Oral canine feed and method for controlling flea infestations in canines - Patents.com

Abstract

An oral canine feed and a method for controlling fleas in a canine in need of flea control by orally administering to the canine a daily feed containing an effective amount of an isoxazoline for an effective period of time, thereby raising and maintaining the amount of isoxazoline in the canine's blood at a therapeutically effective level for controlling fleas.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE

[0001] The teachings of this disclosure relate generally to isoxazolines, canine feeds or chews containing the isoxazolines, and methods of administering the isoxazolines to control flea infestations in canines. [Background technology]

[0002]

[0002] Approximately 471 million dogs are kept as household pets, and dog ownership is increasing worldwide. Globally, the most common ectoparasites of dogs are the cat and dog fleas, Ctenocephalides felis felis and Ctenocephalides canis, respectively. Flea-related infestations are one of the leading causes of canine dermatological problems reported to veterinarians. Additionally, cat fleas are known to transmit tapeworms in dogs and are also involved in the transmission of cat scratch disease and typhus.

[0003]

[0003] The health-related risks of flea infestation in dogs extend to humans as well. [Centers for Disease Control and Prevention, Diseases on the Rise, Vital Signs, May 2018, available at https: / / www.cdc.gov / vitalsigns / vector-borne / ] Infested canines put their human owners at elevated disease risk. One of the recommended ways to control the risk to humans from fleas is to control the risk of infestation in dogs.

[0004]

[0004] Currently available treatments for controlling flea infestations in canines have achieved varying degrees of success. Many treatments involve chemicals that are applied to indoor and outdoor surfaces, as well as to the canine. Chemicals used include various carbamates, pyrethrins and pyrethroids, certain macrocyclic lactones, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines and pyrazoles or fiproles. These compounds often have toxic side effects that are problematic for both canines and their owners. Furthermore, there is evidence that the use of these chemicals can be ineffective due to insecticide resistance and treatment deficiencies [MK Rust, The Biology and Ecology of Cat Fleas and Advancements in Their Pest Management: A Review, Insects 2017, 8 118].

[0005]

[0005] Topical treatment is a well-known method of controlling flea infestations in canines. There are numerous ways to deliver these treatments to the fur and skin of canines, but many of these methods are ineffective and / or pose safety risks to the canine or user during or after the dispensing operation. More specifically, because a physical connection between the applicator tip and the drug delivery device must be obtained when attaching the applicator tip, there is an inherent risk that the connection will be poor, causing some of the treatment to leak out of the device and come into physical contact with the user. For example, with larger canines, it can be difficult to operate the dispenser with one hand and hold the canine in place with the other, resulting in some, but not all, of the material spilling onto the floor or the person applying it instead of reaching the canine's skin. This leakage is not only wasteful and messy, but also exposes the user to an increased risk of suffering from dermatitis or other such health problems, especially if the user comes into direct contact with the drug.

[0006]

[0006] Oral treatments are also available. However, to be effective, canine owners must administer treatments, for example, once every 30 to 90 days. The long time between treatments creates compliance issues when owners forget to administer a dose. Summary of the Invention [Problem to be solved by the invention]

[0007]

[0007] Despite the availability of effective treatments, a recent study by Harris Poll found that 33% of pet owners do not routinely protect their pets from fleas at all. Another study found that, on average, pet owners purchase flea prevention products for only 4 months per year per pet, despite the fact that pets are told that they need to be treated with flea prevention throughout the year. Therefore, there is a continuing need for a relatively safe and effective drug for controlling flea infestations in canines that owners can easily remember to use. [Means for solving the problem]

[0008]

[0008] Surprisingly, the inventors have found that isoxazoline can provide improved control of flea infestation in canines when administered orally at lower, more frequent / longer-lasting doses. Administration is combined with feed, as discussed below. However, it is also contemplated that isoxazoline may be administered alone or in a dosage form other than feed, such as a chew, tablet, liquid, gel, or other form suitable for oral administration. Advantageously, by using lower, more frequent doses, less total isoxazoline is required over the same period to control flea infestation. For example, assume that to reach and maintain a therapeutically effective concentration of isoxazoline for continuous flea control in the blood of a canine, 6.25 mg isoxazoline is required per kg of canine body weight for a single dose over a period of 30 days (one month) according to conventional approaches. With the smaller, more frequent dosing approach of the present invention, only 0.04 to 0.1875 mg of isoxazoline per kg of canine body weight per day, or accumulated over the same 30 day period, 1.25 to 5.625 mg of isoxazoline per kg of canine body weight may be required.

[0009] Advantageously, the total amount of isoxazoline required for a therapeutically effective monthly dose can be reduced by 10-87.5% by converting to daily administration. However, from a practical standpoint, at least two problems arise: (1) producing a uniform supply, and (2) analytical control testing of very small amounts of isoxazoline can be difficult to achieve. Analytical matrices from feed can be very complex and difficult to analyze. Analyses can range from parts per million to parts per billion for some required doses and feed concentrations. It is therefore possible for a person skilled in the art to choose to increase the daily dose so that the total daily dose over a month is the same or even higher than the conventional monthly dose, for example 200% of the conventional monthly dose. This can be done to ensure uniformity when administering the dose as part of the feed, as well as to help increase analytical accuracy and reduce analytical variability.

[0010] The methods and compositions taught herein have the added advantage of increasing compliance, since smaller doses of the isoxazoline can be incorporated into the feed. Owners are less likely to forget or neglect to administer the isoxazoline, since they will naturally follow a daily feeding regimen anyway. Thus, the present disclosure provides a method for long-term control of fleas in a safer and more effective manner than that achieved by previously known treatments. All owners need to remember is to feed their pets as they normally would.

[0011]

[0011] Additionally, the bioavailability of certain isoxazolines can be improved by administering them with the feed. Thus, the present disclosure provides a method for long-term control of fleas in a safer and more effective manner than that achieved by previously known treatments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Isoxazolines are a class of heterocyclic five-membered ring compounds containing one atom each of oxygen and nitrogen located adjacent to each other.

[0013] [ka]

[0014]

[0013] All isoxazolines are derivatives of isoxazoles. They are structural isomers of the more common oxazolines and exist in three different isomeric forms depending on the position of the double bond.

[0015]

[0014] Derivatives of isoxazolines are known. For example, WO2007 / 105814, WO2008 / 122375, and WO2009 / 035004 disclose certain alkylene-linked amides. WO2010 / 032437 discloses that benzylamides can be transferred to the ortho position of isoxazolines. WO2007 / 075459 discloses phenylisoxazolines substituted with 5-6 heterocyclic rings, and WO2010 / 084067 and WO2010 / 025998 disclose phenylisoxazolines substituted with 10-11 fused aryl and heteroaryl rings. Chiral processes for preparing isoxazolines are disclosed in WO2011 / 104089 and WO2009 / 063910.

[0016] Many isoxazoline compounds are known, including but not limited to 4-(5-methyl-5-substituted pyrrolyl-4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; 4-(5-substituted carbamoylmethyl 4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; 3-(5-substituted carbamoylmethyl 5-substituted alkyl-4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; 4-(5-substituted carbamoylmethyl 4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; yl)benzamidine derivatives;4-(5-substituted-5-substituted aryl-4,5-dihydroisoxazol-3-yl)benzoic acid amide compounds;3-(4-substituted phenyl)-4,5-dihydroisoxazole derivatives;5-substituted alkyl-3,5-bis-substituted phenyl-4,5-dihydroisoxazole derivatives;3-alkoxyphenyl-5-substituted-5-phenyl-4,5-dihydroisoxazole derivatives;3-alkoxyphenyl-5-substituted alkyl-5-substituted carbamoyl-4,5-dihydroisoxazole derivatives ;3-(4-Halophenyl)-5-substituted-5-substituted phenyl-4,5-dihydroisoxazole derivatives;3-(4-Nitrophenyl)-5-substituted-5-substituted phenyl-4,5-dihydroisoxazole derivatives;4-Hydroxyiminomethylbenzoic acid amide derivatives;4-Hydroxyiminomethyl N,N-dimethylbenzoic acid amide;4-Hydroxyiminomethylbenzoylpiperidine derivatives;4-Hydroxyiminomethyl N-bicycloalkylbenzoic acid amide derivatives;6-(Hydroxyiminomethyl)pyridine-2-carboxamide including voxamide derivatives; haloalkenylbenzene derivatives, such as substituted 3,3,3-trifluoro-2-propenylbenzene derivatives; 4-(isoxazolinyl)-benzamides, such as substituted 4-(5-(halomethyl)-5-phenyl-isoxazolin-3-yl)-benzamides; 4-(isoxazolinyl)-benzothioamides, such as substituted 4-(5-(halomethyl)-5-phenyl-isoxazolin-3-yl)-benzothioamides; dihydroisoxazole compounds; and spirocyclic substituted isoxazolines.

[0017]

[0016] An isoxazoline of particular interest for controlling flea infestations in canines is afoxolaner (chemical name: (a) 1-naphthalenecarboxamide, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-; or (b) 4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-; or (b) 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-; 1-[5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidin-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)-; or (b) 1-{5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidin-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)-; or (c) 1-{5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidin-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)- -fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-3'-H-spiro[azetidine-3,1'-[2]benzofuran]-1-yl}-2-(methylsulfonyl)ethanone), Lotilaner (chemical name: (a) 2-thiophenecarboxamide, 5-[(5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-;or (b) 3-methyl-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]thiophene-2-carboxamide), esafoxolaner (chemical name: (a) 1-naphthalenecarboxamide, 4-[(5S)-5-[3-chloro-5-(trifluoro (S)-4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-; or (b) (S)-4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)- (a) benzamide, 2-chloro-N-(1-cyanocyclopropyl)-5-[1'-methyl-3'-(1,1,2,2,2-pentafluoroethyl)-4'-(trifluoromethyl)[1,5'-bi-1H-pyrazol]-4-yl]-; or (b) 2-chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4' -(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide), umifoxolaner (chemical name: (a) 1-naphthalenecarboxamide, 4-[(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-;or (b) 4-{(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide), modofuranel (chemical name: 6-fluoro-N-(2-fluoro-3-{[4-(heptafluoropropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]carbamoyl}phenyl)pyridine-3-carboxamide), and mivoliraner / dihydroisoxazole (chemical name: (a) 4H-cyclopentadiene ta[c]thiophene-1-carboxamide, 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl-3-isoxazolyl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-; or (b) 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide.

[0018] More specifically, isoxazolines having the following structure are suitable for the methods and compositions of the present disclosure:

[0019] [ka]

[0020]

[0018] Isoxazolines can react to form salts, which are also useful in the methods and formulations of the present disclosure. The salts may be prepared using standard procedures for salt preparation. For example, suitable salts can be salts of hydrohalogenated acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid, acid addition salts such as nitric acid, sulfuric acid, phosphoric acid, chloric acid, and perchloric acid, salts of sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, salts of carboxylic acids, such as valeric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, and citric acid, or salts of amino acids, such as glutamic acid and aspartic acid. Alternatively, metal salts are also suitable for the present disclosure. For example, alkali metal salts such as lithium, sodium and potassium, and alkaline earth metal salts such as calcium, barium and magnesium, or aluminium salts.

[0021] As used herein, the terms "isoxazoline" and "isoxazoline or a derivative thereof" refer to any isoxazoline, isoxazoline derivative, a salt thereof, a metabolite thereof, or a combination thereof.

[0022]

[0020] Isoxazolines also provide advantages because they are highly effective against fleas when administered orally in smaller, more frequent / longer lasting doses, with protection remaining after treatment. Furthermore, isoxazolines have no known insecticidal cross-resistance to existing compounds. Therefore, they are particularly beneficial against flea populations in canines that have existing levels of resistance to currently used products. Therefore, isoxazolines can be used in integrated pest management (IPM) programs to extend the life of commonly used products where resistance has not yet fully developed or has not yet developed.

[0023] Systemic efficacy (e.g., ingestion of isoxazoline-containing blood by fleas) provides a different mode of exposure compared to topically applied formulations where surface skin contact with the fleas is the mode of exposure. The advantages of oral systemic treatment and killing fleas by their ingestion of blood compared to topical application and killing by contact are: a) reducing exposure to human applicators and objects in children's and canines' living environments (e.g., flooring, carpets, furniture); b) There is no risk of loss due to exposure to water (lakes, streams, bathing, etc.) or loss due to friction; c) No risk of UV exposure and UV degradation; d) There is no problem of oxidation due to oil on the skin, and e) including the certainty that the entire dose is administered (compared to topical application, where some of the dose may drip, rub off, and / or remain in the dispensing tube immediately following treatment).

[0024] The formulations or feeds and methods of the present disclosure may further include one or more other active agents having therapeutic efficacy in combination with the isoxazoline. Such active agents include agents effective against fleas. The active agents may include, for example, spinosyns, certain macrocyclic lactones, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines and pyrazoles, or fiproles.

[0025] The method of the present disclosure is carried out by administering the isoxazoline to the canine in small, frequent doses. To facilitate habitual administration, the isoxazoline administration can be carried out using feed or chews. Many different feeds are contemplated, so long as the manufacturing process and feed composition do not adversely affect the efficacy, stability and safety of the isoxazoline and, if applicable, other active substances. For example, feeds in the broad categories of dry, semi-moist, canned retort feeds or fresh refrigerated feeds, as well as snacks, chews, treats or other supplemental feeds, can be adapted for use according to the present disclosure. The canine is provided with a controlled amount of the isoxazoline by consuming the feed product weekly, approximately weekly, or daily.

[0026] By incorporating smaller doses of the isoxazoline into an animal's feed composition and administering it at an effective rate (most preferably daily), the blood concentration of the isoxazoline will rise over time until it reaches an optimal steady state that can be maintained by daily or substantially daily administration. In contrast, if the isoxazoline is administered orally at higher doses and less frequently, for example, in a single treatment of a higher dose administered once in a 30 day period by a "treat", the level of the isoxazoline in the blood will spike at the time of administration and then decline until the next dose is administered. The less frequent administration of higher doses means that the canine will need to consume more isoxazoline with each dose, so that the blood level of the isoxazoline does not fall below the level required for effective prophylaxis before the next dose is administered.

[0027] All ratios, percentages, and parts discussed herein are "by weight" unless otherwise specified.

[0026] The term "controlling flea infestation" refers to preventing, minimizing or eliminating flea infestation in canines.

[0028]

[0027] The term "flea" refers to any member of the order Siphonaptera. The term "flea" includes the egg, larva, pupae, and adult stages of development.

[0028] The term "canine" refers to any member of the genus Canis, and includes species such as wolves, dogs, coyotes, and jackals.

[0029] In carrying out the methods of the present disclosure, a "feed" is an animal feed, snack, treat or other supplemental feed that can be administered daily or substantially daily. By using different forms of feed, such as kibbles and treats, a pet owner can vary their canine's diet and treats from time to time and still conveniently administer a daily dose of isoxazoline.

[0030]

[0030] The term "chew" refers to a treat that has flavor and aromatic properties that are attractive to canines, but typically has no nutritional value. In carrying out the methods of the present disclosure, "feed" and / or "chew" may be used interchangeably.

[0031] For purposes of this disclosure, the term "effective time", also referred to herein as "effective period", includes at least the period of feed administration necessary to achieve a level of isoxazoline in the canine's blood that is high enough to control fleas, i.e., a "therapeutically effective" level. In some embodiments, the effective time may be as little as three days. In other cases, the effective time may be seven or fifteen days or more. As discussed below, the effective time will vary depending on how frequently the feed or isoxazoline is administered.

[0032] As alluded to above, the "effective time" varies depending on the frequency at which the feed is administered. As used herein, the term "effective frequency" refers to the number of feedings over a given time period that will result in a therapeutically effective concentration of the isoxazoline in the blood of the canine. In all cases, as used herein, "effective frequency" contemplates feedings containing multiple isoxazolines per month. Those skilled in the art will appreciate that the isoxazoline may be administered at a wide range of frequencies. For example, the isoxazoline may be administered daily, every other day, every third day, once per week, or even at inconsistent time intervals.

[0033]

[0033] Furthermore, as discussed above, the frequency of administration can affect the period of time required to achieve a therapeutically effective level of the isoxazoline in the canine's blood. By way of example, if a canine is fed the isoxazoline composition daily, the feeding period, and thus the "effective time," required to achieve a therapeutically effective level of the isoxazoline in the canine's blood will be relatively shorter than if the canine is fed the isoxazoline composition only once or twice per week.

[0034] Furthermore, the frequency of effectiveness is affected by the daily dose in mg / kg of canine body weight, especially at slightly higher daily doses, where missed doses have little effect on efficacy.

[0035] Furthermore, the frequency of effectiveness is affected by the duration of treatment: in the early stages, e.g. before the amount of isoxazoline in the canine blood reaches a therapeutically effective level, the animal feed may need to be administered more frequently than is required after a longer period of use, i.e. after a therapeutically effective level has been achieved.

[0036] For purposes of this disclosure, "substantially daily" means sufficiently regular that the concentration of the isoxazoline in the canine's blood rises to and remains at a therapeutically effective level. For example, the disclosed feed composition can preferably be fed to the canine daily indefinitely. However, in practice, there are many reasons why days may be periodically forgotten or skipped. For example, the canine may become unhealthy or the owner may run out of the medicated feed composition. The disclosed method is sufficiently robust that the canine will receive a significant level of flea protection even if the daily feeding of the medicated animal feed composition is occasionally interrupted. In carrying out the disclosed method, the term "substantially daily" includes at least 10 days per month, more preferably 15 days per month, and even more preferably 20 days per month. All of these delivery frequencies, whether they are, for example, three times per week, every other day, or daily, are suitable for administration substantially daily, so long as they facilitate achieving and maintaining a therapeutically effective level of the isoxazoline in the canine's blood.

[0037]

[0037] The term "therapeutically effective" means that the dose or blood level of the isoxazoline is sufficient to control the flea infestation more than if the drug was not present. The isoxazoline may be present alone or with one or more additional active agents. Preferably, it controls the flea infestation by about at least 50% more than if the drug was not present, and more preferably, it controls the flea infestation by about at least 90% more than if the drug was not present.

[0038] In carrying out the methods of the present disclosure, an effective or therapeutically effective amount of the isoxazoline is orally administered to a canine. The term "effective amount" or "therapeutically effective amount" refers to the amount necessary to control a flea infestation. As one of ordinary skill in the art will appreciate, this amount will vary depending on many factors. These factors include, for example, the type of canine being treated and its weight and overall health.

[0039]

[0039] Isoxazolines vary in potency. Thus, the effective amount of isoxazoline must be calculated for each specific isoxazoline used in the disclosed method. In general, the effective amount of isoxazoline as a daily dose ranges from about 12.5% ​​to 90% of the approved labeled dose for said isoxazoline divided by the length of the administration / retreatment interval (e.g., the dose divided by 30 for a product administered once per month). Those skilled in the art will appreciate that a dose greater than the approved labeled dose for said isoxazoline may be selected, for example, 90% to 200%, for reasons including, but not limited to, manufacturability, ease of testing and analysis. The specific dose selected may be sufficient to raise the canine blood concentration of said isoxazoline to a therapeutically effective level within about 7 days of substantially daily administration, more preferably within about 5 days of substantially daily administration, and most preferably within about 3 days of substantially daily administration.

[0040]

[0040] Although the present disclosure describes the concentration of isoxazoline in terms of feed, e.g., kibble, administration using other dosage forms, e.g., treats or chews, is also contemplated. It is also contemplated that the isoxazoline may be administered alone or in a tablet, liquid, gel, or other suitable form for oral administration. One skilled in the art will appreciate that the concentration of isoxazoline will vary depending on the specific dosage form. For example, if the animal feed is a treat, the concentration of isoxazoline in the treat will be greater than the concentration of isoxazoline in, e.g., a kibble. For example, if the daily dose of isoxazoline based on the weight of a canine is 20 mg, a typical 5 g treat may contain about 0.004 percent isoxazoline (by weight). Because the amount of kibble consumed per day is greater than 5 g, the percentage of isoxazoline in the kibble will be less.

[0041] For example, an effective amount of mivoliraner may be a dose of about 0.04 to about 3.33 mg of mivoliraner per kg of canine body weight. More preferably, an effective amount of mivoliraner may be a dose of about 0.07 to about 1.5 mg of mivoliraner per kg of canine body weight. More typically, the effective amount is about 0.04 to about 1.25 mg of mivoliraner per kg of canine body weight.

[0042]

[0042] Animal feed typically contains about 0.0001 to about 0.08 percent Mivoliraner by weight in the feed. Preferably, between about 0.0002 and about 0.05 percent Mivoliraner by weight in the feed. Most preferably, between about 0.0006 and about 0.03 percent Mivoliraner component by weight in the feed.

[0043] In another example, an effective amount of lotilaner may be a dose of about 0.017 to about 1.33 mg of lotilaner per kg of canine body weight. More preferably, an effective amount of lotilaner may be a dose of about 0.027 to about 0.6 mg of lotilaner per kg of canine body weight. More typically, the effective amount is about 0.017 to about 0.5 mg of lotilaner per kg of canine body weight.

[0044]

[0044] Animal feed typically contains from about 0.00004 to about 0.03 percent rotilaner (by weight) in the feed, preferably between about 0.00008 to about 0.02 percent rotilaner (by weight) in the feed, and most preferably between about 0.0002 to about 0.001 percent rotilaner component (by weight) in the feed.

[0045] In another example, the effective amount of afoxolaner may be a dose of about 0.002 to about 0.167 mg of afoxolaner per kg of canine body weight. More preferably, the effective amount of afoxolaner may be a dose of about 0.003 to about 0.075 mg of afoxolaner per kg of canine body weight. More typically, the effective amount is about 0.002 to about 0.0625 mg of afoxolaner per kg of canine body weight.

[0046]

[0046] Animal feed typically contains from about 0.000005 to about 0.03 percent afoxolaner (by weight) in the feed, preferably between about 0.00001 and about 0.02 percent afoxolaner (by weight) in the feed, and most preferably between about 0.00003 and about 0.0012 percent afoxolaner component (by weight) in the feed.

[0047] In another example, the effective amount of sarolaner may be a dose of about 0.001 to about 0.08 mg of sarolaner per kg of canine body weight. More preferably, the effective amount of sarolaner may be a dose of about 0.0016 to about 0.036 mg of sarolaner per kg of canine body weight. More typically, the effective amount is about 0.001 to about 0.03 mg of sarolaner per kg of canine body weight.

[0048]

[0048] Animal feed typically contains from about 0.000002 to about 0.03 percent sarolaner (by weight) in the feed, preferably between about 0.000004 to about 0.02 percent sarolaner (by weight) in the feed, and most preferably between about 0.0003 to about 0.0006 percent sarolaner component (by weight) in the feed.

[0049] In another example, the effective amount of fluralaner may be a dose of about 0.008 to about 0.67 mg of fluralaner per kg of canine body weight. More preferably, the effective amount of fluralaner may be a dose of about 0.013 to about 0.3 mg of fluralaner per kg of canine body weight. More typically, the effective amount is about 0.008 to about 0.25 mg of fluralaner per kg of canine body weight.

[0050]

[0050] Animal feed typically contains from about 0.00002 to about 0.03 percent fluralaner (by weight) in the feed, preferably between about 0.00004 to about 0.02 percent fluralaner (by weight) in the feed, and most preferably between about 0.0001 to about 0.006 percent fluralaner component (by weight) in the feed.

[0051] In another example, the effective amount of umifoxolaner may be a dose of about 0.001 to about 0.08 mg of umifoxolaner per kg of canine body weight. More preferably, the effective amount of umifoxolaner may be a dose of about 0.0017 to about 0.04 mg of umifoxolaner per kg of canine body weight. More typically, the effective amount is about 0.001 to about 0.03125 mg of umifoxolaner per kg of canine body weight.

[0052]

[0052] Animal feed typically contains from about 0.000002 to about 0.03 percent seafoxolaner (by weight) in the feed, preferably between about 0.000005 to about 0.02 percent seafoxolaner (by weight) in the feed, and most preferably between about 0.00001 to about 0.0006 percent seafoxolaner component (by weight) in the feed.

[0053] In another example, an effective amount of esafoxolaner may be a dose of about 0.001 to about 0.08 mg of esafoxolaner per kg of canine body weight. More preferably, an effective amount of esafoxolaner may be a dose of about 0.0017 to about 0.04 mg of esafoxolaner per kg of canine body weight. More typically, the effective amount is about 0.001 to about 0.03125 mg of esafoxolaner per kg of canine body weight.

[0054]

[0054] Animal feed typically contains from about 0.000002 to about 0.03 percent esafoxolaner (by weight) in the feed, preferably between about 0.000005 to about 0.02 percent esafoxolaner (by weight) in the feed, and most preferably between about 0.00001 to about 0.0006 percent esafoxolaner component (by weight) in the feed.

[0055] In another example, the effective amount of tigolaner may be a dose of about 0.001 to about 0.08 mg of tigolaner per kg of canine body weight. More preferably, the effective amount of tigolaner may be a dose of about 0.0017 to about 0.04 mg of tigolaner per kg of canine body weight. More typically, the effective amount is about 0.001 to about 0.03125 mg of tigolaner per kg of canine body weight.

[0056]

[0056] Animal feed typically contains from about 0.000002 to about 0.03 percent tigolaner (by weight) in the feed, preferably between about 0.000005 to about 0.02 percent tigolaner (by weight) in the feed, and most preferably between about 0.00001 to about 0.0006 percent tigolaner component (by weight) in the feed.

[0057]

[0057] In one aspect, the present disclosure relates to a method for controlling flea infestations in canines by administering a systemically active oral composition comprising an isoxazoline and an animal feed or chew at least once per week, more preferably three times per week, and most preferably substantially daily.

[0058] In another aspect, the present disclosure relates to a systemically active oral composition comprising an isoxazoline and an animal feed or chew.

[0059] The present disclosure also relates to the use of an isoxazoline for the manufacture of an animal feed or chew for controlling flea infestations in canines.

[0059]

[0060] The present disclosure also relates to a method for controlling flea infestations in canines over an extended period of time, comprising orally administering to the canine a daily or substantially daily dose of an effective amount of an isoxazoline. The method is particularly useful for controlling fleas in canines over an extended period of time, and comprises orally administering to the canine a substantially daily dose of an effective amount of an isoxazoline.

[0060]

[0061] An embodiment of the present disclosure is the oral administration of an amount of isoxazoline that is ineffective or suboptimal by itself for controlling flea infestation in canines when administered in a single dose once per month, but that provides effective control of flea infestation when administered repeatedly over time as described herein. By ineffective or suboptimal, we mean that single and multiple doses result in less than a 50% reduction in flea infestation compared to no drug administration at all, including no or substantially no reduction. This reflects the chronic rather than acute administration aspects disclosed herein.

[0061]

[0062] Embodiment 1: A method of controlling flea infestation in a canine in need thereof, comprising orally administering to said canine an effective amount of an isoxazoline for an effective period of time at least four times per month.

[0062]

[0063] Embodiment 2: The method of embodiment 1, wherein the canine is a dog.

[0064] Embodiment 3: The method of any one of embodiments 1 or 2, wherein the isoxazoline is mivorilaner or a salt thereof.

[0063]

[0065] Embodiment 4: The method of embodiment 3, wherein the mivorilaner is provided in the feed in an amount selected from the group consisting of between about 0.0001 and about 0.08 percent by weight of the feed and between about 0.0002 and about 0.05 percent by weight of the feed.

[0064]

[0066] Embodiment 5: The method of any of embodiments 3-4, wherein mivorilaner is administered to the canine in an amount selected from the group consisting of between about 0.04 mg / kg to about 3.33 mg / kg of the canine's body weight and between about 0.07 mg / kg to about 1.5 mg / kg of the canine's body weight.

[0065]

[0067] Embodiment 6: The method of any of embodiments 3 to 5, wherein the administration provides a mivoliraner concentration in the blood of the canine animal of greater than about 40 ng / mL and less than about 12,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0066]

[0068] Embodiment 7: The method of any one of embodiments 1 or 2, wherein the isoxazoline is fluralaner or a salt thereof.

[0069] Embodiment 8: The method of embodiment 7, wherein the fluralaner is provided in the feed in an amount selected from the group consisting of between about 0.00002 and about 0.03 weight percent of the feed and between about 0.00004 and about 0.02 weight percent of the feed.

[0067]

[0070] Embodiment 9: The method of any of embodiments 7-8, wherein the fluralaner is administered to the canine in an amount selected from the group consisting of between about 0.008 mg / kg and about 0.67 mg / kg of the canine's body weight, and between about 0.013 mg / kg and about 0.3 mg / kg of the canine's body weight.

[0068]

[0071] Embodiment 10: The method of any of embodiments 7 to 9, wherein the administration provides a fluralaner concentration in the blood of the canine animal of greater than about 4 ng / mL and less than about 3000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0069]

[0072] Embodiment 11: The method of any one of embodiments 1 or 2, wherein the isoxazoline is sarolaner or a salt thereof.

[0073] Embodiment 12: The method of embodiment 12, wherein the sarolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed, and between about 0.000004 and about 0.02 weight percent of the feed.

[0070]

[0074] Embodiment 13: The method of any of embodiments 11-12, wherein the sarolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight, and between about 0.0016 mg / kg and about 0.036 mg / kg of the canine's body weight.

[0071]

[0075] Embodiment 14: The method of any of embodiments 11-13, wherein the administration provides a concentration of sarolaner in the blood of the canine animal of greater than about 1 ng / mL and less than about 800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0072]

[0076] Embodiment 15: The method of any one of embodiments 1 or 2, wherein the isoxazoline is afoxolaner or a salt thereof.

[0077] Embodiment 16: The method of embodiment 15, wherein the afoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000005 and about 0.03 weight percent of the feed, and between about 0.00001 and about 0.02 weight percent of the feed.

[0073]

[0078] Embodiment 17: The method of any of embodiments 15-16, wherein the afoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.002 mg / kg to about 0.167 mg / kg of the canine's body weight and between about 0.003 mg / kg to about 0.075 mg / kg of the canine's body weight.

[0074]

[0079] Embodiment 18: The method of any of embodiments 15-17, wherein the administration provides a concentration of afoxolaner in the blood of the canine animal of greater than about 2 ng / mL and less than about 1200 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0075]

[0080] Embodiment 19: The method of any one of embodiments 1 or 2, wherein the isoxazoline is lotilaner or a salt thereof.

[0081] Embodiment 20: The method of embodiment 19, wherein the lotilaner is provided in the feed in an amount selected from the group consisting of between about 0.00004 and about 0.03 percent by weight of the feed and between about 0.00008 and about 0.02 percent by weight of the feed.

[0076]

[0082] Embodiment 21: The method of any of embodiments 19-20, wherein the lotilaner is administered to the canine in an amount selected from the group consisting of between about 0.017 mg / kg to about 1.33 mg / kg of the canine's body weight and between about 0.027 mg / kg to about 0.6 mg / kg of the canine's body weight.

[0077]

[0083] Embodiment 22: The method of any of embodiments 19-21, wherein the administration provides a lotilaner concentration of greater than about 8 ng / mL and less than about 3000 ng / mL in the blood of the canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0078]

[0084] Embodiment 23: The method of any one of embodiments 1 to 22, wherein the isoxazoline is administered as a feed ingredient.

[0085] Embodiment 24: The method of embodiment 23, wherein the food is dry dog ​​food.

[0079]

[0086] Embodiment 25: The method of embodiment 23, wherein the food is wet dog food.

[0087] Embodiment 26: The method of any one of embodiments 1-22, wherein the isoxazoline is administered as a component of a chew.

[0080]

[0088] Embodiment 27: The method of any one of embodiments 1 to 26, wherein the frequency is selected from the group consisting of at least three times per week, substantially daily, and daily.

[0089] Embodiment 28: The method of any one of embodiments 1-27, wherein the effective time period comprises administering the isoxazoline for a period selected from the group consisting of at least 1 week and at least 2 weeks.

[0081]

[0090] Embodiment 29: The method of any of embodiments 1-28, wherein the administration provides a therapeutically effective level of the isoxazoline in the blood of the canine for a period of time selected from the group consisting of one week from the first administration of the isoxazoline and two days from the first administration of the isoxazoline.

[0082]

[0091] Embodiment 30: The method of any of embodiments 1-29, wherein the administration provides a therapeutically effective level of the isoxazoline in the blood of the canine for a period selected from the group consisting of at least 30 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days.

[0083]

[0092] Embodiment 31: The method of any one of embodiments 1-30, wherein the isoxazoline is administered for a period selected from the group consisting of at least 15 days out of 30 days, and at least 20 days out of 30 days.

[0084]

[0093] Embodiment 32: The method of any one of embodiments 1 to 31, wherein the isoxazoline is administered as a component of a feed containing one or more other active substances.

[0094] Embodiment 33: The method of any of embodiments 1-32, further comprising discontinuing administration of the isoxazoline for a period of time selected from the group consisting of at least 3 days and at least 7 days, wherein the blood concentration of the isoxazoline in the canine is maintained at a therapeutically effective level.

[0085]

[0095] Embodiment 34: The method of embodiment 33, further comprising discontinuing administration of the isoxazoline, thereby maintaining the canine's blood concentration of the isoxazoline at a therapeutically effective level, and then resuming administration of the isoxazoline.

[0086]

[0096] Embodiment 35: An isoxazoline for use in controlling fleas in a canine in need thereof, wherein the isoxazoline or a salt thereof is administered to the canine in an effective amount for an effective period of time at least four times per month.

[0087]

[0097] Embodiment 36: The isoxazoline of embodiment 35, wherein the canine is a dog.

[0098] Embodiment 37: The isoxazoline of either embodiment 35 or 36, wherein the isoxazoline is mivorilaner or a salt thereof.

[0088]

[0099] Embodiment 38: The isoxazoline of embodiment 37, wherein the mivorilaner is provided in the feed in an amount selected from the group consisting of between about 0.0001 and about 0.08 percent by weight of the feed and between about 0.0002 and about 0.05 percent by weight of the feed.

[0089]

[0100] Embodiment 39: The isoxazoline of any of embodiments 37-38, wherein the mivorilaner is administered to the canine in an amount selected from the group consisting of between about 0.04 mg / kg to about 3.33 mg / kg of the canine's body weight and between about 0.07 mg / kg to about 1.5 mg / kg of the canine's body weight.

[0090]

[0101] Embodiment 40: The isoxazoline of any of embodiments 37-39, wherein the administration provides a mivorilaner concentration in the blood of the canine animal of greater than about 40 ng / mL and less than about 12,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0091]

[0102] Embodiment 41: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is fluralaner or a salt thereof.

[0103] Embodiment 42: The isoxazoline of embodiment 41, wherein the fluralaner is provided in the feed in an amount selected from the group consisting of between about 0.00002 to about 0.03 weight percent of the feed and about 0.00004 to about 0.02 weight percent of the feed.

[0092]

[0104] Embodiment 43: The isoxazoline of any of embodiments 41-42, wherein the fluralaner is administered to the canine in an amount selected from the group consisting of between about 0.008 mg / kg to about 0.67 mg / kg of the canine's body weight and between about 0.013 mg / kg to about 0.3 mg / kg of the canine's body weight.

[0093]

[0105] Embodiment 44: The isoxazoline of any of embodiments 41 to 43, wherein the administration provides a fluralaner concentration in the blood of the canine animal of greater than about 4 ng / mL and less than about 3000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0094]

[0106] Embodiment 45: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is sarolaner or a salt thereof.

[0107] Embodiment 46: The isoxazoline of embodiment 45, wherein the sarolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000004 and about 0.02 weight percent of the feed.

[0095]

[0108] Embodiment 47: The isoxazoline of any of embodiments 45-46, wherein the sarolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg to about 0.08 mg / kg of the canine's body weight and between about 0.0016 mg / kg to about 0.036 mg / kg of the canine's body weight.

[0096]

[0109] Embodiment 48: The isoxazoline of any of embodiments 45-47, wherein the administration provides a concentration of sarolaner in the blood of the canine animal of greater than about 1 ng / mL and less than about 800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0097]

[0110] Embodiment 49: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is afoxolaner or a salt thereof.

[0111] Embodiment 50: The isoxazoline of embodiment 49, wherein the afoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000005 and about 0.03 weight percent of the feed and between about 0.00001 and about 0.02 weight percent of the feed.

[0098]

[0112] Embodiment 51: The isoxazoline of any of embodiments 49-50, wherein the afoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.002 mg / kg to about 0.167 mg / kg of the canine's body weight and between about 0.003 mg / kg to about 0.075 mg / kg of the canine's body weight.

[0099]

[0113] Embodiment 52: The isoxazoline of any of embodiments 49-51, wherein the administration provides a concentration of afoxolaner in the blood of the canine animal of greater than about 2 ng / mL and less than about 1200 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0100]

[0114] Embodiment 53: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is lotilaner or a salt thereof.

[0115] Embodiment 54: The isoxazoline of embodiment 53, wherein the lotilaner is provided in the feed in an amount selected from the group consisting of between about 0.00004 and about 0.03 percent by weight of the feed and between about 0.00008 and about 0.02 percent by weight of the feed.

[0101]

[0116] Embodiment 55: The isoxazoline of any of embodiments 53-54, wherein the lotilaner is administered to the canine in an amount selected from the group consisting of between about 0.017 mg / kg to about 1.33 mg / kg of the canine's body weight and between about 0.027 mg / kg to about 0.6 mg / kg of the canine's body weight.

[0102]

[0117] Embodiment 56: The isoxazoline of any of embodiments 53-55, wherein the administration provides a lotilaner concentration of greater than about 8 ng / mL and less than about 3000 ng / mL in the blood of the canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0103]

[0118] Embodiment 57: The isoxazoline of any of embodiments 35 to 56, wherein the isoxazoline is administered as an ingredient in a feed.

[0119] Embodiment 58: The isoxazoline of embodiment 57, wherein the feed is dry dog ​​food.

[0104]

[0120] Embodiment 59: The isoxazoline of embodiment 57, wherein the feed is wet dog food.

[0121] Embodiment 60: The isoxazoline of any one of embodiments 35 to 56, wherein the isoxazoline is administered as a component of a chew.

[0122] Embodiment 61: The isoxazoline of any of embodiments 35 to 60, wherein the delivery frequency is selected from the group consisting of at least three times per week, substantially daily, and daily.

[0105]

[0123] Embodiment 62: The isoxazoline of any of embodiments 35-61, wherein the effective time period comprises administering the isoxazoline for a period selected from the group consisting of at least 1 week and at least 2 weeks.

[0106]

[0124] Embodiment 63: The isoxazoline of any of embodiments 35-62, wherein the administration provides a therapeutically effective level of the isoxazoline in the blood of the canine for a period of time selected from the group consisting of one week from the first administration of the isoxazoline and two days from the first administration of the isoxazoline.

[0107]

[0125] Embodiment 64: The isoxazoline of any of embodiments 35-63, wherein the administration provides a therapeutically effective level of the isoxazoline in the blood of the canine for a period selected from the group consisting of at least 30 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days.

[0108]

[0126] Embodiment 65: The isoxazoline of any of embodiments 35-64, wherein the isoxazoline is administered at a frequency selected from the group consisting of at least 15 days out of 30 days and at least 20 days out of 30 days.

[0109]

[0127] Embodiment 66: The isoxazoline of any of embodiments 35 to 65, wherein the isoxazoline is administered as a component of a feed containing one or more other active substances.

[0128] Embodiment 67: The isoxazoline of any of embodiments 35-66, further comprising discontinuing administration of the isoxazoline for a period of time selected from the group consisting of at least 3 days and at least 7 days, wherein the blood concentration of the isoxazoline in the canine is maintained at a therapeutically effective level.

[0110]

[0129] Embodiment 68: The isoxazoline of embodiment 67, further comprising discontinuing administration of the isoxazoline, thereby maintaining the canine's blood concentration of the isoxazoline at a therapeutically effective level, followed by resuming administration of the isoxazoline.

[0111]

[0130] Embodiment 69: A feed or chew for controlling fleas in a canine, comprising an effective amount of an isoxazoline when administered to said canine for an effective period of time, at least four times per month.

[0112]

[0131] Embodiment 70: The feed or chew of embodiment 69, wherein the canine is a dog.

[0132] Embodiment 71: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is mivorilaner or a salt thereof.

[0113]

[0133] Embodiment 72: A feed or chew as described in embodiment 71, wherein the mivorilaner is provided in the feed in an amount selected from the group consisting of between about 0.0001 and about 0.08 percent by weight of the feed and between about 0.0002 and about 0.05 percent by weight of the feed.

[0114]

[0134] Embodiment 73: The feed or chew of any of embodiments 71-72, wherein the mivorilaner is administered to the canine in an amount selected from the group consisting of between about 0.04 mg / kg to about 3.33 mg / kg of the canine's body weight and between about 0.07 mg / kg to about 1.5 mg / kg of the canine's body weight.

[0115]

[0135] Embodiment 74: A feed or chew described in any of embodiments 71-73, wherein the administration provides a mivorilaner concentration in the blood of the canine animal of greater than about 40 ng / mL and less than about 12,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0116]

[0136] Embodiment 75: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is fluralaner or a salt thereof.

[0137] Embodiment 76: A feed or chew as described in embodiment 75, wherein the fluralaner is provided in the feed in an amount selected from the group consisting of between about 0.00002 and about 0.03 weight percent of the feed and between about 0.00004 and about 0.02 weight percent of the feed.

[0117]

[0138] Embodiment 77: The feed or chew of any of embodiments 75-76, wherein the fluralaner is administered to the canine in an amount selected from the group consisting of between about 0.008 mg / kg and about 0.67 mg / kg of the canine's body weight and between about 0.013 mg / kg and about 0.3 mg / kg of the canine's body weight.

[0118]

[0139] Embodiment 78: A feed or chew described in any of embodiments 75 to 77, wherein the administration provides a fluralaner concentration in the blood of the canine animal of greater than about 4 ng / mL and less than about 3000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0119]

[0140] Embodiment 79: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is sarolaner or a salt thereof.

[0141] Embodiment 80: The feed or chew of embodiment 79, wherein the sarolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000004 and about 0.02 weight percent of the feed.

[0120]

[0142] Embodiment 81: The feed or chew of any of embodiments 79-80, wherein the sarolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0016 mg / kg and about 0.036 mg / kg of the canine's body weight.

[0121]

[0143] Embodiment 82: The feed or chew of any of embodiments 79-81, wherein the administration provides a concentration of sarolaner in the blood of the canine animal of greater than about 1 ng / mL and less than about 800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0122]

[0144] Embodiment 83: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is afoxolaner or a salt thereof.

[0145] Embodiment 84: The feed or chew of embodiment 83, wherein the afoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000005 and about 0.03 weight percent of the feed and between about 0.00001 and about 0.02 weight percent of the feed.

[0123]

[0146] Embodiment 85: The feed or chew of any of embodiments 83-84, wherein the afoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.002 mg / kg to about 0.167 mg / kg of the canine's body weight and between about 0.003 mg / kg to about 0.075 mg / kg of the canine's body weight.

[0124]

[0147] Embodiment 86: The feed or chew of any of embodiments 83-85, wherein the administration provides a concentration of afoxolaner in the blood of the canine animal of greater than about 2 ng / mL and less than about 1200 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0125]

[0148] Embodiment 87: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is lotilaner or a salt thereof.

[0149] Embodiment 88: A feed or chew as described in embodiment 87, wherein the lotilaner is provided in the feed in an amount selected from the group consisting of between about 0.00004 and about 0.03 weight percent of the feed and between about 0.00008 and about 0.02 weight percent of the feed.

[0126]

[0150] Embodiment 89: The feed or chew of any of embodiments 87-88, wherein the lotilaner is administered to the canine in an amount selected from the group consisting of between about 0.017 mg / kg and about 1.33 mg / kg of the canine's body weight and between about 0.027 mg / kg and about 0.6 mg / kg of the canine's body weight.

[0127]

[0151] Embodiment 90: The feed or chew of any of embodiments 87-89, wherein said administration provides a lotilaner concentration of greater than about 8 ng / mL and less than about 3000 ng / mL in the blood of said canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0128]

[0152] Embodiment 91: A feed or chew according to any of embodiments 69-90, wherein the feed is a dry dog ​​food.

[0153] Embodiment 92: A feed or chew according to any of embodiments 69-90, wherein the feed is a wet dog food.

[0129]

[0154] Embodiment 93: A feed or chew according to any of embodiments 69 to 92, wherein said frequency is selected from the group consisting of at least 3 times per week, substantially daily and daily.

[0130]

[0155] Embodiment 94: A feed or chew according to any of embodiments 69-93, wherein said effective time period comprises administering the feed or chew for a period selected from the group consisting of at least 1 week and at least 2 weeks.

[0131]

[0156] Embodiment 95: A feed or chew according to any of embodiments 69-94, wherein said administration provides a therapeutically effective level of an isoxazoline in the blood of the canine for a period selected from the group consisting of one week from the first administration of the feed or chew and two days from the first administration of the feed or chew.

[0132]

[0157] Embodiment 96: The feed or chew of any of embodiments 69-95, wherein said administration provides a therapeutically effective level of an isoxazoline in the blood of the canine for a period selected from the group consisting of at least 30 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days.

[0133]

[0158] Embodiment 97: A feed or chew according to any of embodiments 69 to 96, wherein the feed or chew is administered at a frequency selected from the group consisting of at least 15 days out of 30 days and at least 20 days out of 30 days.

[0134]

[0159] Embodiment 98: A feed or chew according to any of embodiments 69 to 97, wherein the feed or chew comprises one or more other active substances.

[0160] Embodiment 99: The feed or chew of any of embodiments 69-98, further comprising the step of discontinuing administration of the feed or chew for a period selected from the group consisting of at least 3 days and at least 7 days, wherein the blood concentration of the isoxazoline in the canine is maintained at a therapeutically effective level.

[0135]

[0161] Embodiment 100: The feed or chew of embodiment 99, further comprising the step of discontinuing administration of the feed or chew, thereby maintaining a blood concentration of the isoxazoline in the canine at a therapeutically effective level, and then resuming administration of the feed or chew.

[0136]

[0162] Embodiment 101: The method of any one of embodiments 1 or 2, wherein the isoxazoline is umifoxolaner or a salt thereof.

[0163] Embodiment 102: The method of embodiment 101, wherein the umifoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0137]

[0164] Embodiment 103: The method of any of embodiments 101-102, wherein the umifoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0138]

[0165] Embodiment 104: The method of any of embodiments 101-103, wherein the administration provides a umifoxolaner concentration of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of the canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0139]

[0166] Embodiment 105: The method of any one of embodiments 1 or 2, wherein the isoxazoline is esafoxolaner or a salt thereof.

[0167] Embodiment 106: The method of embodiment 105, wherein the esafoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0140]

[0168] Embodiment 107: The method of any of embodiments 105-106, wherein the esafoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0141]

[0169] Embodiment 108: The method of any of embodiments 105-107, wherein the administration provides a concentration of esafoxolaner in the blood of the canine animal of greater than about 1 ng / mL and less than about 600 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0142]

[0170] Embodiment 109: The method of any one of embodiments 1 or 2, wherein the isoxazoline is tigolaner or a salt thereof.

[0171] Embodiment 110: The method of embodiment 109, wherein the tigolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0143]

[0172] Embodiment 111: The method of any of embodiments 109-110, wherein the tigolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0144]

[0173] Embodiment 112: The method of any of embodiments 109-111, wherein the administration provides a tigolaner concentration of greater than about 1 ng / mL and less than about 800 ng / mL in the blood of the canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0145]

[0174] Embodiment 113: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is umifoxolaner or a salt thereof.

[0175] Embodiment 114: The isoxazoline of embodiment 113, wherein the umifoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0146]

[0176] Embodiment 115: The isoxazoline of any of embodiments 113-114, wherein the umifoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0147]

[0177] Embodiment 116: The isoxazoline of any of embodiments 113 to 115, wherein the administration provides a concentration of umifoxolaner in the blood of the canine animal of greater than about 1 ng / mL and less than about 600 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0148]

[0178] Embodiment 117: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is esafoxolaner or a salt thereof.

[0179] Embodiment 118: The isoxazoline of embodiment 117, wherein the esafoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0149]

[0180] Embodiment 119: The isoxazoline of any of embodiments 117-118, wherein the esafoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0150]

[0181] Embodiment 120: The isoxazoline of any of embodiments 117-119, wherein the administration provides a concentration of esafoxolaner of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of the canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0151]

[0182] Embodiment 121: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is tigolaner or a salt thereof.

[0183] Embodiment 122: The isoxazoline of embodiment 121, wherein the tigolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0152]

[0184] Embodiment 123: The isoxazoline of any of embodiments 120-121, wherein the tigolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg to about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg to about 0.04 mg / kg of the canine's body weight.

[0153]

[0185] Embodiment 124: The isoxazoline of any of embodiments 120-122, wherein the administration provides a tigolaner concentration of greater than about 1 ng / mL and less than about 800 ng / mL in the blood of the canine for a period selected from the group consisting of at least 30 days and at least 365 days.

[0154]

[0186] Embodiment 125: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is umifoxolaner or a salt thereof.

[0187] Embodiment 126: The feed or chew of embodiment 125, wherein the umifoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0155]

[0188] Embodiment 127: The feed or chew of any of embodiments 125-126, wherein the umifoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0156]

[0189] Embodiment 128: A feed or chew described in any of embodiments 125-127, wherein the administration provides a umifoxolaner concentration of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of the canine animal for a period selected from the group consisting of at least 30 days and at least 365 days.

[0157]

[0190] Embodiment 129: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is esafoxolaner or a salt thereof.

[0191] Embodiment 130: The feed or chew of embodiment 129, wherein the esafoxolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0158]

[0192] Embodiment 131: The feed or chew of any of embodiments 129-130, wherein the esafoxolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0159]

[0193] Embodiment 132: The feed or chew of any of embodiments 129-131, wherein said administration provides a concentration of esafoxolaner in the blood of the canine animal of greater than about 1 ng / mL and less than about 600 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0160]

[0194] Embodiment 133: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is tigolaner or a salt thereof.

[0195] Embodiment 134: A feed or chew as described in embodiment 133, wherein the tigolaner is provided in the feed in an amount selected from the group consisting of between about 0.000002 and about 0.03 weight percent of the feed and between about 0.000005 and about 0.02 weight percent of the feed.

[0161]

[0196] Embodiment 135: The feed or chew of any of embodiments 133-134, wherein the tigolaner is administered to the canine in an amount selected from the group consisting of between about 0.001 mg / kg and about 0.08 mg / kg of the canine's body weight and between about 0.0017 mg / kg and about 0.04 mg / kg of the canine's body weight.

[0162]

[0197] Embodiment 136: A feed or chew according to any of embodiments 133 to 135, wherein said administration provides a tigolaner concentration in the blood of said canine animal of greater than about 1 ng / mL and less than about 800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0163]

[0198] In some aspects of any of the embodiments, administration provides a therapeutically effective concentration of the particular isoxazoline in the blood of the canine for at least 30 days. The exact concentration may vary depending on the particular isoxazoline. For example, administration of mivoliraner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 12,000 ng / mL in the blood of the canine for at least 30 days. More preferably, administration of mivoliraner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 2500 ng / mL in the blood of the canine for at least 30 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 2 ng / mL and less than about 1200 ng / mL in the blood of the canine for at least 30 days. More preferably, afoxolaner provides an isoxazoline concentration of greater than about 2 ng / mL and less than about 600 ng / mL in the blood of the canine for at least 30 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 4 ng / mL and less than about 3000 ng / mL in the blood of the canine for at least 30 days. More preferably, fluralaner provides an isoxazoline concentration of greater than about 4 ng / mL and less than about 1500 ng / mL in the blood of the canine for at least 30 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 800 ng / mL in the blood of the canine for at least 30 days. More preferably, sarolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 400 ng / mL in the blood of the canine for at least 30 days. In another example, lotilaner provides an isoxazoline concentration of greater than about 8 ng / mL and less than about 3000 ng / mL in the blood of the canine for at least 30 days. More preferably, lotilaner provides an isoxazoline concentration of greater than about 8 ng / mL and less than about 2000 ng / mL in the blood of said canine for at least 30 days. In another example, tigolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 800 ng / mL in the blood of said canine for at least 30 days.More preferably, tigolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of said canine for at least 30 days. In another example, umifoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of said canine for at least 30 days. More preferably, umifoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of said canine for at least 30 days. In another example, esafoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of said canine for at least 30 days. More preferably, esafoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of said canine for at least 30 days.

[0164]

[0199] In some aspects of any of the embodiments, administration provides a therapeutically effective concentration of the particular isoxazoline in the blood of the canine for at least 365 days. The exact concentration may vary depending on the particular isoxazoline. For example, administration of mivoliraner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 12,000 ng / mL in the blood of the canine for at least 365 days. More preferably, administration of mivoliraner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 2500 ng / mL in the blood of the canine for at least 365 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 2 ng / mL and less than about 1200 ng / mL in the blood of the canine for at least 365 days. More preferably, afoxolaner provides an isoxazoline concentration of greater than about 2 ng / mL and less than about 600 ng / mL in the blood of the canine for at least 365 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 4 ng / mL and less than about 3000 ng / mL in the blood of the canine for at least 365 days. More preferably, fluralaner provides an isoxazoline concentration of greater than about 4 ng / mL and less than about 1500 ng / mL in the blood of the canine for at least 365 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 800 ng / mL in the blood of the canine for at least 365 days. More preferably, sarolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 400 ng / mL in the blood of the canine for at least 365 days. In another example, lotilaner provides an isoxazoline concentration of greater than about 8 ng / mL and less than about 3000 ng / mL in the blood of the canine for at least 365 days. More preferably, lotilaner provides an isoxazoline concentration of greater than about 8 ng / mL and less than about 2000 ng / mL in the blood of said canine for at least 365 days. In another example, tigolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 800 ng / mL in the blood of said canine for at least 365 days.More preferably, tigolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of said canine for at least 365 days. In another example, umifoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of said canine for at least 365 days. More preferably, umifoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of said canine for at least 365 days. In another example, esafoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 600 ng / mL in the blood of said canine for at least 365 days. More preferably, esafoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of said canine for at least 365 days. EXAMPLES

[0165]

[0200] The following examples illustrate the methods of the present disclosure. Example 1

[0201] Efficacy of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis.

[0202] Methods: A pool of 14 dogs is pre-infested with approximately 100 unfed adult C. felis to identify dogs capable of adequately maintaining a reliable infestation rate, defined as approximately 50% of fleas alive at the end of 48 hours. The 12 dogs with the highest live flea counts are selected for inclusion in the study. Dogs are divided into control and test groups.

[0166]

[0203] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0204] Each dog in the treatment group is given a liquid formulation of isoxazoline by mouth. A dose of 0.75 mg / kg is administered to the dog on each of days 0-29.

[0167]

[0205] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 2, 5, 12, 20, and 35. Combined counts of live adult fleas are taken on days 4, 7, 14, 21, and 37.

[0168]

[0206] Results: The percent reduction in live adult flea counts in treatment groups with mivorilaner is shown in the graph below.

[0169] [ka]

[0170]

[0207] Using the same study methodology described above, blood is drawn at 72, 168, 336, 504, 720 and 888 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0171]

[0208] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0172] [Table 1]

[0173] [ka]

[0174] Example 2

[0209] Efficacy of various doses of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis

[0210] Methods: A pool of 46 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 40 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0175]

[0211] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0212] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-59.

[0176] [Table 2]

[0177]

[0213] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, 12, 19, 28, 35, and 42. Combined counts of live adult fleas are taken on days 2, 7, 14, 21, 30, 37, and 44.

[0178]

[0214] Results: The percent reduction in live adult flea counts in the treatment groups for mivorilaner is shown in the graph below.

[0179] [ka]

[0180]

[0215] Using the same study methodology described above, blood is drawn at 0, 72, 120, 168, 336, 504, 720, 888, 1056, 1224 and 1440 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0181]

[0216] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0182] [Table 3]

[0183] [ka]

[0184] Example 3

[0217] Comparison of plasma concentrations of isoxazolines in dogs when administered intravenously and orally in solution and crystal form

[0218] Methods: A pool of 24 dogs, 50% female, 50% male, 6 juveniles and 28 adults, are assigned to 4 study groups according to the table below.

[0185] [Table 4]

[0186]

[0219] Dogs are allowed free access to water. On day 1 of the study, prior to administration of the isoxazoline, juvenile dogs are fed approximately 25% of their daily diet as canned food. Four hours later, juvenile dogs are fed the remainder of their daily diet as dry food. On day 1 of the study, prior to administration, adult dogs are fed approximately 1 / 3 can of dog food and the remainder of their daily diet following the 10 hour blood collection time point. For the remainder of the study, all dogs' daily diets should be fed over approximately 2 hours.

[0187]

[0220] On day 1 of the study, dogs are given one dose of the isoxazoline in a fed state. Dogs are fasted prior to treatment (young animals are fasted for less than 10 hours). The isoxazoline treatment is administered within approximately 30 minutes once the dog is observed to have eaten 25% of its daily ration. This is similar to incorporating the isoxazoline in the feed.

[0188]

[0221] Blood samples are taken for test groups 1 and 2 (administered intravenously) at 0, 0.083, 0.25, 0.5, 1, 3, 6, 10, 24, 48 and 96 hours after initial treatment and at 7, 10, 14, 21, 28 and 32 days after initial treatment. Blood samples are taken for test groups 3 and 4 (administered orally) at 0, 0.25, 0.5, 1, 3, 6, 10, 24, 48 and 96 hours after initial treatment and at 7, 10, 14, 21, 28 and 32 days after initial treatment. After the first sample on day 1, dogs are fasted for a minimum of 4 hours before further blood samples are taken.

[0189]

[0222] Results: The mean plasma concentrations in a study conducted with mivoliraner similar to this example are shown in the figure below.

[0190] [ka]

[0191] [ka]

[0192] [ka]

[0193] [ka]

[0194] Example 4

[0223] Efficacy of various formulations of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis.

[0224] Methods: A pool of 36 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 30 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0195]

[0225] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0226] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-20.

[0196] [Table 5]

[0197]

[0227] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the test group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, and 28. Combined counts of live adult fleas are taken on days 2, 7, and 30.

[0198]

[0228] Results: The percent reduction in live adult flea counts for treatment groups according to this example is shown in the graph below.

[0199] [ka]

[0200] Example 5

[0229] Plasma concentrations of isoxazolines in dogs when administered in medicated feed at a dose of 1.0 mg / kg of dog weight per day

[0230] Methods: A pool of 30 dogs will be assigned by weight into 5 groups to minimize between- and within-group variability. Each group will be fed a different feed formulation containing the isoxazoline, and blood levels of the isoxazoline will be determined over a one-month period after a single dose.

[0201]

[0231] Dogs are individually housed for the duration of the study with water available ad libitum.

[0232] There is an initial acclimation period of at least 4 days during which dogs are transitioned from the standard certified commercial food to a non-medicated version of the daily diet. During the acclimation period, dogs are allowed to consume food for 15 min / day.

[0202]

[0233] On day 1 of the study, dogs are given approximately 9.4 g / kg of isoxazoline-containing chow daily. The amount of drugged chow for each dog is determined according to the dog's most recent body weight prior to the day of the study. The drugged chow is offered for 15 minutes at the start of the study. Any uneaten drugged chow is removed and weighed. An amount of undrugged chow equal to the amount of uneaten drugged chow is offered at the time of the first blood draw 10 hours later.

[0203]

[0234] Blood samples are collected at the following times: 0 hours (at the time of drugged food presentation), 0.25 hours, 0.5 hours, 1 hour, 3 hours, 6 hours, 10 hours, 1 day, 2 days, 4 days, 6 days, 9 days, 13 days, 20 days, 27 days and 31 days after drugged food presentation.

[0204]

[0235] Results: The mean plasma concentrations in a study conducted with mivoliraner similar to this example are shown in the table and figure below.

[0205] [Table 6]

[0206] [ka]

[0207]

[0236] By comparing the examples it can be seen that on average an effective amount of isoxazoline can be administered to a dog via the medicated feed. Example 6

[0237] Plasma concentrations of isoxazolines when administered in medicated diets at different dose levels

[0238] Methods: A pool of dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to generate dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 72 hours. The 24 dogs with the highest live attached tick counts are selected for inclusion in the study. The 18 dogs with the highest live attached tick counts are randomly assigned to one control group and two treatment groups. The next 6 dogs with the highest live attached tick counts are assigned to a third treatment group.

[0239] Dogs are individually housed for the duration of the study with water available ad libitum.

[0208]

[0240] Each dog in the treatment group (study groups 2-4) will be provided with a daily medicated chow on study days 0 through 49. Depending on the study group, the daily medicated chow will be provided to the dog for a 1-h period on each of days 0 through 49.

[0209] [Table 7]

[0210]

[0241] After the initial dose of isoxazoline is administered, blood is drawn at 0, 1, 3, 6, 10, 24, 48, 96, 168, 240 and 336 hours. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0211]

[0242] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0212] [Table 8]

[0213] [ka]

[0214] Example 7

[0243] Efficacy of various formulations of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis.

[0244] Methods: A pool of 24 dogs is pre-infested with approximately 50 unfed adult Rhipicephalus sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 20 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0215]

[0245] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0246] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-27.

[0216] [Table 9]

[0217]

[0247] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, and 33. Combined counts of live adult fleas are taken on days 2, 7, and 35.

[0218]

[0248] Results: The percent reduction in live adult flea counts for treatment groups according to this example is shown in the graph below.

[0219] [ka]

[0220]

[0249] While the invention has been described in an illustrative manner, the invention may be further modified within the spirit and scope of the disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles.

Claims

1. A composition for controlling flea infestation in a canine in need thereof, the composition being used for a method comprising orally administering to the canine an effective amount of an isoxazoline for an effective period of time at least four times per month.

2. The composition described in claim 1, wherein the frequency is selected from the group consisting of at least three times per week, substantially daily, and daily.

3. The composition of claim 1, wherein the effective time comprises administering the isoxazoline for a period selected from the group consisting of at least one week and at least two weeks.

4. The composition of claim 1, wherein the method further comprises discontinuing the administration of the isoxazoline for a period selected from the group consisting of at least 3 days and at least 7 days, wherein a blood concentration of the isoxazoline of the canine is maintained at a therapeutically effective level.

5. The composition described in claim 4, wherein the method further comprises the step of discontinuing the administration of the isoxazoline, thereby maintaining a blood concentration of the isoxazoline in the canine animal at the therapeutically effective level, and then resuming the administration of the isoxazoline.

6. The composition of claim 1, wherein the administration provides a therapeutically effective level of the isoxazoline in the blood of the canine within a period selected from the group consisting of one week from the first administration of the isoxazoline and two days from the first administration of the isoxazoline.

7. The composition of claim 1, wherein the administration provides a therapeutically effective level of isoxazoline in the blood of the canine for a period selected from the group consisting of at least 30 days, at least 60 days, at least 90 days, at least 180 days and at least 365 days.

8. The composition of claim 1, wherein the isoxazoline is administered at a frequency selected from the group consisting of at least 15 days out of 30 days and at least 20 days out of 30 days.

9. The composition of claim 1, wherein the isoxazoline is at least one compound selected from the group consisting of mivoliraner, salts of mivoliraner, afoxolaner, salts of afoxolaner, sarolaner, salts of sarolaner, fluralaner, salts of fluralaner, umifoxolaner, salts of umifoxolaner, esafoxolaner, salts of esafoxolaner, tigoraner, salts of tigoraner, lotilaner, and salts of lotilaner.

10. The composition described in claim 9, wherein the isoxazoline is mivorilaner or a salt thereof.

11. The composition described in claim 10, wherein the mivorilaner or a salt thereof is provided in the feed in an amount selected from the group consisting of between about 0.0001 and about 0.08 percent by weight of the feed and between about 0.0002 and about 0.05 percent by weight of the feed.

12. The composition of claim 10, wherein the mivorilaner or a salt thereof is administered to the canine in an amount selected from the group consisting of between about 0.04 mg / kg to about 3.33 mg / kg of the canine's body weight and between about 0.07 mg / kg to about 1.5 mg / kg of the canine's body weight.

13. The composition of claim 10, wherein the administration provides a mivorilaner concentration in the blood of the canine animal of greater than about 40 ng / mL and less than about 12,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

14. A feed or chew for controlling flea infestation in a canine, comprising an effective amount of an isoxazoline when administered to said canine for an effective period of time and at least four times per month.

15. The feed or chew of claim 14, wherein the feed is a dry feed or a wet feed.

16. The feed or chew of claim 14, wherein the isoxazoline is a component of a feed which contains one or more active substances other than the isoxazoline.

17. The feed or chew of claim 14, wherein the isoxazoline is at least one compound selected from the group consisting of mivoliraner, salts of mivoliraner, afoxolaner, salts of afoxolaner, sarolaner, salts of sarolaner, fluralaner, salts of fluralaner, umifoxolaner, salts of umifoxolaner, esafoxolaner, salts of esafoxolaner, tigoraner, salts of tigoraner, lotilaner, and salts of lotilaner.

18. The feed or chew of claim 17, wherein the isoxazoline is mivorilaner or a salt thereof.

19. The feed or chew of claim 18, wherein the mivorilaner or a salt thereof is provided in the feed or chew in an amount selected from the group consisting of between about 0.0001 and about 0.08 percent by weight of the feed or chew and between about 0.0002 and about 0.05 percent by weight of the feed or chew.

20. The feed or chew of claim 18, wherein the mivorilaner or a salt thereof is administered to the canine in an amount selected from the group consisting of between about 0.04 mg / kg and about 3.33 mg / kg of the canine's body weight and between about 0.07 mg / kg and about 1.5 mg / kg of the canine's body weight.

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