pH modifier citric acid or a US 9,259,417 B2 47 48 citric acid/citrate combination. The amount of the pH modi optionally one or more disintegrants described above, one or fier required to achieve a desired pH depends on the nature of more preservatives described above, one or more stabilizers the active ingredient(s) and non-active excipients. However, described above, one or more antioxidants described above in some embodiments the pH modifier may typically be and one or more pH modifying agents described above. present in an amount of about 0.1 to about 5% (w/w), about In another embodiment, the compositions may comprise 0.1 to about 3% (w/w) or about 0.1 to about 2% (w/w). More one or more solvents selected from various grades of liquid typically, the pH modifier may be present in a concentration polyethylene glycol (PEG) including PEG 200, PEG 300, of about 0.1 to 1% (w/w) in the inventive compositions. PEG 400 and PEG 540; propylene carbonate, propylene gly Many flavoring agents may be used in the compositions of col; triglycerides including, but not limited to caprylic/capric the invention to improve the palatability of the oral veterinary 10 triglyceride, caprylic?capric/linoleic triglyceride, caprylic/ formulations. Preferred flavoring agents are those that are not capric? succinic triglyceride, propylene glycol dicaprylate/di derived from animal sources. In various embodiments, fla caprate, glycerol caprylate/caprate and polyglycolized glyc Voring components derived from fruit, meat (including, but erides, or a combination thereof, one or more fillers selected not limited to pork, beef, chicken, fish, poultry, and the like), from corn starch, pre-gelatinized corn starch, soy protein Vegetable, cheese, bacon, cheese-bacon and/or artificial fla 15 fines, corn cob, and corn and gluten meal, or a combination Vorings may be used. A flavoring component is typically thereof; one or more flavors selected from natural and/or chosen based upon consideration related to the organism that artificial pork, beef, fish or poultry flavor, or a combination will be ingesting the soft chew. For example, a horse may thereof; one or more binders selected from polyvinylpyrroli prefer an apple flavoring component, while a dog may prefer done (e.g. Povidone), cross-linked polyvinylpyrrolidone a meat flavoring component. Although flavoring components (Crospovidone), polyethylene glycols of various grades derived from non-animal sources are preferred, in some including PEG 3350, PEG 4000, PEG 6000, PEG 8000 and embodiments, natural flavors containing beef or liver PEG 20,000; and co-polymers of vinylpyrrolidone and vinyl extracts, etc., may be used such as braised beef flavor artificial acetate (e.g. Copovidone), or a combination thereof, and one powdered beef flavor, roast beef flavor and corned beef flavor or more surfactants selected from glyceryl monooleate, poly among others. 25 oxyethylene Sorbitan fatty acid esters, Sorbitan esters includ Non-animal flavoring agents include, but are not limited to, ing Sorbitan monooleate, polyvinyl alcohol, polysorbates artificial beef flavors, flavors derived from plant proteins such including polysorbate 20 and polysorbate 80, d-C-tocopheryl as soy protein to which artificial flavoring has been added polyethylene glycol 1000 succinate, sodium lauryl sulfate, (e.g. Soy-derived bacon flavoring), and flavors derived from co-polymers of ethylene oxide and propylene oxide, polyeth plant proteins such as soy protein with no artificial flavoring. 30 ylene glycol castor oil derivatives including polyoxyl 35 cas Artificial beef flavors may be obtained from a variety of tor oil, polyoxyl 40 hydrogenated castor oil and polyoxyl 60 sources including Pharma Chemie Inc., TetraCenx, Givaudan hydrogenated castor oil; propylene glycol monolaurate:glyc S.A., Firmenich, Kemin Industries, inc., International Fla eride esters including glycerol caprylate/caprate, polygly Vors & Fragrances Inc., among others. colized glycerides, PEG 300 caprylic/capric glycerides, PEG In another embodiment, the flavoring component include, 35 400 caprylic/capric glycerides, PEG 300 oleic glycerides, but is not limited to, strawberry flavor, tutti fruity flavor, PEG 300 linoleic glycerides; polyethylene glycol stearates orange flavor, banana flavor, mint flavor, and an apple-molas and polyethylene glycol hydroxy Stearates including poly SCS. oxyl 8 Stearate, polyoxyl 40 Stearate and polyethylene glycol For administration to cattle, sheep, horses and other graz 15 12-hydroxyStearate, or a combination thereof, and option ing animals, as well as Small animals such as rabbits, ham 40 ally one or more humectants described above, one or more sters, gerbils, and guinea pigs, grains and seeds are especially lubricants described above, one or more preservatives appealing additional flavoring agents. The grains may be describe above, one or more stabilizers described above, one present in any form consistent with the production of the or more antioxidants described above and one or more pH chew including flour, bran, cereal, fiber, whole grain and meal modifiers described above. forms, including gluten meals, and may be rolled, crimped, 45 In another embodiment, the compositions comprise one or ground, dehydrated or milled. Minerals may also be added as more solvents selected from various grades of liquid polyeth flavorings, such as Salt and other spices. In one embodiment, ylene glycol including PEG 300, PEG 400 and PEG 540: the grain utilized is dehydrated, milled or flaked. Vegetables propylene carbonate; propylene glycol, caprylic/capric trig Such as dehydrated carrots and seeds Such as safflower seeds lyceride, caprylic/capric/linoleic triglyceride, propylene gly or milo seeds are especially appealing to Small animals and 50 col dicaprylate/dicaprate and glycerol caprylate/caprate, or a may be included. Additionally, flavors such as Sweet Apple combination thereof; one or more fillers selected from corn and Molasses Flavor Base and others produced by Pharma starch, pre-gelatinized corn starch, soy protein fines, or a Chemie, Givaudan S. A. or other suppliers may be utilized in combination thereof; one or more flavors selected from natu the compositions. ral and/or artificial pork, beef, fish or poultry flavor, or a The compositions of the invention may include one or 55 combination thereof; one or more binders selected from poly more flavoring agents in an amount that provides the desired vinylpyrrolidone, cross-linked polyvinylpyrrolidone, poly level of palatability to the target animal. The one or more ethylene glycols of various grades including PEG 3350, PEG flavoring agents will typically be presentina concentration of 4000, PEG 6000 and PEG 8000; and co-polymers of about 5% to about 40% (w/w). More typically, the flavoring vinylpyrrolidone and vinyl acetate, or a combination thereof. agents will be present in a concentration of about 10% to 60 one or more humectants selected from glycerol, propylene about 30%, or about 15% to about 25% (w/w). glycol, cetyl alcohol and glycerol monostearate, or a combi In one embodiment, the soft chewable compositions of the nation thereof, and one or more Surfactants selected from invention comprise one or more solvents described above, polyoxyethylene Sorbitan fatty acid esters, Sorbitan esters one or more fillers described above, one or more binders including Sorbitan monooleate, polysorbates including described above, one or more humectants described above, 65 polysorbate 20 and polysorbate 80, co-polymers of ethylene one or more surfactants described above, one or more flavors oxide and propylene oxide, polyethylene glycol castor oil described above, one or more lubricants described above, and derivatives including polyoxyl 35 castor oil, polyoxyl 40 US 9,259,417 B2 49 50 hydrogenated castor oil and polyoxyl 60 hydrogenated castor glycol 15 12-hydroxyStearate, or a combination thereof; one oil; propylene glycol monolaurate; PEG 300 caprylic/capric or more lubricants selected from polyethylene glycols of glycerides, PEG 400 caprylic/capric glycerides, PEG 300 various molecular weight ranges including PEG 3350 and oleic glycerides, PEG 300 linoleic glycerides; polyethylene PEG 4000, caprylic/capric triglycerides and propylene glycol glycol Stearates and polyethylene glycol hydroxy Stearates fatty acid esters, or a combination thereof, and optionally one including polyoxyl 8 Stearate, polyoxyl 40 Stearate and poly or more preservatives described above, one or more stabiliz ethylene glycol 15 12-hydroxyStearate, or a combination ers described above, one or more antioxidants described thereof; and optionally one or more lubricants described above and one or more pH modifiers described above. above, one or more preservatives described above, one or In still another embodiment, the soft chewable composi more stabilizers described above, one or more antioxidants 10 tions of the invention comprise one or more solvents selected described above and one or more pH modifiers described from liquid polyethylene glycols including PEG 300 and above. PEG 400; caprylic/capric triglyceride and propylene glycol In yet another embodiment, the soft chewable composi dicaprylate/dicaprate, or a combination thereof, at a concen tions of the invention comprise one or more solvents selected tration of about 1-20% (w/w) or about 5-20% (w/w); one or from liquid polyethylene glycols including PEG 200, PEG 15 more fillers selected from corn starch, pre-gelatinized corn 300 and PEG 400; caprylic/capric triglyceride and propylene starch and soy protein fines, or a combination thereof, at a glycol dicaprylate/dicaprate, or a combination thereof; one or concentration of about 30-60% (w/w) or about 30-50% more fillers selected from corn starch, pre-gelatinized corn (w/w); one or more flavors selected from natural and/or arti starch and soy protein fines, or a combination thereof; one or ficial beef, fish or poultry flavor, or a combination thereof, at more flavors selected from natural and/or artificial beef, fish a concentration of about 10-30% (w/w) or about 15-25% or poultry flavor, or a combination thereof; one or more bind (w/w); one or more binders selected from polyvinylpyrroli ers selected from polyvinylpyrrolidone, cross-linked polyvi done and polyethylene glycols of various grades including nylpyrrolidone, polyethylene glycols of various grades PEG 3350, PEG 4000 and PEG 6000, or a combination including PEG 3350, PEG 4000 and PEG 6000; and co thereof, at a concentration of about 1-10% (w/w) or about polymers of vinylpyrrolidone and vinyl acetate, or a combi 25 5-15% (w/w); one or more humectants selected from glycerol nation thereof; one or more humectants selected from glyc and propylene glycol, or a combination thereof, at a concen erol, propylene glycol and cetyl alcohol, or a combination tration of about 1-15% (w/w) or about 5-15% (w/w); and one thereof, and one or more Surfactants selected from polyoxy or more surfactants selected from Sorbitan esters including ethylene Sorbitan fatty acid esters, Sorbitan esters including Sorbitan monooleate, polysorbates including polysorbate 20 Sorbitan monooleate, polysorbates including polysorbate 20 30 and polysorbate 80, polyethylene glycol castor oil derivatives and polysorbate 80, polyethylene glycol castor oil derivatives including polyoxyl 40 hydrogenated castor oil and polyoxyl including polyoxyl 35 castor oil, polyoxyl 40 hydrogenated 60 hydrogenated castor oil; PEG 400 caprylic/capric glycer castor oil and polyoxyl 60 hydrogenated castor oil; PEG 300 ides and polyethylene glycol Stearates and polyethylene gly caprylic?capric glycerides, PEG 400 caprylic/capric glycer col hydroxy Stearates including polyoxyl 8 Stearate, polyoxyl ides and polyethylene glycol Stearates and polyethylene gly 35 40 stearate and polyethylene glycol 15 12-hydroxystearate, col hydroxy Stearates including polyoxyl 8 Stearate, polyoxyl or a combination thereof, at a concentration of about 1-5% 40 stearate and polyethylene glycol 15 12-hydroxystearate, (w/w) or about 5-10% (w/w); one or more lubricants selected or a combination thereof; one or more lubricants selected from polyethylene glycols of various molecular weight from polyethylene glycols of various molecular weight ranges including PEG 3350 and PEG 4000, caprylic/capric ranges including PEG 3350 and PEG 4000, hydrogenated 40 triglycerides and propylene glycol fatty acid esters, or a com Vegetable oils, castor oil, a medium chain triglyceride includ bination thereof, at a concentration of about 1-10% (w/w) or ing caprylic/capric triglycerides and propylene glycol fatty about 1-5% (w/w); and optionally one or more preservatives acid esters, or a combination thereof, and optionally one or described above, one or morestabilizers described above, one more preservatives described above, one or more stabilizers or more antioxidants described above and one or more pH described above, one or more antioxidants described above 45 modifiers described above. and one or more pH modifiers described above. In another embodiment, the soft chewable compositions of In another embodiment, the soft chewable compositions of the invention comprise one or more solvents selected from the invention comprise one or more solvents selected from liquid polyethylene glycols including PEG 300 and PEG 400; liquid polyethylene glycols including PEG 300 and PEG 400; and caprylic/capric triglyceride, or a combination thereof, at caprylic?capric triglyceride and propylene glycol dicaprylate/ 50 a concentration of about 5-20% (w/w); one or more fillers dicaprate, or a combination thereof; one or more fillers selected from corn starch, pre-gelatinized corn starch and Soy selected from corn starch, pre-gelatinized corn starch and Soy protein fines, or a combination thereof, at a concentration of protein fines, or a combination thereof; one or more flavors about 30-50% (w/w); one or more flavors selected from natu selected from natural and/or artificial beef, fish or poultry ral and/or artificial beef, fish or poultry flavor, or a combina flavor, or a combination thereof; one or more binders selected 55 tion thereof, at a concentration of about 15-25% (w/w); one or from polyvinylpyrrolidone and polyethylene glycols of vari more binders selected from polyvinylpyrrolidone and poly ous grades including PEG 3350, PEG 4000 and PEG 6000, or ethylene glycols of various grades including PEG 3350, PEG a combination thereof; one or more humectants selected from 4000 and PEG 6000, or a combination thereof, at a concen glycerol, propylene glycol and cetyl alcohol, or a combina tration of about 5-15% (w/w); one or more humectants tion thereof, and one or more surfactants selected from Sor 60 selected from glycerol and propylene glycol, or a combina bitan esters including Sorbitan monooleate, polysorbates tion thereof, at a concentration of about 5-15% (w/w); and including polysorbate 20 and polysorbate 80, polyethylene one or more Surfactants selected from polysorbates including glycol castor oil derivatives including polyoxyl 40 hydroge polysorbate 20 and polysorbate 80, polyethylene glycol cas nated castor oil and polyoxyl 60 hydrogenated castor oil; tor oil derivatives including polyoxyl 40 hydrogenated castor PEG 400 caprylic/capric glycerides and polyethylene glycol 65 oil and polyoxyl 60 hydrogenated castor oil; PEG 400 Stearates and polyethylene glycol hydroxy Stearates including caprylic/capric glycerides and polyethylene glycol Stearates polyoxyl 8 Stearate, polyoxyl 40 stearate and polyethylene and polyethylene glycol hydroxy Stearates including poly US 9,259,417 B2 51 52 oxyl 8 Stearate, polyoxyl 40 Stearate and polyethylene glycol wherein the active ingredient(s) are homogeneously distrib 15 12-hydroxyStearate, or a combination thereof, at a concen uted. The resulting dough-like mixture is then formed into tration of about 1-5% (w/w) or about 5-10% (w/w); one or soft chewable dosage units of different sizes for different size more lubricants selected from polyethylene glycols of vari animals. ous molecular weight ranges including PEG 3350 and PEG In one embodiment, the process to manufacture the soft 4000 and caprylic/capric triglycerides, or a combination chews will not include the addition of water, although there thereof at a concentration of about 1-5% (w/w); and option may be some amount of water included with certain compo ally one or more preservatives described above, one or more nents used. The presence of significant amounts of water in stabilizers described above, one or more antioxidants veterinary compositions is known to affect the stability of described above and one or more pH modifiers described 10 certain active agents. Thus, in certain embodiments of the above. invention water will not be added to the composition where In another embodiment, the oral veterinary compositions active agents and/or excipients are used that are Susceptible to of the invention are in the form of a chewable tablet. The tablet degradation in the presence of water. compositions will comprise an effective amount of at least The temperature at which the soft chewable veterinary one systemically-acting active agent described herein, and 15 compositions of the invention are prepared is dependent on typically a flavor, a filler, a lubricant, and a flow aid. Option the stability requirements of the active and non-active com ally, the inventive tablets may further contain at least one of ponents of the compositions. In certain cases where ingredi the following ingredients: colorants, binders, antioxidants, ents that are not temperature-sensitive are used, higher pro disintegrants, or preservatives. Moreover, in an alternative cessing temperatures may be tolerable. However, when active embodiment the invention provides for tablets which are and non-active ingredients are used that are sensitive to tem coated. The inventive tablets are prepared according to meth perature, the process may be adapted to operate at a tempera ods conventional in the art, Such as wet and dry granulation ture range that will not adversely impact the stability of the processes. composition. In some embodiments, the process will prefer Many of the ingredients for the tablet include those pro ably not impart significant amounts of heat during any one vided for in the soft chewable formulations described above. 25 processing step to avoid the possible degradation of any of the With respect to fillers (or diluents), the inventive tablets con components of the composition. Thus, in some embodiments, template all the fillers which are known in the tablet art. any one step of the process may be operated so that the Non-limiting examples of fillers include anhydrous lactose, average temperature of the mixture does not rise more than hydrated lactose, sprayed dried lactose, crystalline maltose about 20° C. above room temperature (room temperature will and maltodextrins. 30 be considered 20-25°C.). In other embodiments, the process Flow aids or glidants are also well known in the art and will be conducted so that the average temperature of the include, for example, silicon dioxide (CARBOSIL) or silica mixture does not rise more than about 15°C., more than about gel (SYLOID), talc, starch, calcium, Stearate, magnesium 10°C. or more than about 5°C. above room temperature. In stearate, and aluminum magnesium silicate (NEUSILIN). still another embodiment, the process may be conducted so Amounts of flow aids are readily determined by a practitioner 35 that the average temperature of the mixture will not rise more in this art and include for using about 0.01 to about 25%, than about 3° C. above room temperature. In some embodi based upon weight of total composition. Non-limiting ments, the required temperature may be maintained by the use examples of lubricants for the tablets include magnesium and of process cooling devices. In other embodiments, the calcium Stearate and Stearic acid. Again, the various lubri required temperature may be maintained by using equipment cants are well known to a practitioner of this art as well as the 40 that does not produce Sufficient heat to maintain the required amounts of these compounds. Ranges include from about temperature of the mixture during processing. 0.01 to about 20% (w/w). In one embodiment, active and inactive ingredients for the In various embodiments, the oral compositions of the Soft chews of the invention are added to a mixing vessel Such invention may be coated. Any Suitable coating may be used. as a planetary or double planetary mixer or a horizontal mixer In an embodiment, a coating is chosen that will not interfere 45 capable of blending the material and casting it against the side with an additive. In another embodiment, an additive is cho of the mixing vessels. This action permits the ingredients to sen that can modify the time for digestion of the additive(s), be well and consistently blended without application of heat thereby at least partially controlling the release of the or addition of pharmaceutical grade water to the mixture. additive(s). Suitable coatings include, but are not limited to, Horizontal mixers generally comprise a mixing chamber, and may be any pharmaceutically acceptable, and/or neutra 50 an elongated, horizontal mixing shaft which rotates, and a ceutically acceptable coating, as is common in the art. (poly plurality of mixing tools which depend generally perpendicu mers, monomers). Reference can be had to U.S. Pat. No. larly from the horizontal shaft to rotate around the inside of 6,498,153, incorporated herein by reference, to Cady etal. for the chamber (see, e.g., U.S. Pat. No. 5,735,603, the disclosure a list of polymers that can function as coatings. of which is incorporated herein by this reference). The mixing In other embodiments, coatings for the oral veterinary for 55 tools are configured and dimensioned as required for the mulations include gelatin, glyceryl behenate, cocabutter, and mixing process to follow the shape of the chamber walls as beeswax. Other coatings would be known to a practitioner in rotated for proper mixing of all of material present. Some this art. Coatings for tablets include Sugar coatings. Such as Such mixing chambers are cylindrically shaped, while others seal coatings, Subcoatings, and syrup coatings, as well as film are trough-shaped, such as mixers which are commonly coatings, such as pan-pour coatings and pan spray coatings. 60 referred to in the art as double-arm mixers or ribbon mixers. As well known to a practitioner of this art, the coatings con In one embodiment, the soft chewable compositions of the tain additional components such as solvents, plasticizers, invention may beformed from the dough-like mixture by any colorants, opaquant-extenders and film formers. Suitable forming techniques known in the art including form Method of Manufacture ing by hand. One of skill in the art will understand that once The soft chews of the invention are prepared by mixing the 65 the homogeneous dough mixture having the required proper active ingredient(s) with the non-active excipients in a mixer ties is prepared the individual dosage units of various sizes and mixing the components to achieve a dough-like mixture may be formed by weighing the required amount of the US 9,259,417 B2 53 54 dough-like mixture and forming the Soft chewable composi benzimidazole active agents including thiabendazole, oxi tions by handor using any other molding techniques known in bendazole, mebendazole, fenbendazole, oxfendazole, the art. In one embodiment, the dough-like mixture is albendazole, triclabendazole and febantel; or active agents of extruded to form the soft chewable dosage forms. In another other classes including levamisole, pyrantel, morantel, praZi embodiment, the soft chewable dosage forms are formed quantel, closantel, clorSulon, one or more amino acetonitrile using a forming machine. A variety of forming equipment active agents, one or more insect growth regulators, one or may be utilized in the invention including molding machines more neonicotinoid active agents or one or more aryloazol developed for use in producing molded food products, such as 2-yl cyanoethylamino active agents, or a combination pre-formed hamburger patties and chicken nuggets. For thereof. example, the molding machines described in U.S. Pat. Nos. 10 In one embodiment, the oral Veterinary composition is a 3,486, 186: 3,887,964; 3,952,478; 4,054,967; 4,097,961: 4,182,003; 4,334,339; 4,338,702; 4,343,068; 4,356,595; soft chewable composition. In another embodiment, the oral 4,372,008; 4,523,520; 4,535,505; 4,597,135; 4,608,731; Veterinary composition is a chewable tablet composition. 4,622,717; 4,697,308; 4,768,941; 4,780,931; 4,818,446; The methods and uses of the invention comprise the admin 4,821,376; 4,872,241; 4,975,039: 4,996,743; 5,021,025; 15 istration of any of the compositions of the invention described 5,022,888; 5,165,218: 5,655,436; 5,980,228 and 7,780,931 herein to an animal in need thereof. The compositions of the (the disclosures of which are incorporated herein by refer invention have been found to provide long-lasting efficacy ence) are representative of forming equipment that may be against ectoparasites (e.g. fleas and ticks) and/or endopara utilized in the invention. sites with a very fast onset of action, as described above. In one embodiment forming equipment that does not apply Furthermore, it has been found that the administration of the compression heat to the chew mixture may be utilized. Non active agents in the inventive oral compositions of the inven limiting examples of forming machines include those manu tion provide a very high level of bioavailability of the active factured by NuTec Manufacturing including model nos. 710, agent after oral administration to the animal. Thus, depending 720, 745, 750 and 760; and those manufactured by the For on the active agent included in the compositions, the inven max Corporation, including the VerTex 1000, NovaMax 500, 25 tion provides methods and uses for the treatment and preven Maxum 700, Ultra 26, F-19, F-400 and F-6. The order of tion of endoparasitic infections and/or ectoparasitic infesta mixing the components is not critical and various processing tions in an animal, which comprise administering an effective schemes may be used to form the dough-like mixture prior to amount of an oral composition of the invention to the animal. forming the soft chew dosage units. In some embodiments, In one embodiment for treatment against ectoparasites, the the active ingredient(s) and possibly some non-active com 30 ectoparasite is one or more insector arachnid including those ponents such as preservatives or antioxidants may first be of the genera Ctenocephalides, Rhipicephalus, Dermacentor, dissolved in a solvent(s) prior to mixing with other non-active Ixodes, Boophilus, Ambylomma, Haemaphysalis, components of the composition in a blender to form a dough Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, like mixture. The liquid components may be added at a con Hypoderma, Gasterophilus, Lucilia, Dermatobia, trolled rate to ensure homogeneity of the mixture. Alterna 35 Cochliomyia, Chrysomyia, Damalinia, Linognathus, Hae tively, the active ingredient(s) may be mixed in dry form matopinus, Solenopotes, Trichodectes, and Felicola. (Solid state) with other non-active components in a blender In another embodiment for the treatment against ectopara and liquid components may be added to the dry blended sites, the ectoparasite is from the genera Ctenocephalides, mixture with further mixing to form a uniform dough-like Rhipicephalus, Dermacentor, Ixodes and/or Boophilus. The mixture. In still another embodiment, the liquid components 40 ectoparasites treated include but are not limited to fleas, ticks, of the invention may first be placed in the blender and the dry mites, mosquitoes, flies, lice, blowfly and combinations components, including active agent(s) may be added to the thereof. Specific examples include, but are not limited to, cat liquid with further mixing to form a uniform dough-like mix and dog fleas (Ctenocephalides felis, Ctenocephalides sp. and ture. the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor Methods of Treatment 45 sp., Amblyomma sp., Haemaphysalis sp., and the like), and In another aspect of the invention, a method for preventing mites (Demodex sp., Sarcoptes sp., Otodectes sp., Cheyle and/or treating a parasite infestation and/or infection in an tiella sp., and the like), lice (Trichodectes sp., Felicola sp., animal is provided, comprising administering to the animal Linognathus sp., and the like), mosquitoes (Aedes sp., Culex an oral Veterinary composition comprising an effective sp., Anopheles sp., and the like) and flies (Hematobia sp. amount of at least one systemically-acting active agent 50 including Haematobia irritans, Musca sp., Stomoxys sp. together with a pharmaceutically acceptable carrier to the including Stomoxys calcitrans, Dermatobia sp., Cochliomyia animal. In one embodiment, the compositions comprise at sp., and the like). least one isoxazoline active agent. In another embodiment, Additional examples of ectoparasites include but are not the compositions may include one or more macrocyclic lac limited to the tick genus Boophilus, especially those of the tone active agents, one or more spinosyn or spinosoid com 55 species microplus (cattle tick), decoloratus and annulatus; pounds, one or more benzimidazole agents including thia myiases such as Dermatobia hominis (known as Berne in bendazole, oxibendazole, mebendazole, fenbendazole, Brazil) and Cochliomyia hominivorax (greenbottle); sheep oxfendazole, albendazole, triclabendazole and febantel; or myiases such as Lucilia sericata, Lucilia cuprina (known as active agents of other classes including levamisole, pyrantel, blowfly strike in Australia, New Zealand and South Africa) morantel, praziquantel, closantel, clorSulon, one or more 60 and Gasterophilus in horses. Flies proper, namely those insect growth regulators, one or more neonicotinoid active whose adult constitutes the parasite. Such as Haematobia agents, one or more amino acetonitrile active agents, or one or irritans (horn fly) and Stomoxys calcitrans (stable fly); lice more aryloazol-2-yl cyanoethylamino active agents, or a Such as Linognathus vituli, etc.; and mites such as Sarcoptes combination thereof. In still another embodiment the compo scabiei and Psoroptes ovis. The above list is not exhaustive sitions may include at least one isoxazoline active agent in 65 and other ectoparasites are well known in the art to be harmful combination with one or more macrocyclic lactones, one or to animals and humans. These include, for example migrating more spinosyn and/or spinosoid compounds, one or more dipteran larvae. US 9,259,417 B2 55 56 In some embodiments of the invention, the composition amectin, ML-1.694,554 and milbemycins including, but not can also be used to treat animals for endoparasite infestations limited to, milbemectin, milbemycin D. milbemycin A, mil Such as those comprised of helminths selected from the group bemycin A milbemycin Oxime, moxidectin and nemadectin. consisting of Anaplocephala, Ancylostoma, Anecator; In another embodiment, method comprises administering an Ascaris, Capillaria, Cooperia, Cyathostomum, Dipylidium, effective amount of a soft chewable composition comprising Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemon one or more of abamectin, emamectin, eprinomectin, iver chus, Oesophagostumum, Ostertagia, Parascaris, Toxocara, mectin, doramectin or Selamectin. In yet another embodi Strongylus, Strongyloides, Toxascaris, Trichinella, Trichuris ment, the method comprises administering an effective and Tricho strongylus, among others. amount of a soft chewable composition comprisingivermec In one embodiment, the invention provides methods for the 10 tin, milbemectin, milbemycin Oxime or moxidectin, or a com treatment and prevention of parasitic infections and infesta bination thereof. tions of animals (either wild or domesticated), including live In yet embodiment of the invention, the methods and uses stock and companion animals such as cats, dogs, horses, birds of the invention comprising one or more macrocyclic lac including chickens, sheep, goats, pigs, turkeys and cattle, tones, one or more spinosyn compounds, one or more benz with the aim of ridding these hosts of parasites commonly 15 imidazoles, levamisole, pyrantel, morantel, praziquantel, encountered by Such animals. closantel, clorSulon, one or more amino acetonitrile active In another embodiment, the invention provides methods agents or one or more aryloazol-2-yl cyanoethylamino active for the treatment and/or prevention of parasitic infections and agents, or a combination of thereof, in the compositions will infestations in companion animals including, but not limited provide an efficacy of at least about 90% against roundworm to, cats and dogs. Some methods and compositions of the (Toxocara canis), whipworm (Trichuris vulpis) or hookworm invention that comprise isoxazoline active agents are particu (Ancylostoma caninum). In another embodiment, the meth larly effective for preventing or treating parasitic infestations ods and uses of the invention comprising an active agent that of cats and dogs with fleas and ticks or other ectoparasites. is active against internal parasites including, but not limited In another embodiment, the methods and compositions of to, one or more macrocyclic lactones, will provide an efficacy the invention are used for the treatment or prevention of 25 of at least 95% against roundworm (Toxocara Canis), whip parasitic infections and infestations in cattle or sheep. When worm (Trichuris vulpis) or hookworm (Ancylostoma cani treating livestock animals such as cattle or sheep, the methods num). In still another embodiment, the methods and uses of and compositions of the invention that comprise an isoxazo the invention will provide an efficacy of up to 100% against line active agent are particularly effective against Rhipiceph Dirofilaria immitis (heartworm). alus (Boophilus) microplus, Haematobia irritans (horn fly), 30 In some embodiments, the combination of certain active Stomoxys calcitrans (stable fly), and sheep myiases Such as agents with an isoxazoline active agent will expand the scope Lucilia sericata, Lucilia cuprina (known as blowfly strike in of coverage of the method depending on the biological activ Australia, New Zealand and South Africa). ity of the additional active agent. For example, it is contem In one embodiment, the invention provides a method for plated that combination of the isoxazoline active agent with preventing and/or treating a parasitic infestation and/or infec 35 one or more additional active agents that are active against tion in an animal that comprises administering to the animal internal parasites Such as parasitic nematodes, (including a soft chewable veterinary composition comprising an effec roundworm, hookworm, whipworm and others), and/or tive amount of at least one isoxazoline active agent in com Dirofilaria immitis (Heartworm) will provide treatment and/ bination with an effective amount at least a second active or protection against internal parasites as well as external agent in a pharmaceutically acceptable carrier. Any of the 40 parasites (e.g. fleas and ticks, etc.). Thus, the invention pro additional active agents described above may be combined vides a method for the treatment and/or prevention of an with the isoxazoline active agent in the soft chewable veteri ectoparasitic infestation and an endoparasitic infection, com nary compositions. prising administering to the animal in need a soft chewable In another embodiment, the invention provides a method Veterinary composition comprising at least one isoxazoline for preventing and/or treating an endoparasitic infection in an 45 compound in combination with at least one compound that is animal that comprises administering to the animal a soft active against internal parasites. chewable veterinary composition comprising an effective In one embodiment, the invention provides a method for amount of a systemically-acting active agent that is active treating and/or preventing an endoparasitic infestation and against internal parasites including one or more macrocyclic ectoparasitic infection in an animal that comprises adminis lactones, one or more benzimidazole active agents including 50 tering a soft chewable veterinary composition comprising an thiabendazole, oxibendazole, mebendazole, fenbendazole, effective amount at least one isoxazoline active agent together oxfendazole, albendazole, triclabendazole and febantel; or with an effective amount of at least one macrocyclic lactone anthelmintics of other classes including levamisole, pyrantel, active agent. In some embodiments, the composition may morantel, praziquantel, closantel, clorSulon, one or more comprise at least one isoxazoline compound in combination amino acetonitrile active agents, or one or more aryloazol-2- 55 with abamectin, dimadectin, doramectin, emamectin, epri yl cyanoethylamino active agents, or a combination thereof. nomectin, ivermectin, latidectin, lepimectin, Selamectin, The methods of the invention for the treatment and/or pre ML-1,694,554 and milbemycins including, but not limited to, vention of endoparasites are effective against parasitic nema milbemectin, milbemycin D. milbemycin A, milbemycin todes, (including roundworm, hookworm, whipworm and A milbemycin Oxime, moxidectin or nemadectin, or a com others), and/or Dirofilaria immitis (Heartworm). 60 bination thereof. In another embodiment, the invention provides a method In another embodiment, methods and uses for the treatment for preventing and/or treating an endoparasitic infection in an and/or prevention of an ectoparasitic infestation and animal that comprises administering to the animal a soft endoparasitic infection are provided wherein the composition chewable veterinary composition comprising an effective administered comprises at least one isoxazoline active agent amount of one or more macrocyclic lactones including, but 65 in combination with one or more macrocyclic lactones and not limited to, abamectin, dimadectin, doramectin, emamec one or more spinosyn compounds, one or more spinosoid tin, eprinomectin, ivermectin, latidectin, lepimectin, sel compounds, one or more benzimidazoles, levamisole, pyran US 9,259,417 B2 57 58 tel, morantel, praziquantel, closantel, clorSulon, one or more concentration to provide a dose of about 0.001 mg/kg to about amino acetonitrile active agent, one or more insect growth 5 mg/kg, about 000.1 mg/kg to about 0.1 mg/kg or about regulators, one or more neonicotinoids or one or more ary 0.001 mg/kg to about 0.01 mg/kg. In still other embodiments, loazol-2-yl cyanoethylamino active agents, or a combination the active agent is present in an amount Sufficient to deliver a of thereof. dose of about 0.01 mg/kg to about 2 mg/kg or about 0.1 mg/kg In one embodiment, the invention provides methods and to about 1 mg/kg per body weight of the animal. In still other uses for the treatment and prevention of parasitic infections embodiments, the active agent may be present in an amount to and infestations of animals (either wild or domesticated), deliver a dose of about 1 lug/kg to about 200 ug/kg or about 0.1 including livestock and companion animals such as cats, mg/kg to about 1 mg/kg weight of animal. dogs, horses, birds including chickens, sheep, goats, pigs, 10 In one embodiment of the invention, the methods and uses turkeys and cattle, with the aim of ridding these hosts of of the invention comprising an isoxazoline active agent pro parasites commonly encountered by Such animals. vide protection of at least 90% efficacy against fleas (C. felis) In another embodiment, the invention provides methods for at least 30 days or at least 36 days as measured against and uses for the treatment or prevention of parasitic infections untreated controls according to the methods described in the and infestations in companion animals including, but not 15 examples. In another embodiment, the Soft chewable compo limited to, cats and dogs. sitions of the invention provide at least 90% efficacy against The compositions of the invention are administered in fleas for at least 44 days or for at least 58 days. parasiticidally effective amounts which are suitable to control In certain embodiments of the invention, methods and uses the parasite in question to the required extent, as described comprising an isoxazoline active agent are provided that pro herein. vide a high level of efficacy against fleas for periods of time in In some embodiments for methods that comprise an isox excess of 60 days. For example, in one embodiment, the azoline active agent, a dose of from about 0.05 about 100 mg compositions of the invention provide an efficacy of at least per kg of body weight of the isoxazoline active agent given as 90% against fleas for at least 72 days. In other embodiments, a single dose or in divided doses for a period of from 1 to 5 the compositions of the invention provide an efficacy of at days will be satisfactory but, of course, there can be instances 25 least 90% against fleas for at least 79 days, at least 86 days or where higher or lower dosage ranges are indicated, and Such even at least 93 days. In still other embodiments, the very long are within the scope of this invention. More typically, the dose lasting oral compositions of the invention provide an efficacy of the isoxazoline active agent may be between about 0.1 to of at least 90% against fleas for at least about 100 days, at least about 50 mg per kg, about 0.1 to about 25 mg/kg or about 0.1 about 107 days or even at least about 114 days. to about 10 mg/kg of body weight. In one embodiment, the 30 In yet another embodiment, methods and uses of the inven dose of the isoxazoline active agent administered will be tion comprising an isoxazoline active agent provide an effi about 0.1 to about 5 mg/kg or about 1 to about 5 mg/kg of cacy of at least about 95% against fleas (C. felis) for at least body weight. In another embodiment for long-lasting com about 30 days or at least about 36 days. In yet another embodi positions, the compositions will contain a dose of about 10 ment, the methods and uses of the invention provide an effi mg/kg to about 100 mg/kg of an isoxazoline active agent. 35 cacy of at least about 95% against fleas for at least about 44 More typically, the higher dose compositions will contain a days, at least about 58 days or at least about 72 days. In still dose of about 10 mg/kg to about 50 mg/kg or about 10 mg/kg other embodiments, the methods and uses of the invention to about 30 mg/kg of an isoxazoline active agent. In one provide an efficacy of at least about 95% against fleas for at embodiment, the high dose compositions will contain a dose least about 79 days, at least about 86 days or even about 93 of about 15 mg/kg to about 25 mg/kg per body weight of an 40 days or longer. For example, the methods and uses of the isoxazoline active agent. It is well within the routine skill of invention wherein compositions containing higher doses of the practitioner to determine a particular dosing regimen for a an isoxazoline active agent are administered may provide an specific host and parasite. efficacy of at least about 95% against fleas for at least about In various other embodiments of the invention, the meth 100 days, or even at least about 107 days or longer. ods and uses of the invention will include administering a soft 45 In yet another embodiment of the invention, the methods chewable veterinary composition comprising systemically and uses of the invention comprising administering a compo acting active agents that are active against internal parasites sition comprising an isoxazoline active agent provide about (endoparasiticidal) including, but not limited to, one or more 100% efficacy against fleas for at least about 23 days, at least macrocyclic lactones, one or more spinosyn compounds, one about 30 days or at least about 36 days. In still other embodi or more spinosoid compounds, a benzimidazole, levamisole, 50 ments, the methods and uses of the invention provide an pyrantel, morantel, praziquantel, closantel, clorSulon, one or efficacy of about 100% against fleas for at least about 44 days, more amino acetonitrile active agent, or one or more aryloa at least about 58 days or at least about 72 days. Zol-2-yl cyanoethylamino active agents, or a combination of In another embodiment of the invention, the methods and thereof. uses of the invention that comprise administering an oral Generally, the active agent active against internal parasites 55 composition comprising an isoxazoline active agent provide may be included in the composition to deliver a dose of about an efficacy of at least about 90% against ticks (including, but 0.05 mg/kg to about 50 mg/kg or about 0.5 mg/kg to about 50 not limited to, Dermacentor variabilis, Ixodes Scapularis, mg/kg of body weight of the animal. In other embodiments, Amblyomma americanum, Rhipicephalus sanguineus, Ixodes the endoparasiticidal active agent will typically be present in ricinus, Dermacentor reticulatus and Ixodes holocyclus) for an amount sufficient to deliver a dose of about 0.05 mg/kg to 60 at least about 23 days. More typically, the compositions will about 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg, about 0.1 provide an efficacy of at least about 90% against ticks for at mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 1 mg/kg least about 30 days or at least about 36 days. In still another or about 0.5 mg/kg to about 50 mg/kg per body weight of the embodiment, the methods and uses of the invention will pro animal. vide an efficacy of at least about 95% for at least about 23 In certain embodiments of the invention where the 65 days, at least about 30 days or at least about 36 days. endoparasiticidal active agent is a very potent compound Such In some embodiments, the methods and uses of the inven as a macrocyclic lactone, the active agent will be present in a tion comprising administering a composition that includes an US 9,259,417 B2 59 60 isoxazoline active agent provide an efficacy against ticks of at azoline active agent will provide an efficacy of up to 100% least about 90% for at least about 44 days, at least about 58 against Dirofilaria immitis (heartworm) while also control days, or at least about 72 days. In other embodiments, the ling fleas and ticks with a high level of efficacy (see above). methods and uses of the invention provide an efficacy against By “treating or “treat' or “treatment' is intended the ticks of at least about 90% for at least about 79 days, at least application or administration of a composition of the inven about 86 days or at least about 93 days. In other embodiments, tion to an animal that has a parasitic infestation for the eradi the methods and uses of the invention provide an efficacy cation of the parasite or the reduction of the number of the against ticks of at least about 95% for at least about 44 days, parasites infesting the animal undergoing treatment. It is at least about 58 days, at least about 72 days or even at least noted that the compositions of the invention may be used to about 79 days. In certain other embodiments, the methods and 10 prevent and control Such a parasitic infestation. uses of the invention with higher doses of the isoxazoline The compositions of the invention are administered in active agent may provide an efficacy against ticks of at least parasiticidally effective amounts which are suitable to control 90%, at least 95% or even 100% for at least about 100 days or the parasite in question to the desired extent, as described even for at least about 107 days, depending on the species of below. In each aspect of the invention, the compounds and ticks. This very high level of efficacy against ticks for such 15 extended periods of time from an oral dosage form is striking compositions of the invention can be applied against a single and without precedence in immediate release oral dosage pest or combinations thereof. forms. Furthermore, the methods and uses of the invention are The compositions of the invention may be administered Surprisingly effective against hard to control ticks, including continuously, for treatment or prevention of parasitic infec Amblyomma americanum and others. tions or infestations. In this manner, the compositions of the In yet another embodiment of the invention, the methods invention deliver an effective amount of the active com and uses of the invention of the invention that comprise a pounds to the animal in need thereof to control the target combination of an isoxazoline active agent in combination parasites. with a macrocyclic lactone active agent will provide an effi cacy of at least about 90% against roundworm (Toxocara 25 EXAMPLES canis), whipworm (Trichuris vulpis) or hookworm (Ancylos toma Caninum) while also controlling ectoparasites (e.g. fleas The invention is further described by the following non and ticks) with a high level of efficacy, as described above. In limiting examples which further illustrate the invention, and another embodiment, the methods and uses of the invention are not intended, nor should they be interpreted to, limit the comprising an isoxazoline active agent in combination with a 30 macrocyclic lactone will provide an efficacy of at least 95% Scope of the invention. Soft chews containing the isoxazoline active agent 4-5-3- against roundworm (Toxocara canis), whipworm (Trichuris chloro-5-(trifluoromethyl)phenyl-4,5-dihydro-5-(trifluo vulpis) or hookworm (Ancylostoma Caninum). In still another romethyl)-3-isoxazolyl-N-(2-oxo-2-(2.2.2-trifluoroethyl) embodiment, the methods and uses of the invention will pro aminoethyl-1-naphthalenecarboxamide (Compound A) as a vide an efficacy of up to 100% against Dirofilaria immitis 35 (heartworm) while also controlling fleas and ticks with a high representative isoxazoline compound alone and in combina level of efficacy (see above). Thus, administration of the soft tion with a macrocyclic lactone were prepared with a variety chewable compositions of the invention will prevent heart of non-active excipients and evaluated for effectiveness to worm infection and control infection of endoparasites while control endoparasites and ectoparasites in cats and dogs. In also controlling ectoparasites (e.g. fleas and ticks). 40 addition, Soft chewable compositions comprising one or more In another embodiment, the methods and uses of the inven parasiticides that are active against endoparasites were pre tion of the invention that comprise at least one systemically pared and evaluated for efficacy against various internal para acting endoparasiticidal active agent, with or without an isox sites. aZoline active agent, including one or more macrocyclic lactones, one or more spinosyn compounds, one or more 45 Example 1 spinosoid compounds, one or more benzimidazoles, levami sole, pyrantel, morantel, praziquantel, closantel, clorSulon, one or more amino acetonitrile active agents or one or more Preparation of Soft Chewable Veterinary aryloazol-2-yl cyanoethylamino active agents, or a combina Formulations tion of thereof, will provide an efficacy of at least about 90% 50 against roundworm (Toxocara Canis), whipworm (Trichuris The soft chewable formulation of Table 1 was prepared by vulpis) or hookworm (Ancylostoma Caninum). In another the following procedure: the active agent(s) and potassium embodiment, the methods and uses of the invention compris Sorbate (if present) were dissolved in the corresponding ing comprise at least one systemically-acting endoparasiti amount of solvent by mixing at ambient temperature. In a cidal active agent including one or more macrocyclic lac 55 blender, the filler (e.g. soy protein fines and/or starch) are tones, one or more spinosyn compounds, one or more mixed together at ambient temperature until blended, then the spinosoid compounds, one or more benzimidazoles, levami other non-active components and the pre-made solution of the sole, pyrantel, morantel, praziquantel, closantel, clorSulon, active agent(s) and potassium Sorbate (if present) are added to one or more amino acetonitrile active agents or one or more the mixture. The mixture is stirred further until a well aryloazol-2-yl cyanoethylamino active agents, or a combina 60 blended dough-type mixture is formed. tion of thereof, with or without an isoxazoline active agent, The dough-like mixture is then formed into individual soft will provide an efficacy of at least 95% against roundworm chewable dosage units in nominal sizes of 0.5g, 1 g and 4g. (Toxocara Canis), whipworm (Trichuris vulpis) or hookworm The formulations in Tables 2-24 may be prepared by similar (Ancylostoma Caninum). In still another embodiment, the procedures. In the tables below, the abbreviation “QS’ mean methods and uses of the invention comprising administering 65 ing “Quantum sufficit is intended to mean that the amount of a soft chewable composition that includes one or more mac corresponding component may be adjusted to bring the com rocyclic lactone active agents in combination with an isox position to 100% (w/w). US 9,259,417 B2 61 62 TABLE 1. TABLE 5-continued Ingredients Function % (w.fw) Ingredients Function % (w.fw) Cmpd. A -- Active 2.2 Polyoxyl 60 hydrogenated castor oil Surfactant 4.0 Soy Protein Fines Filler 26.5 (QS) 5 Glycerin Humectant S.1 Corn Starch Filler 31.0 artificialM meat flavor Flavoring S.1 Potassium Sorbate Preservative O.3 artificial beef flavor Flavoring 7.1 Propylene glycol dicaprylatedicaprate Solvent Lubricant 3.2 Powidone K-30 Binder 2.8 PEG 400 Solvent 5.4 PEG 400 Solvent 7.1 PEG 4OOO Binder 6.4 10 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Glycerin Humectant S.1 TABLE 6 Potassium Sorbate Preservative O.3 Caprylicicapric triglyceride Solvent Lubricant 3.2 Ingredients Function % (w.fw) 15 Cmpd. A Active 1.5 Soy Protein Fines Filler 46.5 (QS) beef flavor Flavoring 2O.O TABLE 2 Powidone K-30 Binder 7.0 0. PEG 400 Solvent 15 Ingredients Function % (w.fw) polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Cmpd. A Active 2.2 2O Caprylicicapric triglyceride Solvent lubricant 7.0 Soy Protein Fines Filler 56.0 (QS) artificial meat flavor Flavoring 5.5 artificial beef flavor Flavoring 7.5 Powidone K-30 Binder 2.8 TABLE 7 PEG 4OOO Binder 6.4 Sorbitan monooleate Surfactant 4.0 25 Ingredients Function % (w.fw) Glycerin Humectant S.1 Potassium Sorbate Preservative O.3 Cmpd. A Active 1875 Propylene glycol dicaprylate dicaprate Solvent Lubricant 3.2 Soy Protein Fines Filler 46.1 (QS) Propylene glycol Solvent 7.0 beef flavor Flavoring 2O.O Powidone K-30 Binder 8.5 PEG 400 Solvent 15.5 30 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 TABLE 3 Caprylicicapric triglyceride Solvent lubricant S.O

Ingredients Function % (w.fw) Cmpd. A Active 2.2 TABLE 8 Soy Protein Fines Filler 31 (QS) 35 Corn Gluten Meal Filler 3O.O Ingredients Function % (w.fw) artificial beef flavor Flavoring 12.0 Powidone K-30 Binder 2.8 Cmpd. A Active 1875 PEG 4OOO Binder 6.4 Soy Protein Fines Filler 36.1 (QS) Polyoxyl 60 hydrogenated castor oil Surfactant 4.0 beef flavor Flavoring 2O.O Potassium Sorbate Preservative O.3 40 Povidone K-30 Binder 8.5 Propylene glycol dicaprylate dicaprate Solvent Lubricant 3.2 PEG 400 Solvent 15.5 PEG 400 Solvent 8.0 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Caprylicicapric triglyceride Solvent lubricant S.O Croscarmellose sodium disintegrant 1O.O

TABLE 4 45 Ingredients Function % (w.fw) TABLE 9 Cmpd. A Active 2.2 Ingredients Function % (w.fw) Soy Protein Fines Filler 32.0 (QS) Pre-gelatinized Corn Starch Filler 31.0 50 Cmpd. A Active 2.3 artificial beef flavor Flavoring 12.0 Soy Protein Fines Filler 20.6 (QS) Powidone K-30 Binder 2.8 Corn Starch Filler 2SO PEG 4OOO Binder 6.4 beef flavor Flavoring 2O.S polyoxyl 35 castor oil Surfactant 4.0 Powidone K-30 Binder 2.8 Potassium Sorbate Preservative O.3 PEG 400 Solvent 7.2 Propylene glycol dicaprylate dicaprate Solvent Lubricant 3.2 55 PEG 4OOO Binder 6.4 PEG 400 Solvent 6.0 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Glycerin Humectant 8.6 Potassium Sorbate Preservative O.3 Caprylicicapric triglyceride Solvent Lubricant 3.1 TABLE 5 60 Ingredients Function % (w.fw) TABLE 10 Cmpd. A Active 2.2 Soy Protein Fines Filler 26.0 (QS) Ingredients Function % (w.fw) Pre-gelatinized Corn Starch Filler 3O.O beef flavor Flavoring 1S.O Cmpd. A Active 2.3 Copovidone Binder 3.3 65 Soy Protein Fines Filler 20.0 (QS) PEG 4OOO Binder 5.5 Corn Starch Filler 2SO US 9,259,417 B2 63 64 TABLE 10-continued TABLE 14-continued Ingredients Function % (w.fw) Ingredients Function % (w.fw) beef flavor Flavoring 2O.O Powidone K-30 Binder 2.8 5 Soy Protein Fines Filler 20.5 (QS) PEG 400 Solvent 7.1 Corn Starch Filler 24.0 PEG 4OOO Binder 6.4 beef flavor Flavoring 2O.O polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Copovidone Binder 2.75 Glycerin Humectant 1O.O Potassium Sorbate Preservative O.3 PEG 300 solvent 8.0 Caprylicicapric triglyceride Solvent Lubricant 3.2 10 PEG 4OOO Binder 6.35 Polyoxyl 60 hydrogenated castor oil Surfactant 3.1 Glycerin Humectant 1O.O Propylene glycol dicaprylatedicaprate Solvent Lubricant 2.15 TABLE 11 Potassium Sorbate Preservative O.3 BHT Antioxidant O.14 Ingredients Function % (w/w) 15 Citric Acid Monohydrate pH modifier OSO Milbemycin Oxime Active 0.375 Soy Protein Fines Filler 21.0 (QS) Corn Starch Filler 25.7 beef flavor Flavoring 2O2 Powidone K-30 Binder 2.7 2O TABLE 1.5 PEG 400 Solvent 7.1 Ingredients Function % (w.fw) PEG 4OOO Binder 6.3 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Cmpd. A Active 1875 Glycerin Humectant 10.1 Ivermectin Active 0.375 Caprylicicapric triglyceride Solvent Lubricant 3.1 Soy Protein Fines Filler 29.4 (QS) Potassium Sorbate Preservative O.3 25 Pre-gelatinized corn starch Filler 1S.O BHT Antioxidant O.14 beef flavor Flavoring 2O.O Copovidone Binder 2.75 Caprylate caprate glyceride Solvent 8.O PEG 4OOO Binder 6.35 TABLE 12 polyoxyl 35 castor oil (Cremophor (REL) Surfactant 3.1 30 Propylene glycol Humectant 1O.O Ingredients Function % (w.fw) Propylene glycol dicaprylatedicaprate Solvent Lubricant 2.2 Potassium Sorbate Preservative O.3 Cmpd. A Active 1.89 BHT Antioxidant 0.14 Milbemycin Oxime Active 0.375 Citric Acid Monohydrate pH modifier O.SO Soy Protein Fines Filler 20.0 (QS) Corn Starch Filler 24.7 beef flavor Flavoring 2O2 35 Powidone K-30 Binder 2.7 TABLE 16 PEG 400 Solvent 7.1 PEG 4OOO Binder 6.3 ngredients Function % (w.fw) polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Glycerin Humectant 10.1 Cmpd. A Active 2.2 Caprylicicapric triglyceride Solvent Lubricant 3.1 40 moxidectin Active OSO Potassium Sorbate Preservative O.3 Soy Protein Fines Filler 29.4 (QS) BHT Antioxidant O.14 Pre-gelatinized corn starch Filler 1S.O beef flavor Flavoring 2O.O Powidone K30 Binder 2.75 Caprylate caprate glyceride Solvent 8.0 TABLE 13 45 PEG 4OOO Binder 6.O Polyoxyl 40 hydrogenated castor oil Surfactant 3.1 Ingredients Function % (w.fw) (Cremophor (R) RH40) Propylene glycol Humectant Solvent 1O.O Cmpd. A Active 1875 Propylene glycol dicaprylatedicaprate Solvent Lubricant 2.2 Milbemycin Oxime Active 0.375 Potassium Sorbate Preservative O.3 Soy Protein Fines Filler 19.4 (QS) so BHT Antioxidant O.14 Corn Starch Filler 2SO Citric Acid Monohydrate pH modifier OSO beef flavor Flavoring 2O.O Powidone K-30 Binder 2.75 PEG 400 Solvent 7.1 PEG 4OOO Binder 6.35 TABLE 17 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 55 Glycerin Humectant 1O.O Ingredient Functi 9. Caprylicicapric triglyceride Solvent Lubricant 3.15 gredients CO 6 (wiw) Potassium Sorbate Preservative O.3 Cmpd. A Active O.S BHT Antioxidant O.14 Soy Protein Fines Filler 16.6 Citric Acid Monohydrate pH modifier OSO Corn Starch Filler 32.5 (QS) 60 beef flavor Flavoring 19.4 Powidone K-30 Binder 2.6 PEG 400 Solvent 7.8 TABLE 1.4 PEG 4OOO Binder 6.1 polyethylene glycol 12-hydroxyStearate Surfactant 4.7 Ingredients Function % (w.fw) Lauroyl polyoxyl-32 glycerides Surfactant 4.7 Potassium Sorbate Preservative O.3 Cmpd. A Active 1875 65 Caprylic/capric triglyceride Solvent Lubricant 4.9 Milbemycin Oxime Active 0.375 US 9,259,417 B2 65 66 TABLE 18 TABLE 22-continued

Ingredients Function % (w.fw) Ingredients Function % (w.fw) Cmpd. A Active O.S Soy Protein Fines Filler 19.4 Potassium Sorbate Preservative O.3 Pre-gelatinized corn Starch Filler 29.7 (QS) Caprylicicapric triglyceride Solvent Lubricant S.6 beef flavor Flavoring 18.0 Copovidone Binder 3.0 PEG 540 Solvent 8.3 PEG 4OOO Binder 6.1 Polyoxyl 60 hydrogenated castor oil Surfactant S.1 10 TABLE 23 (Cremophor (R) RH6O) Lauroyl polyoxyl-32 glycerides Surfactant 4.7 Ingredients Function % (w.fw) Potassium Sorbate Preservative O.3 Cmpd. A Active O.S Caprylicicapric triglyceride Solvent Lubricant 4.9 Corn Starch Filler 40.8 (QS) 15 beef flavor Flavoring 19.9 Powidone K-30 Binder 5.7 PEG 400 Solvent 11.4 TABLE 19 PEG 4OOO Binder 5.7 polyethylene glycol 12-hydroxyStearate Surfactant 2.7 Ingredients Function % (w.fw) Lauroyl polyoxyl-32 glycerides Surfactant 2.7 Potassium Sorbate Preservative O.3 Cmpd. A Active O.S Caprylicicapric triglyceride Solvent Lubricant 5.4 Soy Protein Fines Filler 26.9 (QS) Sodium Starch glycolate Disintegrate S.O Corn Starch Filler 23.4 beef flavor Flavoring 2O.O PEG 400 Solvent 6.8 PEG 4OOO Binder 5.8 TABLE 24 polyethylene glycol 12-hydroxyStearate Surfactant 4.8 25 Lauroyl polyoxyl-32 glycerides Surfactant 6.3 Ingredients Function % (w.fw) Potassium Sorbate Preservative O.3 Caprylicicapric triglyceride Solvent Lubricant 5.2 Cmpd. A Active O.S Soy Protein Fines Filler 19.4 Corn Starch Filler 24.0 (QS) 30 beef flavor Flavoring 19.2 TABLE 20 Powidone K-30 Binder 2.6 PEG 400 Solvent 8.6 Ingredients Function % (w.fw) PEG 4OOO Binder 6.O polyethylene glycol 12-hydroxyStearate Surfactant 4.6 Cmpd. A Active O.S Lauroyl polyoxyl-32 glycerides Surfactant 4.6 Soy Protein Fines Filler 24.3 (QS) 35 Potassium Sorbate Preservative O.3 Pre-gelatinized corn starch Filler 26.0 Caprylicicapric triglyceride Solvent Lubricant 5.3 beef flavor Flavoring 19.0 Glycerin Humectant 4.8 PEG 540 Solvent 6.8 Crospovidone Binder 5.8 polyoxyl 35 castor oil (Cremophor (REL) Surfactant 5.2 Lauroyl polyoxyl-32 glycerides Surfactant 6.9 40 TABLE 25 Potassium Sorbate Preservative O.3 Caprylicicapric triglyceride Solvent Lubricant 5.2 Ingredients Function % (w.fw) Cmpd. A Active 2.3 Soy Protein Fines Filler 22.0 (QS) TABLE 21 45 Corn Starch Filler 26.4 beef flavor Flavoring 1O.O Ingredients Function % (w.fw) Artificial Powdered Meat Flavor Flavoring 1O.O Powidone K-30 Binder 2.7 Cmpd. A Active O.S PEG 400 Solvent 7.0 Soy Protein Fines Filler 41.6 (QS) PEG 4OOO Binder 6.25 beef flavor Flavoring 19.9 50 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Powidone K-30 Binder 4.6 Glycerin Humectant 7.0 PEG 400 Solvent 15.1 Potassium Sorbate Preservative O.3 PEG 4OOO Binder 8.1 Caprylicicapric triglyceride Solvent Lubricant 3.0 polyethylene glycol 12-hydroxyStearate Surfactant 4.6 Potassium Sorbate Preservative O.3 Caprylicicapric triglyceride Solvent Lubricant 4.6 55 TABLE 26 Ingredients Function % (w.fw) TABLE 22 Cmpd. A Active 13.6 Ingredients Function % (w.fw) Soy Protein Fines Filler 15-25 (QS) 60 Corn Starch Filler 15-25 Cmpd. A Active O.S beef flavor Flavoring 2O Soy Protein Fines Filler 44.2 (QS) PEG 400 Solvent 11.9 beef flavor Flavoring 18.0 PEG 4OOO Binder 5 Powidone K-30 Binder 4.6 polyethylene glycol 12-hydroxyStearate Surfactant 3-5 PEG 400 Solvent 15.1 Glycerin Humectant 2-5 Cross-linked polyvinylpyrrollidone Binder 7.1 65 Potassium Sorbate Preservative O.3 propylene glycol monolaurate Surfactant 4.6 US 9,259,417 B2 67 TABLE 27 TABLE 32

Ingredients Function % (w.fw) Ingredients Function Cmpd. A Active 13.6 Cmpd. A Active 13.6 Corn Starch Filler 41 (QS) Soy protein fines Filler 24.2 (QS) beef flavor Flavoring 15-25 Corn Starch Filler 15 PEG 400 Solvent 11.9 beef flavor Flavoring 2O Cross-linked polyvinylpyrrollidone Binder 5 PEG 400 Solvent 11.9 polyoxyl 35 castor oil Surfactant 3-5 PEG 4OOO Binder S.O Propylene glycol Humectant 2-5 polyethylene glycol 12-hydroxyStearate Surfactant S.O Potassium Sorbate Preservative O.3 10 Caprylicicapric triglyceride Solvent lubricant 1.O Glycerin Humectant 4.0 Potassium Sorbate Preservative O.3

TABLE 28 Ingredients Function % (w.fw) 15 TABLE 33 Cmpd. A Active 13.6 Ingredients Function % (w.fw) Soy Protein Fines Filler 12.6 Corn Starch Filler 25 (QS) Milbemycin Oxime Active 0.375 beef flavor Flavoring 2O Soy protein fines Filler 47.7 (QS) Powidone K-30 Binder 2.75 beef flavor Flavoring 2O.O PEG 400 Solvent 5.5 Powidone K-30 Binder 7.5 PEG 4OOO Binder 6.2 PEG 400 Solvent 16.O polyethylene glycol 12-hydroxyStearate Surfactant S.O polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Glycerin Humectant 7-8 Caprylicicapric triglyceride Solvent lubricant S.O Potassium Sorbate Preservative O.3 Potassium sorbate Preservative O.3 Caprylicicapric triglyceride Solvent Lubricant 2.0 BHT Antioxidant O.14 25

TABLE 29 TABLE 34

Ingredients Function % (w.fw) 30 Ingredients Function Cmpd. A Active 13.6 Compound A Active 1875 Soy protein fines Filler 25.0 (QS) Milbemycin Oxime Active 0.375 Corn Starch Filler 15-18 Corn starch Filler 2O.O beef flavor Flavoring 2O Soy protein fines Filler 28.3 (QS) PEG 400 Solvent 11.9 beef flavor Flavoring 2S.O Cross-linked polyvinylpyrrollidone Binder 5 35 Powidone K-30 Binder 6.O polyoxyl 35 castor oil Surfactant 3-5 PEG 400 Solvent 12.O Propylene glycol Humectant 2-5 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Potassium Sorbate Preservative O.3 Caprylicicapric triglyceride Solvent lubricant 3.0 Potassium sorbate Preservative O.3 BHT Antioxidant O.14 40 TABLE 30 Ingredients Function % (w.fw) TABLE 35

Cmpd. A Active 13.6 Ingredients Function Soy protein fines Filler 15.2 (QS) 45 Corn Starch Filler 25 Milbemycin Oxime Active 0.375 beef flavor Flavoring 2O Soy protein fines Filler 21 (QS) PEG 400 Solvent 11.9 Starch Filler 25 PEG 4OOO Binder S.O beef flavor Flavoring 2O polyethylene glycol 12-hydroxyStearate Surfactant S.O Powidone K-30 Binder 2.75 Caprylicicapric triglyceride Solvent lubricant 1.O 50 PEG 400 Solvent 7.1 Glycerin Humectant 3.0 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Potassium Sorbate Preservative O.3 Binder 6.35 Caprylicicapric triglyceride Solvent lubricant 3.15 Glycerin Humectant Potassium sorbate Preservative TABLE 31 BHT Antioxidant 55 Citric acid Preservative Ingredients Function % (w.fw) Cmpd. A Active 13.6 Soy protein fines Filler 19.2 (QS) TABLE 36 Corn Starch Filler 2O 60 beef flavor Flavoring 2O Ingredients Function PEG 400 Solvent 11.9 PEG 4OOO Binder S.O Moxidectin Active O.O3 polyethylene glycol 12-hydroxyStearate Surfactant S.O Soy protein fines Filler 21 (QS) Caprylicicapric triglyceride Solvent lubricant 1.O Starch Filler 25 Glycerin Humectant 4.0 beef flavor Flavoring 2O Potassium Sorbate Preservative O.3 65 Powidone K-30 Binder 2.75 PEG 400 Solvent 7.1 US 9,259,417 B2 69 70 TABLE 36-continued TABLE 40-continued Ingredients Function % (w.fw) Ingredients Function % (w.fw) polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Soy protein fines Filler 44.23 (QS) PEG 4OOO Binder 6.35 5 beef flavor Flavoring 15 Caprylicicapric triglyceride Solvent lubricant 3.15 Powidone K-30 Binder 6 Glycerin Humectant 1O.O Propylene glycol Solvent 7.0 Potassium sorbate Preservative O.3 polyoxyl 40 hydrogenated castor oil Surfactant 4 BHT Antioxidant O.14 Ethanol Solvent 5 Citric acid Preservative O.S Caprylicicapric triglyceride Solvent lubricant 6 10 Tocopherol Antioxidant 1 Potassium sorbate Preservative O.30 TABLE 37 BHT Antioxidant O.14

Ingredients Function % (w.fw) Ivermectin Active O.O2 15 TABLE 41 Soy protein fines Filler 21 Starch Filler 25 Ingredients Function % (w.fw) beef flavor Flavoring 2O Powidone K-30 Binder 2.75 Praziquantel Active 1875 PEG 400 Solvent 7.1 Febantel Active 9.375 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 20 Moxidectin Active 0.075 PEG 4OOO Binder 6.35 Soy protein fines Filler 44.16 (QS) Caprylicicapric triglyceride Solvent lubricant 3.15 beef flavor Flavoring 15 Glycerin Humectant 1O.O Powidone K-30 Binder 6 Potassium sorbate Preservative O.3 Propylene glycol Solvent 7.0 BHT Antioxidant O.14 polyoxyl 40 hydrogenated castor oil Surfactant 4 Citric acid Preservative O.S 25 Ethanol Solvent 5 Caprylicicapric triglyceride Solvent lubricant 6 Tocopherol Antioxidant 1 Potassium sorbate Preservative O.30 TABLE 38 BHT Antioxidant O.14 Ingredients Function % (w/w) 30 Moxidectin Active O.O3 TABLE 42 Milbemycin Oxime Active 0.375 Compound A Active 1875 Ingredients Function % (w.fw) Soy protein fines Filler 23 (QS) Starch Filler 21 Praziquantel Active 1875 beef flavor Flavoring 2O 35 Febantel Active 9.375 Powidone K-30 Binder 2.75 Milbemycin Oxime Active 0.375 PEG 400 Solvent 7.1 Soy protein fines Filler 43.85 (QS) polyethylene glycol 12-hydroxyStearate Surfactant 3.1 beef flavor Flavoring 15 PEG 4OOO Binder 6.35 Powidone K-30 Binder 6 Caprylicicapric triglyceride Solvent lubricant 3.15 Propylene glycol Solvent 7.0 Glycerin Humectant 1O.O 40 polyoxyl 40 hydrogenated castor oil Surfactant 4 Potassium sorbate Preservative O.3 Ethanol Solvent 5 BHT Antioxidant O.14 Caprylicicapric triglyceride Solvent lubricant 6 Citric acid Preservative O.S Tocopherol Antioxidant 1 Potassium sorbate Preservative O.30 BHT Antioxidant O.14 45 TABLE 39 Ingredients Function % (w.fw) TABLE 43 Moxidectin Active O.O15 Ingredients Function % (w.fw) Soy protein fines Filler 21 (QS) 50 Starch Filler 25 Milbemycin Oxime Active 0.375 beef flavor Flavoring 2O Soy protein fines Filler 47.69 (QS) Powidone K-30 Binder 2.75 beef flavor Flavoring 2O PEG 400 Solvent 7.1 Powidone K-30 Binder 7.5 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 PEG 400 Solvent 16.0 PEG 4OOO Binder 6.35 55 polyethylene glycol 12-hydroxyStearate Surfactant 3.0 Caprylicicapric triglyceride Solvent lubricant 3.15 Caprylicicapric triglyceride Solvent lubricant 5 Glycerin Humectant 1O.O Potassium sorbate Preservative O.30 Potassium sorbate Preservative O.3 BHT Antioxidant O.14 BHT Antioxidant O.14 Citric acid Preservative O.S

60 TABLE 44 TABLE 40 Ingredients Function % (w.fw) Ingredients Function % (w.fw) Milbemycin Oxime Active 0.375 Soy protein fines Filler 47.69 (QS) Praziquantel Active 1875 65 beef flavor Flavoring 2O Febantel Active 9.375 Powidone K-30 Binder 7.5 US 9,259,417 B2 71 72 TABLE 44-continued TABLE 48-continued Ingredients Function % (w.fw) Ingredients Function % (w.fw) Propylene glycol Solvent 16.O Soy protein fines Filler 19.3 (QS) polyoxyl 40 hydrogenated castor oil Surfactant 3.0 5 Corn starch Filler 25 Caprylicicapric triglyceride Solvent lubricant 5 beef flavor Flavoring 2O Potassium sorbate Preservative O.30 Powidone K-30 Binder 2.75 BHT Antioxidant O.14 PEG 400 Solvent 7.1 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 PEG 4OOO Binder 6.35 10 Caprylicicapric triglyceride Solvent lubricant 3.15 Glycerin Humectant 1O.O TABLE 45 Potassium sorbate Preservative O.3 BHT Antioxidant O.14 Ingredients Function % (w.fw) Citric acid Preservative O.S Milbemycin Oxime Active 0.375 Soy protein fines Filler 21.24 (QS) 15 Corn starch Filler 25 beef flavor Flavoring 2O TABLE 49 Powidone K-30 Binder 2.75 PEG 400 Solvent 7.1 Ingredients Function % (w.fw) PEG 4OOO Binder 6.35 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Moxidectin Active O.O3 Glycerin Humectant 10 Milbemycin Oxime Active 0.375 Caprylicicapric triglyceride Solvent lubricant 3.15 Soy protein fines Filler 21.2 (QS) Potassium sorbate Preservative O.30 Corn starch Filler 25 BHT Antioxidant O.14 beef flavor Flavoring 2O Powidone K-30 Binder 2.75 PEG 400 Solvent 7.1 25 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 PEG 4OOO Binder 6.35 TABLE 46 Caprylicicapric triglyceride Solvent lubricant 3.15 Glycerin Humectant 1O.O Ingredients Function % (w.fw) Potassium sorbate Preservative O.3 Ivermectin Active O.O15 BHT Antioxidant O.14 Milbemycin Oxime Active 0.375 30 Citric acid Preservative O.S Compound A Active 1875 Soy protein fines Filler 19.3 (QS) Corn starch Filler 25 beef flavor Flavoring 2O Example 2 Powidone K-30 Binder 2.75 PEG 400 Solvent 7.1 35 polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Efficacy of Soft Chewable Compositions Comprising PEG 4OOO Binder 6.35 Compounda Against Fleas (Ctenocephalides felis) Caprylicicapric triglyceride Solvent lubricant 3.15 and Ticks (Dermacentor variabilis) on Dogs Glycerin Humectant 1O.O Potassium sorbate Preservative O.3 BHT Antioxidant O.14 40 Sixteen beagles were studied to determine the effective Citric acid Preservative O.S ness of a soft chewable veterinary composition comprising Compound A against induced infestations of Dermacentor variabilis and Ctenocephalides felis. TABLE 47 Four Treatment Groups containing four dogs each were 45 formed. Dogs in Group 1 were untreated. Dogs in Groups 2, Ingredients Function % (w.fw) 3 and 4 were treated with the soft chewable composition Ivermectin Active O.O15 described in Table 6 of nominal sizes of 0.5 g and 1 g con Milbemycin Oxime Active 0.375 taining Compound A at concentrations of 7.35 mg/chew and Soy protein fines Filler 21.2 (QS) 14.7 mg/chew, respectively, to deliverdoses of approximately Corn starch Filler 25 50 1.5 mg/kg, 2.5 mg/kg or 3.5 mg/kg. All dogs were treated beef flavor Flavoring 2O Powidone K-30 Binder 2.75 once on Day 0. PEG 400 Solvent 7.1 All dogs were infested with approximately 100 C. felis on polyethylene glycol 12-hydroxyStearate Surfactant 3.1 Days -1, 8, 15, 22, 29, 35, 43, 57 and 71. All dogs were also PEG 4OOO Binder 6.35 Caprylicicapric triglyceride Solvent lubricant 3.15 infested with approximately 50 D. variabilis on Days -1, 7. Glycerin Humectant 1O.O 55 14, 21, 28, 34 and 42. Both ticks and fleas were counted upon Potassium sorbate Preservative O.3 removal on Days 2, 9, 16, 23, 30, 36 and 44. Fleas were BHT Antioxidant O.14 counted upon removal for all Treatment Groups on Days 58 Citric acid Preservative O.S and 72. Flea efficacy is listed in Table 50 and tick efficacy is listed in Table 51 below. 60 Percent reduction (also referred as efficacy) against fleas TABLE 48 was 100% through and including Day 30 for all treatment groups (see Table 50). Percent reduction against fleas was Ingredients Function % (w.fw) above 95% through Day 44 for all groups and above 95% Moxidectin Active O.O3 through Day 58 for Groups 3 and 4. Milbemycin Oxime Active 0.375 65 The percent reduction against ticks was >90% through and Compound A Active 1875 including Day 30 (see Table 51) for all treatment groups and remained above 90% through Day 36 for Groups 3 and 4. US 9,259,417 B2 73 74 These study data demonstrate that soft chewable composi observed. Following infestation at later timepoints, the com tions comprising an isoxazoline compound (Cmpd. A) at position started working within 30 minutes, and by 12 hours three different doses provides excellent efficacy against fleas after infestation on Days 7, 14 and 21, efficacy of >98% was and ticks in dogs. achieved. TABLE 50 Flea Efficacy % Reduction Fleas Treatment Day Day Day Day Day Day Day Day Day Study Group' 2 9 16 23 30 36 44 58 72

Group 2 1OOO 1OO.O 1OOO 1OO.O 1OOO 99.2 97.8 89.4 79.6 % Reduction Group 3 1OOO 1OO.O 1OOO 1OO.O 1OOO 1OOO 99.3 96.7 94.4 % Reduction Group 4 1OOO 1OO.O 1OOO 1OO.O 1OOO 99.6 98.3 95.2 80.6 % Reduction

TABLE 51 Example 4 Tick Efficacy Efficacy of Soft Chewable Compositions Comprising Compounda Against Amblyomma americanum % Reduction Ticks Ticks on Dogs 25 Treatment Day Day Day Day Day Day Day Following a procedure very similar to that described in Group' 2 9 16 23 30 36 44 Example 2 above with the chewable formulation described in Group 2 1OOO 99.2 10O.O 92.1 99.5 82.4 68.3 Table 10, sixteen beagles were studied to determine the effec % Reduction tiveness of a soft chewable veterinary composition compris Group 3 1OOO 100.O. 99.1 97.2 94.3 96.9 88.1 30 ing Compound Aagainst induced infestations of Amblyomma % Reduction americanum (lone star tick). Group 4 1OO.O 100.0 99.S 10O.O 98.1 91.9 84.7 Two treatment groups were formed, each containing eight % Reduction dogs each. Dogs in Group 1 were untreated. Dogs in Group 2 were treated once on Day 0 with soft chewable compositions 35 containing Compound A at a concentration to deliver a dose of at least approximately 2.5 mg/kg. Example 3 Dogs in both groups were infested with approximately 50 Amblyomma americanum on Days -1, 7, 14, 21, 28 and 35. Ticks were counted on Days 2, 9, 16, 23, 30 and 38. The Efficacy and Speed of Kill Efficacy of Soft Chewable 40 percent efficacy of the treated group versus the untreated Compositions Comprising Compounda Against control group 48 hours after infestation exceeded 91% at Fleas (Ctenocephalides felis) on Dogs Days 2, 9, 16 and 23, with percent efficacy values of 99.2, 98.7, 99.4 and 91.7, respectively (p-values.<0.001). At Day 38 Following a procedure very similar to that described in the percent efficacy was measured at 89.7%. The study dem Example 2 above, beagles were studied to determine the 45 onstrates that the chewable compositions of the invention effectiveness and speed of kill against induced infestations of provided excellent control of Amblyomma americanum in Ctenocephalides felis. excess of 30 days. Three Treatment Groups were formed. Dogs in Group 1 Example 5 were untreated. Dogs in Groups 2 and 3 were treated with the 50 Soft chewable compositions containing Compound A Efficacy of Soft Chewable Compositions Comprising described in Tables 7 and 8, respectively, at concentrations to Compounda Against Ixodes holocyclus Ticks on deliver a dose of approximately 2.5 mg/kg. Groups 1 and 2 Dogs contained 12 dogs each and Group 3 contained 4 dogs. All dogs were treated once on Day 0. 55 Following a procedure very similar to that described in Example 2 and Example 3 above with the chewable formu All dogs were infested with approximately 75 C. felis on lations described in Tables 10 and 13, twenty four foxhounds Days 0 and 7. The dogs in Group 3 and dogs in pre-allocated were studied to determine the effectiveness of two soft chew Subgroups in Groups 1 and 2 were also infested with approxi able veterinary compositions comprising Compound A alone mately 75 C. felis on Days 14, 21 and 28. Fleas were counted 60 and Compound A in combination with milbemycin Oxime upon removal from selected Subjects at 30 minutes, 4 hours, (Tables 10 and 13, respectively), against induced infestations and 12 hours after treatment or infestation on Days 0 and 7. of Ixodes holocyclus. Three treatment groups consisting of On Days 14, 21 and 28, fleas were counted upon removal from eight dogs each were formed. Group 1 was an untreated selected subjects at 8 and 12 hours after infestation. The data control. The dogs in Group 2 were treated on Day 0 with a soft shows that the compositions started working within 30 min 65 chewable composition comprising Compound A alone to utes after treatment on Day 0 and that 12 hours after admin deliver a dose of at least 2.5 mg/kg body weight and dogs in istration of the composition, flea efficacy of 100% was Group 3 were treated on Day 0 with a soft chewable compo US 9,259,417 B2 75 76 sition comprising a combination of Compound A and milbe Forty two beagles were allotted to seven groups of six dogs mycin Oxime to deliver doses of at least 2.5 mg/kg of body each. Groups 1 and 2 served as untreated controls. Groups 3. weight of Compound A and at least 0.5 mg/kg of body weight 4 and 5 were each treated on Day 0 with three different of milbemycin Oxime. compositions of the invention described in Tables 30, 31 and 32, respectively, containing Compound A in an amount to Dogs in the three groups were infested with approximately deliver a dose of about 20 mg/kg of body weight. Similarly, on 50 Ixodes holocyclus on Days -1, 7, 14, 21, 28 and 35. Ticks Day 0, Groups 6 and 7 were each treated with the composi were counted on at 24 hours, 48 hours and 72 hours post tions described in Tables 30 and 32, respectively, containing infestation on Days 1, 2, 3, 8, 9, 10, 15, 16, 17, 22, 23, 24, 29. Compound A to deliver a dose of about 20 mg/kg of body 30, 31, 36, 37 and 38. weight. Treatment Group 2 (Compound A alone) exhibited a per 10 Dogs in Groups 1, 3, 4 and 5 were infested with approxi cent efficacy of at least 99.2% at 72 hours post infestation at mately 50 A. americanum and dogs in Groups 2, 6 and 7 were all time points measured. At 48 hours post infestation, dogs in infested with approximately 50 D. variabilis on Days -1, 42, Group 2 had percent efficacies of at least 98.7% at all time 56,70,77, 84,91 and 98. Dogs in Groups 1,2,3, 6 and 7 were points measured. At 24 hours post infestation, dogs in Group also infested on Day 105. Ticks were counted upon removal at 2 had efficacies of at least 95.8% on Days 1, 8, 15 and 22. 15 approximately 48 hours post treatment on Day 2 and 48 hours Treatment Group 3 (Compound A and milbemycin oxime) post infestation on Days 44, 58, 72,79, 86, 93, 100 and 107. exhibited an efficacy of at least 98.6% 72 hours post infesta Tables 52 and 53 below show the exceptional long-lasting tion at all time points. At 48 hours post infestation, dogs in efficacy of the inventive compositions against A. americanum Group 3 demonstrated an efficacy of at least 99.1% for all and D. variabilis. The efficacy exhibited against these two time points. At 24 hours post infestation, dogs in Group 3 had tick species is remarkable considering that the dogs were efficacies of at least 96.1% for all time points. This example treated only once on Day 0. TABLE 52 Efficacy Against A. americanum % Reduction Ticks

Treatment Day Day Day Day Day Day Day Day Day Group' 2 44 58 72 79 86 93 100 107 Group 3 1OOO 98.4 98.8 99.5 94.4 98.9 99.5 95.6 93.4 % Reduction Group 4 10O.O 99.4 99.4 97.7 88.6 97.5 97.7 90.9 % Reduction Group 5 1OOO 1OO.O 99.S 10O.O 98.8 97.8 98.2 87.8 % Reduction

TABLE 53 Efficacy Against D. variabilis % Reduction Ticks

Treatment Day Day Day Day Day Day Day Day Day Group' 2 44 58 72 79 86 93 100 107 Group 6 1OOO 100.0 99.S 10O.O 98.8 10O.O 98.9 99.4 99.4 % Reduction Group 7 1OOO 100.0 100.0 100.0 1 OOO 10O.O 97.9 100.0 1OO.O % Reduction demonstrates the exceptional efficacy of the soft chewable 50 Examples 7-12 compositions of the invention against ticks for duration of at least 38 days post treatment. The extent and duration of effi Following similar procedures to those described in cacy from one oral dose is exceptional and Surprising. Examples 2 and 3, the oral compositions of the invention were 55 found to be highly effective against Rhipicephalus San Example 6 guineus, Dermacentor reticulatus, Dermacentor variabilis, Ixodes ricinus, Ixodes scapularis and Haemaphysalis longi Long Lasting Efficacy of Soft Chewable cornis on dogs. For example, at a dose of 2.5 mg/kg, a chew Composition Containing Compounda Against able composition according to Table 10 was found to be have Amblyomma americanum and Dermacentor 60 an efficacy of greater than 95% through Day 37 against D. variabilis on Dogs sanguineus; an efficacy of greater than 95% through Day 30 against D. reticulatus and D. variabilis; and an efficacy of The efficacy of a soft chewable composition of the inven 100% against I. ricinus (99.6% at Day 30 and 100.0% again tion comprising a higher concentration of the active agent at Day 37): greater than 98% through Day 23 and greater than against two tick species was evaluated using a procedure 65 94% through Day 30 against I. Scapularis; and greater than similar to that described in Examples 2 and 3 above with the 95% through Day 23 and greater than 90% through Day 30 chewable formulations described in Tables 30, 31 and 32. against H. longicornis. US 9,259,417 B2 77 78 Example 13 Example 13 containing milbemycin oxime alone (Group 2) or a combination of milbemycin oxime and Compound A Efficacy of Soft Chewable Compositions Comprising (Group 3) to deliver doses of 0.5 mg/kg milbemycin oxime Compounda in Combination with a Macrocyclic and 2.5 mg/kg Compound A. After 7 days, the dogs were evaluated for the presence of A. Lactone Against Toxocara canis (Roundworm) in caninum infections. Examination of fecal samples prior to Dogs administration of the soft chew compositions confirmed that the dogs in the study shed 250 hookworm eggs per gram of Three Treatment Groups of nine Beagle dogs infected with fecal matter. Parasite counts indicated that the composition T. canis were formed. Dogs in Group 1 were not treated. On containing either milbemycin Oxime alone or a combination Day 0 of the study, dogs in Group 2 were treated with the soft 10 of milbemycin oxime and Compound A had efficacies of chewable composition described in Table 11 containing 7.5 >95% against A. caninum. The study shows that soft chew mg milbemycin Oxime, a macrocyclic lactone active agent, able compositions containing milbemycin Oxime alone or in per 2 gram soft chew to deliver a dose of approximately 0.5 combination with an isoxazoline active agent (Compound A) mg/kg of the active agent per body weight of animal. The On are highly effective against A. caninum. Day 0, the dogs in Group 3 were treated with the soft chew 15 able composition described in Table 12 containing 7.5 mg Example 16 milbemycin Oxime and 37.5 mg Compound A per 2 gram Efficacy of Soft Chewable Compositions Comprising chew to deliverdoses of 0.5 mg/kg milbemycin oxime and 2.5 Compounda in Combination with a Macrocyclic mg/kg Compound A. After 8 days, the dogs were evaluated Lactone Against Dirofilaria immitis (Heartworm) in for the presence of T. canis infections. Dogs The dogs in the control group (Group 1) were found to contain from 6 to 32 adult T. canis worms (geometric mean Three Treatment Groups of eight dogs infected with D. 13.5). No worms were found in any dog in Group 2 and one immitis were formed. Dogs in Group 1 were not treated. On worm was found in one dog of Group 3. The study shows that Day 0 of the study, dogs in Group 2 were treated with the soft Soft chewable compositions containing milbemycin Oxime 25 chewable composition described in Table 33 containing 7.5 alone or in combination with an isoxazoline active agent mg milbemycin oxime, a macrocyclic lactone active agent, (Compound A) were highly efficacious against T. canis infec per 2 gram soft chew to deliver a dose of approximately 0.5 tions in dogs. mg/kg of the active agent per body weight of animal. The dogs in Group 3 were treated with the soft chewable composition Example 14 30 described in Table 34 containing 7.5 mg milbemycin oxime and 37.5 mg Compound Aper 2 gram chew to deliverdoses of Efficacy of Soft Chewable Compositions Comprising 0.5 mg/kg milbemycin Oxime and 2.5 mg/kg Compound A on Compounda in Combination with a Macrocyclic Day 0 of the study. Lactone Against Trichuris vulpis (Whipworm) in After 119 days, the dogs were evaluated for the presence of Dogs 35 D. immitis infections. Dogs in the control group exhibited 0 to 15 adult D. immitis worms (geometric mean of 2.4). Adult worms were recovered from 5 of the 8 control animals. No Three Treatment Groups of eight dogs naturally infected worms were recovered from any of the treated dogs in Groups with T. vulpis were formed. Dogs in Group 1 were not treated. 2 and 3. Therefore, the study demonstrates that soft chewable On Day 0 of the study, dogs in Groups 2 and 3 were treated compositions containing milbemycin Oxime alone or in com with the softchewable compositions described in Example 13 40 bination with an isoxazoline active agent (Compound A) are containing milbemycin oxime alone (Group 2) or a combina highly effective against D. immitis (heartworm) in dogs. tion of milbemycin oxime with Compound A (Group 3) to deliver doses of 0.5 mg/kg milbemycin oxime and 2.5 mg/kg Example 17 Compound A. Efficacy of Soft Chewable Compositions Comprising After 7 days, the dogs were evaluated for the presence of T. 45 a Combination of Moxidectin and Milbemycin vulpis infections. Seven of the dogs in Group 1 were found to Oxime Against Dirofilaria immitis (Heartworm) in contain at least nine T. vulpis. Parasite counts indicated that Dogs the composition containing milbemycin Oxime alone had an efficacy of >94% against T. vulpis while the soft chew com Following a procedure similar to that of Example 16, the position containing a combination of milbemycin oxime and 50 effectiveness of the soft chewable compositions comprising Compound A exhibited an efficacy of 98% against T. vulpis. moxidectin and milbemycin oxime were evaluated against D. The study shows that soft chewable compositions containing immitis in dogs. Dogs in the treatment group were treated milbemycin oxime alone or in combination with an isoxazo with the Soft chewable compositions containing moxidectin line active agent (Compound A) are highly effective against T. or milbemycin oxime described in Tables 35 and 36 to pro vulpis. 55 vide doses of 40 micrograms/kg moxidectin and 500 micro grams/kg milbemycin oxime. At the conclusion of the study, Example 15 the soft chewable compositions were found have a high level of efficacy versus an untreated control group. Efficacy of Soft Chewable Compositions Comprising Example 18 Compounda in Combination with a Macrocyclic 60 Lactone Against Ancylostoma Caninum Efficacy of Soft Chewable Compositions Comprising (Hookworms) in Dogs a Combination of Ivermectin and Milbemycin Oxime Against Dirofilaria immitis (Heartworm) in Three Treatment Groups of nine dogs naturally infected Dogs with A. caninum were formed. Dogs in Group 1 were not 65 treated. On Day 0 of the study, dogs in Groups 2 and 3 were Following a procedure similar to that of Example 16, the treated with the soft chewable compositions described in effectiveness of the soft chewable compositions comprising US 9,259,417 B2 79 80 ivermectin and milbemycin oxime were evaluated against D. R" and Rare taken together with the nitrogen to which immitis in dogs. Dogs in the treatment group were treated they are attached to form a ring containing 2 to 6 atoms of with the Soft chewable compositions containingivermectin or carbon and optionally one additional atom selected from the milbemycin oxime described in Tables 37 and 39 to provide group consisting of N, S and O, said ring optionally Substi doses of 20 micrograms/kgivermectin and 500 micrograms/ tuted with 1 to 4 substituents independently selected from the kg milbemycin oxime. At the conclusion of the study, the soft group consisting of C-C alkyl, halogen, —CN, —NO and chewable compositions were found have a high level of effi C-Calkoxy: cacy versus an untreated control group. each R is independently halogen, C-C alkyl, As the non-limiting examples above demonstrate, the soft C-Calkoxy, C-C alkylthio, C-C alkylsulfinyl, C-C, chewable veterinary compositions of the invention compris 10 alkylsulfonyl, —CN or —NO; ing at least one isoxazoline active agent show Superior long each R" is independently halogen; C1-C alkyl, C-C, lasting efficacy against ectoparasites in a mammal (e.g. dog cycloalkyl, C-Calkoxy, C-C alkylthio, C-C alkylsulfi and cat), and compositions comprising at least one isoxazo nyl, C-C alkylsulfonyl, C-C alkylamino, C-Cs dialky line active agent in combination with a macrocyclic lactone lamino, C-C cycloalkylamino, C-C, alkylcarbonyl, C-C, active agent are highly efficacious against endoparasites in 15 alkoxycarbonyl, C-C, alkylaminocarbonyl, C-Co dialky mammals. laminocarbonyl, C-C, haloalkylcarbonyl, C-C, The invention is further described in the following num haloalkoxycarbonyl, C-C, haloalkylaminocarbonyl, C-Co bered paragraphs: dihaloalkylaminocarbonyl, hydroxy, —NH, —CN or 1. A Soft chewable veterinary composition for treating and/or - NO; or Q: preventing a parasitic infection or infestation in an animal each R is independently halogen, C-C alkoxy, C-C, comprising: haloalkoxy, C-C alkylthio. C-C haloalkylthio, C-C, a) alkylsulfinyl, C-C haloalkylsulfinyl, C-C alkylsulfonyl, (i) at least one isoxazoline active agent of Formula (I): C-C haloalkylsulfonyl, C-C alkylamino, C-C dialky lamino, C-C alkoxycarbonyl, —CN or NO; 25 each R is independently halogen, C-C alkyl, (I) C-Chaloalkyl, C-C cycloalkyl, C-C halocycloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkylthio, C-C, haloalkylthio, C-C alkylsulfinyl, C-C haloalkylsulfinyl. C-C alkylsulfonyl, C-C haloalkylsulfonyl, C-C alky 30 lamino, C-C dialkylamino. —CN, NO phenyl orpyridi nyl: R" is H; or C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, C-C, alkylcycloalkyl or C-C, cycloalky lalkyl, each optionally substituted with one of more halogen; 35 R'' is H. C-C alkyl, C-C alkenyl, C-C alkynyl, C-C, wherein: cycloalkyl, Ca-C, alkylcycloalkyl, C-C, cycloalkylalkyl, A", A, A, A, A and Aare independently selected from C-C, alkylcarbonyl or C-C, alkoxycarbonyl: the group consisting of CR and N, provided that at most 3 of R" is H.; Q; or C-C alkyl, C-C alkenyl, C-C alkynyl, A, A, A, A, A and Aare N: C-C cycloalkyl, Ca-C, alkylcycloalkyl or C-C, cycloalky B', B and B are independently selected from the group 40 lalkyl, each optionally substituted with one or more substitu consisting of CR and N: ents independently selected from R'; or W is O or S; R'' and R'' are taken together with the nitrogen to which R" is C-C alkyl, C-C alkenyl, C-C alkynyl, Cs-Co they are attached to form a ring containing 2 to 6 atoms of cycloalkyl, Ca-C, alkylcycloalkyl or C-C cycloalkylalkyl, carbon and optionally one additional atom selected from the each optionally substituted with one or more substituents 45 group consisting of N, S and O, said ring optionally Substi independently selected from R: tuted with 1 to 4 substituents independently selected from the each R is independently H, halogen, C-C alkyl, group consisting of C-C alkyl, halogen, —CN. —NO and C-Chaloalkyl, C-Calkoxy, C-Chaloalkoxy, C-C alky C-C alkoxy; lthio, C-Chaloalkylthio. C-C, alkylsulfinyl, Q" is a phenyl ring, a 5- or 6-membered heterocyclic ring, C-Chaloalkylsulfinyl, C-C, alkylsulfonyl, 50 or an 8-, 9- or 10-membered fused bicyclic ring system C-Chaloalkylsulfonyl, C-C alkylamino, C-C dialky optionally containing one to three heteroatoms selected from lamino, C-C alkoxycarbonyl, —CN or —NO; up to 1 O. up to 1 S and up to 3 N, each ring or ring system each R is independently H, halogen, C-C alkyl, optionally substituted with one or more substituents indepen C-Chaloalkyl, C-C cycloalkyl, C-C halocycloalkyl, dently selected from R: C-Calkoxy, C-C haloalkoxy, C-C alkylthio. 55 each Q is independently a phenyl ring or a 5- or 6-mem C-Chaloalkylthio. C-C, alkylsulfinyl, bered heterocyclic ring, each ring optionally Substituted with C-Chaloalkylsulfinyl, C-C, alkylsulfonyl, one or more substituents independently selected from R: C-Chaloalkylsulfonyl, C-C alkylamino, C-C dialky Q is a phenyl ring or a 5- or 6-membered heterocyclic ring, lamino, —CN or - NO; each ring optionally Substituted with one or more Substituents R" is H. C-C alkyl, C-C alkenyl, C-C alkynyl, Cs-Co 60 independently selected from R. and cycloalkyl, C-C, alkylcycloalkyl, C-C, cycloalkylalkyl, n is 0, 1 or 2; or C-C, alkylcarbonyl or C-C, alkoxycarbonyl: (ii) at least one systemically-acting active agent that is R is H, OR, NR'R' or Q'; or C-C alkyl, C-C, active against internal parasites, wherein the systemi alkenyl, C-C alkynyl, C-C cycloalkyl, Ca-C, alkylcy cally-acting active agent is one or more macrocyclic cloalkyl or C-C cycloalkylalkyl, each optionally Substituted 65 lactones, one or more benzimidazoles, levamisole, pyr with one or more substituents independently selected from antel, morantel, praziquantel, closantel, clorSulon, one R"; or or more amino acetonitrile active agents, one or more US 9,259,417 B2 81 82 insect growth regulators or one or more aryloazol-2-yl caprate, glycerol caprylate/caprate and polyglycolized cyanoethylamino active agents, or a combination of glycerides, or a combination thereof; thereof; or c) a binder selected from polyvinylpyrrolidone, polyethyl (iii) a combination of at least one isoxazoline active agent ene glycols, co-polymers of vinyl acetate and vinylpyrroli of formula (I) and at least one systemically-acting active done, potato starch and corn starch, or a combination thereof. agent, wherein the systemically active agent is one or d) a humectant selected from glycerol, propylene glycol, more macrocyclic lactones, one or more spinosyn com cetyl alcohol, glycerin monostearate and polyethylene gly pounds, one or more spinosoid compounds, one or more cols, or a combination thereof; benzimidazoles, levamisole, pyrantel, morantel, praZi e) a Surfactant selected from glyceryl monooleate, poly 10 oxyethylene Sorbitan fatty acid esters, Sorbitan esters, poly quantel, closantel, clorSulon, one or more amino aceto vinyl alcohol, polysorbates, Sodium lauryl Sulfate, co-poly nitrile active agents, one or more insect growth regula mers of ethylene oxide and propylene oxide, propylene glycol tors, one or more neonicotinoids or one or more monolaurate, glycerol caprylate/caprate, polyglycolized aryloazol-2-ylcyanoethylamino active agents, or a com glycerides and polyethylene glycol hydroxy Stearate, or a bination of thereof, and 15 combination thereof, and b) a pharmaceutically acceptable carrier. f) a natural or artificial beef or meat flavor. 2. The Soft chewable veterinary composition of paragraph 1, 12. The soft chewable veterinary composition of paragraph wherein: 11, wherein the composition comprises a compound of for W is O: mula (I) at a concentration of about 1% to about 20% by R" is H or C-C alkyl: weight. R is CHC(O)NHCHCF: 13. The soft chewable veterinary composition of paragraph each of A, A, A, A, A and A is CH: 12, wherein: R" is C-C alkyl each optionally substituted with one or a) the filler is a combination of corn starch and soy protein more substituents independently selected from R: fines and is present at a concentration of about 30% to about R is halogen or C-C alkyl; and 25 50% (w/w); B', B, and Bare independently CH, C-halogen, C. C b) the solvent is a mixture of liquid polyethylene glycoland Calkyl, C-C-Chaloalkyl, or C-C-C alkoxy. caprylic/capric triglycerides and is presentata concentration 3. The Soft chewable veterinary composition of paragraph 1, of about 5% to about 20% (w/w); wherein: c) the binder is polyethylene glycol or polyvinylpyrroli W is O: 30 done, or a combination thereof, and is presentata concentra R" is CF; tion of about 5% to about 15% (w/w): B is CH: d) the humectant is glycerin and is present at a concentra B' is C Cl; tion of about 5% to about 20%: B is C CF; e) the Surfactant is polyethylene glycol 12-hydroxy Stearate each of A, A, A, A, A and A is CH: 35 or polyoxyl hydrogenated castor oil and is present at a con R is H; and centration of about 1% to about 5% (w/w). R is CHC(O)NHCHCF. 14. The soft chewable veterinary composition of paragraph 4. The Soft chewable veterinary composition of paragraph 1, 12, wherein the compound of Formula (I) is present at a wherein the carrier comprises one or more fillers, at least one concentration of about 1% to about 5% by weight. flavoring agent, at least one binder, one or more solvents, one 40 15. The soft chewable veterinary composition of paragraph or more surfactants, at least one humectant, optionally an 12, wherein the compound of Formula (I) is present at a antioxidant, and optionally a preservative. concentration of about 10% to about 20% by weight. 5. The Soft chewable veterinary composition of paragraph 4. 16. The soft chewable veterinary composition of paragraph 1, wherein the one or more fillers is soy protein fines, corn wherein the composition comprises a systemically-acting starch, or a mixture thereof 45 active agent that is active against selected from the group 6. The Soft chewable veterinary composition of paragraph 4. consisting of one or more macrocyclic lactones, one or more wherein the binder is polyvinylpyrrolidone or a polyethylene spinosyn compounds, one or more spinosoid compounds, one glycol, or a combination thereof or more benzimidazoles, levamisole, pyrantel, morantel, 7. The Soft chewable veterinary composition of paragraph 4. praziquantel, closantel, clorSulon, one or more amino aceto wherein the solvent is a liquid polyethylene glycol or a 50 nitrile active agents, one or more insect growth regulators, caprylic?capric triglyceride, or a combination thereof. one or more neonicotinoids and one or more aryloazol-2-yl 8. The Soft chewable veterinary composition of paragraph 4. cyanoethylamino active agents, or a combination of thereof. wherein the Surfactant is polyethylene glycol hydroxy Stear 17. The soft chewable veterinary composition of paragraph 1, ate. wherein the composition comprises a combination of at least 9. The soft chewable veterinary composition of paragraph 4, 55 one isoxazoline active agent of formula (I) and at least one wherein the humectant is glycerin. systemically-acting active agent selected from the group con 10. The soft chewable veterinary composition of paragraph 4, sisting of one or more macrocyclic lactones, one or more wherein the flavoring agent is an artificial meat or beef flavor. spinosyn compounds, one or more spinosoid compounds, one 11. The Soft chewable veterinary composition of paragraph 4. or more benzimidazoles, levamisole, pyrantel, morantel, wherein the composition comprises: 60 praziquantel, closantel, clorSulon, one or more amino aceto a) a filler selected from corn starch, pre-gelatinized corn nitrile active agents, one or more insect growth regulators, starch, corn gluten meal and soy protein fines, or a combina one or more neonicotinoids and one or more aryloazol-2-yl tion thereof; cyanoethylamino active agents, or a combination of thereof. b) a solvent selected from liquid polyethylene glycols, 18. The soft chewable veterinary composition of paragraph propylene glycol, propylene carbonate, caprylic/capric trig 65 17, wherein the macrocyclic lactone is eprinomectin, iver lycerides, caprylic/capric/linoleic triglycerides, caprylic/ca mectin, Selamectin, milbemectin, milbemycin D. milbemy pric/Succinic triglycerides, propylene glycol dicaprylate/di cin oxime, or moxidectin, or a combination thereof. US 9,259,417 B2 83 84 19. The soft chewable veterinary composition of paragraph wherein the effect is achieved at a dosage of about 10 17, wherein the isoxazoline active agent is 4-5-3-chloro-5- mg/kg to about 100 mg/kg of active agent of Formula (trifluoromethyl)phenyl-4,5-dihydro-5-(trifluoromethyl)-3- (II); and isoxazolyl-N-(2-oxo-2-(2.2.2-trifluoroethyl)aminoethyl wherein the composition is effective for fleas for at least 79 1-naphthalenecarboxamide and the systemically-acting days. active agent is an avermectin, milbemycin oxime or moxidec 2. The solid soft chewable veterinary composition of claim tin, or a combination thereof. 1, wherein the humectant further comprises soybean oil. 20. A method for the treatment and/or prevention of a para 3. The solid soft chewable veterinary composition of claim sitic infestation and/or infection in an animal comprising 1, wherein the carrier further comprises a lubricant which is administering to the animal an effective amount of the soft 10 chewable veterinary composition of claim 1 to the animal. magnesium Stearate. 21. The method of paragraph 20, wherein the composition 4. The solid soft chewable veterinary composition of claim comprises an isoxazoline active agent, and wherein the isox 1, wherein the carrier further comprises a flavoring agent azoline active agent is 4-5-3-chloro-5-(trifluoromethyl) which is liver extract, pork, or artificial pork. phenyl-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl-N- 15 5. The solid soft chewable veterinary composition of claim 2-oxo-2-(2.2.2-trifluoroethyl)aminoethyl)-1- 4, wherein the flavoring agent is present in a concentration of naphthalenecarboxamide. about 10% to about 30% (w/w). 22. The method of paragraph 20, wherein the soft chewable 6. The solid soft chewable veterinary composition of claim composition comprises a systemically-acting active agent 1, wherein the filler is present in a concentration of about 10% selected from the group consisting of one or more avermectin to about 40% (w/w). or milbemycin compounds, one or more benzimidazole 7. The solid soft chewable veterinary composition of claim active agents, one or more a spinosyn compounds, one or 3, wherein the lubricant is present in a concentration of about more a spinosoid compounds, levamisole, pyrantel, morantel, 0.01 to about 20% (w/w). praziquantel, closantel, clorSulon, one or more amino aceto 8. The solid soft chewable veterinary composition of claim nitrile active agents, one or more insect growth regulators, 25 1, wherein the humectant is present in a concentration of one or more neonicotinoids and one or more aryloazol-2-yl about 1% to about 10% (w/w). cyanoethylamino active agents, or a combination thereof. 9. The solid soft chewable veterinary composition of claim 23. The method of paragraph 20, wherein the parasite are fleas 1, wherein the binder is presentata concentration of about 1% or ticks. to about 20% (w/w). 24. The method of paragraph 21, wherein the parasite is a 30 10. The solid soft chewable veterinary composition of nematode, a cestode, a trematode or a filarial parasite. claim 1, wherein the pharmaceutically acceptable Salt is a 25. Use of a compound of Formula (I) in paragraph 1 in the dicarboxylic acid or an aromatic salt. manufacture of a soft chewable veterinary composition for 11. A solid soft chewable veterinary composition effective the treatment and/or prevention of a parasitic infestation and/ for treating and/or preventing fleas or ticks infection or infes or infection in an animal. 35 tation in an animal comprising: Having thus described in detail various embodiments of the a) an isoxazoline active agent of Formula (II) at a concen present invention, it is to be understood that the invention tration of about 1% to about 20% by weight: defined by the above paragraphs is not to be limited to par ticular details set forth in the above description as many apparent variations thereof are possible without departing 40 from the spirit or scope of the present invention.

What is claimed is: 1. A solid soft chewable veterinary composition effective for treating and/or preventing fleas or ticks infection or infes 45 tation in an animal comprising: a) an isoxazoline active agent of Formula (II) at a concen tration of about 5% to about 15% by weight: or a pharmaceutically acceptable salt thereof, and 50 b) a pharmaceutically acceptable carrier, wherein the carrier comprises: i) a filler which is corn starch or pre-gelatinized corn starch C FC or a combination thereof; ii) a flavoring agent which is natural or artificial meat 55 flavor; C iii) a binder which is polyethylene glycol; iv) a solvent which is a triglyceride; C V) a surfactant which is sodium lauryl Sulfate at a concen tration of about 1 to about 5% (w/w); or a pharmaceutically acceptable salt thereof, and 60 vi) a humectant which is glycerol; b) a pharmaceutically acceptable carrier, vii) optionally an antioxidant; and wherein the carrier comprises a binder, a surfactant, a filler viii) optionally a preservative; and a humectant, wherein the binder is PEG 3350; the wherein the effect is achieved at a dosage of about 10 Surfactant is sodium lauryl Sulfate at a concentration of mg/kg to about 100 mg/kg of active agent of Formula about 1 to about 5% (w/w); 65 (II); and the filler is corn Starch or pre-gelatinized corn starch or a wherein the composition is effective for fleas for at least 79 combination thereof, and the humectant is glycerol; days after administration to the animal. US 9,259,417 B2 85 86 12. A solid soft chewable veterinary composition effective 14. The solid soft chewable veterinary composition of for treating and/or preventing fleas or ticks infestation in an claim 11 wherein the effect is achieved at a dosage of about 10 animal comprising: mg/kg to about 50 mg/kg of active agent of Formula (II). a) an isoxazoline active agent of Formula (II) at a concen 15. The solid soft chewable veterinary composition of claim 12 wherein the effect is achieved at a dosage of about 10 tration of about 1% to about 20% by weight: 5 mg/kg to about 50 mg/kg of active agent of Formula (II). 16. The solid soft chewable veterinary composition of claim 1 wherein the effect provides an efficacy of at least (II) about 70% against fleas about 8 hours after administration to C FC O-N O 10 the animal. \ /NCH, 17. The solid soft chewable veterinary composition of claim 11 wherein the effect provides an efficacy of at least O- C - about 70% against fleas about 8 hours after administration to the animal. O C CH3 18. The solid soft chewable veterinary composition of 15 claim 12 wherein the effect provides an efficacy of at least about 70% against fleas about 8 hours after administration to or a pharmaceutically acceptable salt thereof, and the animal. b) a pharmaceutically acceptable carrier, 19. The solid soft chewable veterinary composition of wherein the carrier comprises a binder, a surfactant, a filler claim 1 wherein the effect is at least about 90% against fleas about 12 hours after administration to the animal. and a humectant, 2O 20. The solid soft chewable veterinary composition of wherein claim 11 wherein the effect is at least about 90% against fleas the binder is PEG 3350, about 12 hours after administration to the animal. the Surfactant is sodium lauryl Sulfate at a concentration of 21. The solid soft chewable veterinary composition of about 1 to about 5% (w/w), 25 claim 12 wherein the effect is at least about 90% against fleas the filler is corn Starch or pre-gelatinized corn starch or a about 12 hours after administration to the animal. combination thereof, and 22. The solid soft chewable veterinary composition of the humectant is glycerol; claim 1 wherein the composition is effective for ticks for at wherein the effect is achieved at a dosage of about 10 least about 44 days after administration to the animal. mg/kg to about 100 mg/kg of active agent of Formula 30 23. The solid soft chewable veterinary composition of (II); and claim 11 wherein the composition is effective for ticks for at wherein the composition is effective for fleas for at least least about 44 days after administration to the animal. 79 days after administration to the animal. 24. The solid soft chewable veterinary composition of 13. The solid soft chewable veterinary composition of claim 12 wherein the composition is effective for ticks for at claim 1 wherein the effect is achieved at a dosage of about 10 35 least about 44 days after administration to the animal. mg/kg to about 50 mg/kg of active agent of Formula (II). k k k k k