Oral feline feed and method for controlling flea infestations in felines - Patents.com

Abstract

An oral feline feed and a method for controlling fleas in a feline in need of flea control by orally administering to the feline 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 feline'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, feline feeds containing isoxazolines, and methods of administering isoxazolines in the feed to control flea infestations in felines. [Background technology]

[0002]

[0002] Fleas are the most common of all ectoparasites of felines, the most common of which is the cat flea or Ctenocephalides felis. Flea infestations are usually very unpleasant for most cats and can be a cause of life-threatening illness. Flea bites cause itching, and the resulting scratches by the cat can cause skin wounds that are susceptible to infection. Furthermore, fleas themselves often carry pathogens. For example, cat fleas can carry the larval stage of the tapeworm Dipylidium caninum, which cats can become infected by ingesting the fleas while grooming themselves.

[0003]

[0003] Furthermore, fleas are involved in the transmission of "cat scratch disease" to humans, an infection caused by the bacterium Bartonella hensellae that is spread when fleas suck blood. Cat scratch disease causes unpleasant symptoms in humans, which may include, among others, swelling or blisters at the scratch site, swollen lymph nodes, fatigue, headache, fever and body aches. One of the recommended ways to control the risk from fleas to humans is to control the risk of infestation in cats.

[0004]

[0004] Treatments currently available for controlling flea infestations in felines have achieved varying degrees of success. Many treatments involve chemicals that are applied to indoor and outdoor surfaces, as well as to the feline. 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 felines 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 infestation in felines. There are numerous ways to deliver these treatments to the fur and skin of felines, but many of these methods are ineffective and / or pose safety risks to the feline or user during or after the dispensing operation. More specifically, because a physical connection must be obtained between the applicator tip of the drug delivery device at the skin surface when the applicator tip is attached, 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 uncooperative felines, it can be difficult to operate the dispenser with one hand and hold the feline in place with the other, resulting in some, but not all, of the material spilling onto the floor or onto the person applying it instead of reaching the feline'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, feline owners must administer the treatments, for example, once every 30 to 90 days. The long time between treatments creates compliance problems 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 regularly 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 for their 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 felines 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 felines 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 feline, 24 mg of isoxazoline is required per kg of feline body weight for a single administration over a period of 30 days (one month) according to conventional approaches. According to the smaller, more frequent dosing approach of the present invention, only 0.1 to 0.72 mg of isoxazoline per kg of feline body weight per day, or accumulated over the same 30 day period, 3 to 21.6 mg of isoxazoline per kg of feline 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 felines 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:

[0018]

[0019] [ka]

[0020]

[0019]

[0021] [ka]

[0022]

[0020] 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.

[0023] 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.

[0024]

[0022] 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 felines 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.

[0025] 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 feline's living environments (e.g., flooring, carpets, furniture); b) there is no risk of loss due to feline 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).

[0026] 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.

[0027] The method of the present disclosure is carried out by administering the isoxazoline to the feline 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 feline is provided with a controlled amount of the isoxazoline by consuming the feed product weekly, approximately weekly, or daily.

[0028] 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 larger doses and less frequently, for example, in a single treatment of a larger dose administered once in a 30 day period by "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 larger doses means that the feline 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.

[0029] All ratios, percentages, and parts discussed herein are "by weight" unless otherwise specified.

[0028] The term "controlling flea infestation" refers to preventing, minimizing or eliminating flea infestation in felines.

[0030]

[0029] The term "flea" refers to any member of the order Siphonaptera. The term "flea" includes the egg, larva, pupae, and adult stages of development.

[0030] The term "feline" refers to any member of the subfamily Felidae, and includes such species as the domestic cat, bobcat, wild cat, ocelot, members of the genus lynx, the Pallas's cat, and the cougar.

[0031] 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 feline's diet and treats from time to time and still conveniently administer a daily dose of isoxazoline.

[0032]

[0032] The term "chew" refers to a treat that has a flavor and aromaticity that is attractive to felines, but typically has no nutritional value. In carrying out the methods of the present disclosure, "feed" and / or "chew" may be used interchangeably.

[0033] 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 feline'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.

[0034] As alluded to above, the "effective time" varies depending on the frequency with 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 feline. 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.

[0035]

[0035] Furthermore, as discussed above, the frequency of administration may affect the period of time required to obtain a therapeutically effective level of the isoxazoline in the feline's blood. By way of example, if a feline is fed the isoxazoline composition daily, the feeding period, and thus the "effective time," required to obtain a therapeutically effective level of the isoxazoline in the feline's blood will be relatively shorter than if the feline is fed the isoxazoline composition only once or twice per week.

[0036] Furthermore, the frequency of effectiveness is affected by the daily dose in mg / kg of feline body weight, especially at slightly higher daily doses, missed doses have less effect on efficacy.

[0037] 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 blood of a feline 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.

[0038] For purposes of this disclosure, "substantially daily" means sufficiently regular that the concentration of the isoxazoline in the blood of the feline rises to and remains at a therapeutically effective level. For example, the disclosed feed composition can preferably be provided to the feline daily indefinitely. However, as a practical matter, there are many reasons why days may be periodically forgotten or skipped. For example, the feline may become unhealthy or the owner may run out of the medicated feed composition. The disclosed method is sufficiently robust that the feline will receive a significant level of flea protection even if the daily supply 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 use substantially daily, so long as they facilitate achieving and maintaining a therapeutically effective level of the isoxazoline in the feline's blood.

[0039]

[0039] 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.

[0040] In carrying out the methods of the present disclosure, an effective or therapeutically effective amount of the isoxazoline is orally administered to the feline. 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 feline being treated and its weight and overall health.

[0041]

[0041] 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 feline's 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.

[0042]

[0042] 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 by weight for a feline is 20 mg, a typical 5 g treat may contain about 0.4 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.

[0043] For example, an effective amount of mivoliraner may be a dose of about 0.06 to about 5 mg of mivoliraner per kg of feline body weight. More preferably, an effective amount of mivoliraner may be a dose of about 0.1 to about 2.25 mg of mivoliraner per kg of feline body weight. More typically, the effective amount is about 0.06 to about 1.875 mg of mivoliraner per kg of feline body weight.

[0044]

[0044] Animal feed typically contains from about 0.0002 to about 0.12 percent mivoliraner (by weight) in the feed, preferably between about 0.0003 and about 0.075 percent mivoliraner (by weight) in the feed, and most preferably between about 0.0009 to about 0.045 percent mivoliraner component (by weight) in the feed.

[0045] In another example, an effective amount of lotilaner may be a dose of about 0.026 to about 2 mg of lotilaner per kg of feline body weight. More preferably, an effective amount of lotilaner may be a dose of about 0.04 to about 0.9 mg of lotilaner per kg of feline body weight. More typically, the effective amount is about 0.026 to about 0.75 mg of lotilaner per kg of feline body weight.

[0046]

[0046] Animal feed typically contains from about 0.00006 to about 0.045 percent rotilaner (by weight) in the feed, preferably between about 0.00012 to about 0.03 percent rotilaner (by weight) in the feed, and most preferably between about 0.0003 to about 0.0015 percent rotilaner component (by weight) in the feed.

[0047] In another example, the effective amount of afoxolaner may be a dose of about 0.003 to about 0.25 mg of afoxolaner per kg of the feline's body weight. More preferably, the effective amount of afoxolaner may be a dose of about 0.0045 to about 0.113 mg of afoxolaner per kg of the feline's body weight. More typically, the effective amount is about 0.003 to about 0.094 mg of afoxolaner per kg of the feline's body weight.

[0048]

[0048] Animal feed typically contains from about 0.0000075 to about 0.045 percent afoxolaner (by weight) in the feed, preferably between about 0.000015 to about 0.03 percent afoxolaner (by weight) in the feed, and most preferably between about 0.000045 to about 0.0018 percent afoxolaner component (by weight) in the feed.

[0049] In another example, the effective amount of sarolaner may be a dose of about 0.0015 to about 0.12 mg of sarolaner per kg of feline body weight. More preferably, the effective amount of sarolaner may be a dose of about 0.0024 to about 0.054 mg of sarolaner per kg of feline body weight. More typically, the effective amount is about 0.0015 to about 0.045 mg of sarolaner per kg of feline body weight.

[0050]

[0050] Animal feed typically contains from about 0.000003 to about 0.045 percent sarolaner (by weight) in the feed, preferably between about 0.000006 to about 0.03 percent sarolaner (by weight) in the feed, and most preferably between about 0.00045 to about 0.0009 percent sarolaner component (by weight) in the feed.

[0051] In another example, the effective amount of fluralaner may be a dose of about 0.012 to about 1 mg of fluralaner per kg of feline body weight. More preferably, the effective amount of fluralaner may be a dose of about 0.019 to about 0.45 mg of fluralaner per kg of feline body weight. More typically, the effective amount is about 0.012 to about 0.375 mg of fluralaner per kg of feline body weight.

[0052]

[0052] Animal feed typically contains from about 0.00003 to about 0.045 percent fluralaner (by weight) in the feed, preferably between about 0.00006 to about 0.03 percent fluralaner (by weight) in the feed, and most preferably between about 0.00015 to about 0.009 percent fluralaner component (by weight) in the feed.

[0053] In another example, the effective amount of umifoxolaner may be a dose of about 0.0015 to about 0.12 mg of umifoxolaner per kg of feline body weight. More preferably, the effective amount of umifoxolaner may be a dose of about 0.0025 to about 0.06 mg of umifoxolaner per kg of feline body weight. More typically, the effective amount is about 0.0015 to about 0.047 mg of umifoxolaner per kg of feline body weight.

[0054]

[0054] Animal feed typically contains from about 0.000003 to about 0.045 percent seafoxolaner (by weight) in the feed, preferably between about 0.0000075 to about 0.03 percent seafoxolaner (by weight) in the feed, and most preferably between about 0.000015 to about 0.0009 percent seafoxolaner component (by weight) in the feed.

[0055] In another example, the effective amount of esafoxolaner may be a dose of about 0.0015 to about 0.12 mg of esafoxolaner per kg of feline body weight. More preferably, the effective amount of esafoxolaner may be a dose of about 0.0025 to about 0.06 mg of esafoxolaner per kg of feline body weight. More typically, the effective amount is about 0.0015 to about 0.047 mg of esafoxolaner per kg of feline body weight.

[0056]

[0056] Animal feed typically contains from about 0.000003 to about 0.045 percent esafoxolaner (by weight) in the feed, preferably between about 0.0000075 to about 0.03 percent esafoxolaner (by weight) in the feed, and most preferably between about 0.000015 to about 0.0009 percent esafoxolaner component (by weight) in the feed.

[0057] In another example, the effective amount of tigolaner may be a dose of about 0.0015 to about 0.12 mg of tigolaner per kg of feline body weight. More preferably, the effective amount of tigolaner may be a dose of about 0.0025 to about 0.06 mg of tigolaner per kg of feline body weight. More typically, the effective amount is about 0.0015 to about 0.047 mg of tigolaner per kg of feline body weight.

[0058]

[0058] Animal feed typically contains from about 0.000003 to about 0.045 percent tigolaner (by weight) in the feed, preferably between about 0.0000075 to about 0.03 percent tigolaner (by weight) in the feed, and most preferably between about 0.000015 to about 0.0009 percent tigolaner component (by weight) in the feed.

[0059] In another example, an effective amount of modolaner may be a dose of about 0.003 to about 0.25 mg of modolaner per kg of feline body weight. More preferably, an effective amount of modolaner may be a dose of about 0.0045 to about 0.113 mg of modolaner per kg of feline body weight. More typically, the effective amount is about 0.003 to about 0.094 mg of modolaner per kg of feline body weight.

[0060]

[0060] Animal feed typically contains from about 0.0000075 to about 0.045 percent Modflanel (by weight) in the feed, preferably between about 0.000015 to about 0.03 percent Modflanel (by weight) in the feed, and most preferably between about 0.000045 to about 0.0018 percent Modflanel component (by weight) in the feed.

[0061]

[0061] In one aspect, the present disclosure relates to a method for controlling flea infestations in felines 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.

[0062] In another aspect, the disclosure relates to a systemically active oral composition comprising an isoxazoline and an animal feed or chew.

[0063] 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 felines.

[0063]

[0064] The present disclosure also relates to a method for controlling flea infestations in felines over an extended period of time, comprising orally administering to the feline a daily or substantially daily dose of an effective amount of an isoxazoline. The method is particularly useful for controlling fleas in felines over an extended period of time, and comprises orally administering to the feline a substantially daily dose of an effective amount of an isoxazoline.

[0064]

[0065] An embodiment of the present disclosure is the oral administration of an amount of isoxazoline that is ineffective or suboptimal in controlling flea infestation in felines 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 a single dose and multiple doses result in less than 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.

[0065]

[0066] Embodiment 1: A method of controlling flea infestation in a feline in need thereof, comprising orally administering to said feline an effective amount of an isoxazoline for an effective period of time at least four times per month.

[0066]

[0067] Embodiment 2: The method of embodiment 1, wherein the feline is a domestic cat.

[0068] Embodiment 3: The method of any one of embodiments 1 or 2, wherein the isoxazoline is mivorilaner or a salt thereof.

[0067]

[0069] 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 0.0002 and about 0.12 weight percent of the feed and between about 0.0003 and about 0.075 weight percent of the feed.

[0068]

[0070] Embodiment 5: The method of any of embodiments 3-4, wherein the mivolilaner is administered to the feline in an amount selected from the group consisting of between about 0.06 mg / kg and about 5 mg / kg of the feline's body weight and between about 0.1 mg / kg and about 2.25 mg / kg of the feline's body weight.

[0069]

[0071] Embodiment 6: The method of any of embodiments 3-5, wherein the administration provides a mivoliraner concentration in the blood of the feline of greater than about 60 ng / mL and less than about 18,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0070]

[0072] Embodiment 7: The method of any one of embodiments 1 or 2, wherein the isoxazoline is fluralaner or a salt thereof.

[0073] 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 0.00003 and about 0.045 weight percent of the feed and between about 0.00006 and about 0.03 weight percent of the feed.

[0071]

[0074] Embodiment 9: The method of any of embodiments 7-8, wherein the fluralaner is administered to the feline in an amount selected from the group consisting of between about 0.012 mg / kg and about 1 mg / kg of the feline's body weight, and between about 0.019 mg / kg and about 0.45 mg / kg of the feline's body weight.

[0072]

[0075] Embodiment 10: The method of any of embodiments 7 to 9, wherein the administration provides a fluralaner concentration in the blood of the feline of greater than about 6 ng / mL and less than about 4500 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0073]

[0076] Embodiment 11: The method of any one of embodiments 1 or 2, wherein the isoxazoline is sarolaner or a salt thereof.

[0077] 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 0.000003 and about 0.045 percent by weight of the feed, and between about 0.000006 and about 0.03 percent by weight of the feed.

[0074]

[0078] Embodiment 13: The method of any of embodiments 11-12, wherein the sarolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight, and between about 0.0024 mg / kg and about 0.054 mg / kg of the feline's body weight.

[0075]

[0079] Embodiment 14: The method of any of embodiments 11-13, wherein the administration provides a concentration of sarolaner in the blood of the feline of greater than about 1.5 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.

[0076]

[0080] Embodiment 15: The method of any one of embodiments 1 or 2, wherein the isoxazoline is afoxolaner or a salt thereof.

[0081] 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 0.0000075 and about 0.045 percent by weight of the feed, and between about 0.000015 and about 0.03 percent by weight of the feed.

[0077]

[0082] Embodiment 17: The method of any of embodiments 15-16, wherein the afoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.003 mg / kg and about 0.25 mg / kg of the feline's body weight and between about 0.0045 mg / kg and about 0.113 mg / kg of the feline's body weight.

[0078]

[0083] Embodiment 18: The method of any of embodiments 15-17, wherein the administration provides a concentration of afoxolaner in the blood of the feline of greater than about 3 ng / mL and less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0079]

[0084] Embodiment 19: The method of any one of embodiments 1 or 2, wherein the isoxazoline is lotilaner or a salt thereof.

[0085] 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 0.00006 and about 0.045 percent by weight of the feed and between about 0.00012 and about 0.03 percent by weight of the feed.

[0080]

[0086] Embodiment 21: The method of any of embodiments 19-20, wherein the lotilaner is administered to the feline in an amount selected from the group consisting of between about 0.026 mg / kg and about 2 mg / kg of the feline's body weight and between about 0.04 mg / kg and about 0.9 mg / kg of the feline's body weight.

[0081]

[0087] Embodiment 22: The method of any of embodiments 19-21, wherein the administration provides a lotilaner concentration of greater than about 12 ng / mL and less than about 4500 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0082]

[0088] Embodiment 23: The method of any one of embodiments 1 to 22, wherein the isoxazoline is administered as a component of feed.

[0089] Embodiment 24: The method of embodiment 23, wherein the feed is dry cat food.

[0083]

[0090] Embodiment 25: The method of embodiment 23, wherein the food is wet cat food.

[0091] Embodiment 26: The method of any one of embodiments 1-22, wherein the isoxazoline is administered as a component of a chew.

[0084]

[0092] 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.

[0093] 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.

[0085]

[0094] 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 feline within 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.

[0086]

[0095] 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 feline 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.

[0087]

[0096] 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.

[0088]

[0097] 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.

[0098] Embodiment 33: The method of any one 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 feline's blood concentration of the isoxazoline is maintained at a therapeutically effective level.

[0089]

[0099] Embodiment 34: The method of embodiment 33, further comprising discontinuing administration of the isoxazoline, thereby maintaining the feline's blood concentration of the isoxazoline at a therapeutically effective level, followed by resuming administration of the isoxazoline.

[0090]

[0100] Embodiment 35: An isoxazoline for use in controlling fleas in a feline in need thereof, wherein the isoxazoline or a salt thereof is administered to the feline in an effective amount for an effective period of time at least four times per month.

[0091]

[0101] Embodiment 36: The isoxazoline of embodiment 35, wherein the feline is a domestic cat.

[0102] Embodiment 37: The isoxazoline of either embodiment 35 or 36, wherein the isoxazoline is mivorilaner or a salt thereof.

[0092]

[0103] 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 0.0002 and about 0.12 percent by weight of the feed and between about 0.0003 and about 0.075 percent by weight of the feed.

[0093]

[0104] Embodiment 39: The isoxazoline of any of embodiments 37-38, wherein the mivorilaner is administered to the feline in an amount selected from the group consisting of between about 0.06 mg / kg and about 5 mg / kg of the feline's body weight and between about 0.1 mg / kg and about 2.25 mg / kg of the feline's body weight.

[0094]

[0105] Embodiment 40: The isoxazoline of any of embodiments 37-39, wherein the administration provides a mivorilaner concentration in the blood of the feline of greater than about 60 ng / mL and less than about 18,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0095]

[0106] Embodiment 41: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is fluralaner or a salt thereof.

[0107] 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 0.00003 and about 0.045 weight percent of the feed and between about 0.00006 and about 0.03 weight percent of the feed.

[0096]

[0108] Embodiment 43: The isoxazoline of any of embodiments 41-42, wherein the fluralaner is administered to the feline in an amount selected from the group consisting of between about 0.012 mg / kg and about 1 mg / kg of the feline's body weight and between about 0.019 mg / kg and about 0.45 mg / kg of the feline's body weight.

[0097]

[0109] Embodiment 44: The isoxazoline of any of embodiments 41 to 43, wherein the administration provides a fluralaner concentration in the blood of the feline of greater than about 6 ng / mL and less than about 4500 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0098]

[0110] Embodiment 45: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is sarolaner or a salt thereof.

[0111] 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 0.000003 and about 0.045 percent by weight of the feed and between about 0.000006 and about 0.03 percent by weight of the feed.

[0099]

[0112] Embodiment 47: The isoxazoline of any of embodiments 45-46, wherein the sarolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg to about 0.12 mg / kg of the feline's body weight and between about 0.0024 mg / kg to about 0.054 mg / kg of the feline's body weight.

[0100]

[0113] Embodiment 48: The isoxazoline of any of embodiments 45-47, wherein the administration provides a concentration of sarolaner in the blood of the feline of greater than about 1.5 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.

[0101]

[0114] Embodiment 49: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is afoxolaner or a salt thereof.

[0115] 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 0.0000075 and about 0.045 weight percent of the feed and between about 0.000015 and about 0.03 weight percent of the feed.

[0102]

[0116] Embodiment 51: The isoxazoline of any of embodiments 49-50, wherein the afoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.003 mg / kg to about 0.25 mg / kg of the feline's body weight and between about 0.0045 mg / kg to about 0.113 mg / kg of the feline's body weight.

[0103]

[0117] Embodiment 52: The isoxazoline of any of embodiments 49-51, wherein the administration provides a concentration of afoxolaner in the blood of the feline of greater than about 3 ng / mL and less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0104]

[0118] Embodiment 53: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is lotilaner or a salt thereof.

[0119] 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 0.00006 and about 0.045 percent by weight of the feed and between about 0.00012 and about 0.03 percent by weight of the feed.

[0105]

[0120] Embodiment 55: The isoxazoline of any of embodiments 53-54, wherein the lotilaner is administered to the feline in an amount selected from the group consisting of between about 0.026 mg / kg to about 2 mg / kg of the feline's body weight and between about 0.04 mg / kg to about 0.9 mg / kg of the feline's body weight.

[0106]

[0121] Embodiment 56: The isoxazoline of any of embodiments 53-55, wherein the administration provides a lotilaner concentration of greater than about 12 ng / mL and less than about 4500 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0107]

[0122] Embodiment 57: The isoxazoline of any of embodiments 35 to 56, wherein the isoxazoline is administered as an ingredient in a feed.

[0123] Embodiment 58: The isoxazoline of embodiment 57, wherein the feed is dry cat food.

[0108]

[0124] Embodiment 59: The isoxazoline of embodiment 57, wherein the feed is a wet cat food.

[0125] Embodiment 60: The isoxazoline of any of embodiments 35-56, wherein the isoxazoline is administered as a component of a chew.

[0109]

[0126] 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.

[0110]

[0127] 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.

[0111]

[0128] Embodiment 63: The isoxazoline of any of embodiments 35-62, wherein said administration provides a therapeutically effective level of the isoxazoline in the blood of the feline within 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.

[0112]

[0129] 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 feline 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.

[0113]

[0130] 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.

[0114]

[0131] 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.

[0132] 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 feline has a blood concentration of the isoxazoline maintained at a therapeutically effective level.

[0115]

[0133] Embodiment 68: The isoxazoline of embodiment 67, further comprising discontinuing administration of the isoxazoline, thereby maintaining the feline's blood concentration of the isoxazoline at a therapeutically effective level, followed by resuming administration of the isoxazoline.

[0116]

[0134] Embodiment 69: A feed or chew for controlling fleas in a feline, the feed or chew comprising an effective amount of an isoxazoline when administered to said feline for an effective period of time, at least four times per month.

[0117]

[0135] Embodiment 70: The feed or chew of embodiment 69, wherein the feline is a domestic cat.

[0136] Embodiment 71: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is mivorilaner or a salt thereof.

[0118]

[0137] 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 0.0002 and about 0.12 weight percent of the feed and between about 0.0003 and about 0.075 weight percent of the feed.

[0119]

[0138] Embodiment 73: The feed or chew of any of embodiments 71-72, wherein the mivorilaner is administered to the feline in an amount selected from the group consisting of between about 0.06 mg / kg and about 5 mg / kg of the feline's body weight and between about 1 mg / kg and about 2.25 mg / kg of the feline's body weight.

[0120]

[0139] 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 feline of greater than about 60 ng / mL and less than about 18,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0121]

[0140] Embodiment 75: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is fluralaner or a salt thereof.

[0141] 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 0.00003 and about 0.045 weight percent of the feed and between about 0.00006 and about 0.03 weight percent of the feed.

[0122]

[0142] Embodiment 77: The feed or chew of any of embodiments 75-76, wherein the fluralaner is administered to the feline in an amount selected from the group consisting of between about 0.012 mg / kg and about 1 mg / kg of the feline's body weight and between about 0.019 mg / kg and about 0.45 mg / kg of the feline's body weight.

[0123]

[0143] Embodiment 78: A feed or chew described in any of embodiments 75-77, wherein the administration provides a fluralaner concentration in the blood of the feline of greater than about 6 ng / mL and less than about 4500 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0124]

[0144] Embodiment 79: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is sarolaner or a salt thereof.

[0145] 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 0.0000003 and about 0.045 percent by weight of the feed and between about 0.000006 and about 0.03 percent by weight of the feed.

[0125]

[0146] Embodiment 81: The feed or chew of any of embodiments 79-80, wherein the sarolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0024 mg / kg and about 0.054 mg / kg of the feline's body weight.

[0126]

[0147] 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 feline of greater than about 1.5 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.

[0127]

[0148] Embodiment 83: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is afoxolaner or a salt thereof.

[0149] 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 0.0000075 and about 0.045 percent by weight of the feed and between about 0.000015 and about 0.03 percent by weight of the feed.

[0128]

[0150] Embodiment 85: The feed or chew of any of embodiments 83-84, wherein the afoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.003 mg / kg and about 0.25 mg / kg of the feline's body weight and between about 0.0045 mg / kg and about 0.113 mg / kg of the feline's body weight.

[0129]

[0151] 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 feline of greater than about 3 ng / mL and less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0130]

[0152] Embodiment 87: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is lotilaner or a salt thereof.

[0153] 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 0.00006 and about 0.045 percent by weight of the feed and between about 0.00012 and about 0.03 percent by weight of the feed.

[0131]

[0154] Embodiment 89: The feed or chew of any of embodiments 87-88, wherein the lotilaner is administered to the feline in an amount selected from the group consisting of between about 0.026 mg / kg and about 2 mg / kg of the feline's body weight and between about 0.04 mg / kg and about 0.9 mg / kg of the feline's body weight.

[0132]

[0155] Embodiment 90: The feed or chew of any of embodiments 87-89, wherein said administration provides a lotilaner concentration of greater than about 12 ng / mL and less than about 4500 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0133]

[0156] Embodiment 91: A feed or chew according to any of embodiments 69 to 90, wherein the feed is a dry cat food.

[0157] Embodiment 92: A feed or chew according to any of embodiments 69-90, wherein the feed is a wet cat food.

[0134]

[0158] 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.

[0135]

[0159] 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.

[0136]

[0160] 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 feline within a period selected from the group consisting of one week from the first administration of said feed or chew and two days from the first administration of said feed or chew.

[0137]

[0161] 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 feline 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.

[0138]

[0162] 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.

[0139]

[0163] 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.

[0164] 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 feline is maintained at a therapeutically effective level.

[0140]

[0165] Embodiment 100: The feed or chew of embodiment 99, further comprising the step of discontinuing administration of the feed or chew, thereby maintaining the feline's blood concentration of the isoxazoline at a therapeutically effective level, followed by resuming administration of the feed or chew.

[0141]

[0166] Embodiment 101: The method of any one of embodiments 1 or 2, wherein the isoxazoline is umifoxolaner or a salt thereof.

[0167] 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 0.000003 and about 0.045 weight percent of the feed and between about 0.0000075 and about 0.03 weight percent of the feed.

[0142]

[0168] Embodiment 103: The method of any of embodiments 101-102, wherein the umifoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0143]

[0169] Embodiment 104: The method of any of embodiments 101-103, wherein the administration provides a umifoxolaner concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0144]

[0170] Embodiment 105: The method of any one of embodiments 1 or 2, wherein the isoxazoline is esafoxolaner or a salt thereof.

[0171] 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 0.000003 and about 0.045 percent by weight of the feed and between about 0.0000075 and about 0.03 percent by weight of the feed.

[0145]

[0172] Embodiment 107: The method of any of embodiments 105-106, wherein the esafoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0146]

[0173] Embodiment 108: The method of any of embodiments 105-107, wherein the administration provides a concentration of esafoxolaner in the blood of the feline of greater than about 1.5 ng / mL and less than about 900 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0147]

[0174] Embodiment 109: The method of any one of embodiments 1 or 2, wherein the isoxazoline is tigolaner or a salt thereof.

[0175] 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 0.000003 and about 0.045 weight percent of the feed and between about 0.0000075 and about 0.03 weight percent of the feed.

[0148]

[0176] Embodiment 111: The method of any of embodiments 109-110, wherein the tigolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0149]

[0177] Embodiment 112: The method of any of embodiments 109 to 111, wherein the administration provides a tigolaner concentration in the blood of the feline of greater than about 1.5 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.

[0150]

[0178] Embodiment 113: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is umifoxolaner or a salt thereof.

[0179] 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 0.000003 and about 0.045 weight percent of the feed and between about 0.0000075 and about 0.03 weight percent of the feed.

[0151]

[0180] Embodiment 115: The isoxazoline of any of embodiments 113-114, wherein the umifoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0152]

[0181] Embodiment 116: The isoxazoline of any of embodiments 113 to 115, wherein the administration provides a umifoxolaner concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0153]

[0182] Embodiment 117: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is esafoxolaner or a salt thereof.

[0183] 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 0.000003 and about 0.45 percent by weight of the feed and between about 0.0000075 and about 0.03 percent by weight of the feed.

[0154]

[0184] Embodiment 119: The isoxazoline of any of embodiments 117-118, wherein the esafoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0155]

[0185] Embodiment 120: The isoxazoline of any of embodiments 117-119, wherein the administration provides a concentration of esafoxolaner in the blood of the feline of greater than about 1.5 ng / mL and less than about 900 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0156]

[0186] Embodiment 121: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is tigolaner or a salt thereof.

[0187] 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 0.000003 and about 0.045 weight percent of the feed and between about 0.0000075 and about 0.03 weight percent of the feed.

[0157]

[0188] Embodiment 123: The isoxazoline of any of embodiments 121-122, wherein the tigolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg to about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg to about 0.06 mg / kg of the feline's body weight.

[0158]

[0189] Embodiment 124: The isoxazoline of any of embodiments 121 to 123, wherein the administration provides a tigolaner concentration of greater than about 1.5 ng / mL and less than about 1200 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0159]

[0190] Embodiment 125: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is umifoxolaner or a salt thereof.

[0191] 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 0.000003 and about 0.045 percent by weight of the feed and between about 0.0000075 and about 0.03 percent by weight of the feed.

[0160]

[0192] Embodiment 127: The feed or chew of any of embodiments 125-126, wherein the umifoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0161]

[0193] Embodiment 128: A feed or chew described in any of embodiments 125 to 127, wherein the administration provides a umifoxolaner concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of the feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0162]

[0194] Embodiment 129: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is esafoxolaner or a salt thereof.

[0195] 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 0.000003 and about 0.045 percent by weight of the feed and between about 0.0000075 and about 0.03 percent by weight of the feed.

[0163]

[0196] Embodiment 131: The feed or chew of any of embodiments 129-130, wherein the esafoxolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0164]

[0197] 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 feline of greater than about 1.5 ng / mL and less than about 900 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0165]

[0198] Embodiment 133: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is tigolaner or a salt thereof.

[0199] 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 0.000003 and about 0.045 weight percent of the feed and between about 0.0000075 and about 0.03 weight percent of the feed.

[0166]

[0200] Embodiment 135: The feed or chew of any of embodiments 133-134, wherein the tigolaner is administered to the feline in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg of the feline's body weight and between about 0.0025 mg / kg and about 0.06 mg / kg of the feline's body weight.

[0167]

[0201] 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 feline of greater than about 1.5 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.

[0168]

[0202] Embodiment 137: The method of any one of embodiments 1 or 2, wherein the isoxazoline is modfuranel or a salt thereof.

[0203] Embodiment 138: The method of embodiment 137, wherein the Modflannel is provided in the feed in an amount selected from the group consisting of between about 0.0000075 and about 0.045 weight percent of the feed and between about 0.000015 and about 0.03 weight percent of the feed.

[0169]

[0204] Embodiment 139: The method of any of embodiments 137-138, wherein the modfuranel is administered to the feline in an amount selected from the group consisting of between about 0.003 mg / kg and about 0.25 mg / kg of the feline's body weight and between about 0.0045 mg / kg and about 0.113 mg / kg of the feline's body weight.

[0170]

[0205] Embodiment 140: The method of any of embodiments 137-139, wherein the administration provides a Modoflanel concentration in the blood of the feline of greater than about 3 ng / mL and less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0171]

[0206] Embodiment 141: The isoxazoline of any of embodiments 35 or 36, wherein the isoxazoline is modfuranel or a salt thereof.

[0207] Embodiment 142: The isoxazoline of embodiment 141, wherein the modflannel is provided in the feed in an amount selected from the group consisting of between about 0.0000075 and about 0.045 weight percent of the feed and between about 0.000015 and about 0.03 weight percent of the feed.

[0172]

[0208] Embodiment 143: The isoxazoline of any of embodiments 141-142, wherein the modfuranel is administered to the feline in an amount selected from the group consisting of between about 0.003 mg / kg to about 0.25 mg / kg of the feline's body weight and between about 0.0045 mg / kg to about 0.113 mg / kg of the feline's body weight.

[0173]

[0209] Embodiment 144: The isoxazoline of any of embodiments 141 to 143, wherein the administration provides a modofuranel concentration in the blood of the feline of greater than about 3 ng / mL and less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0174]

[0210] Embodiment 145: A feed or chew according to any of embodiments 69 or 70, wherein the isoxazoline is modofuranel or a salt thereof.

[0211] Embodiment 146: A feed or chew as described in embodiment 145, wherein the Modflannel is provided in the feed in an amount selected from the group consisting of between about 0.0000075 and about 0.045 weight percent of the feed and between about 0.000015 and about 0.03 weight percent of the feed.

[0175]

[0212] Embodiment 147: The feed or chew of any of embodiments 145-146, wherein the Modflannel is administered to the feline in an amount selected from the group consisting of between about 0.003 mg / kg and about 0.25 mg / kg of the feline's body weight and between about 0.0045 mg / kg and about 0.113 mg / kg of the feline's body weight.

[0176]

[0213] Embodiment 148: A feed or chew according to any of embodiments 145 to 147, wherein said administration provides a Modoflanel concentration in the blood of said feline of greater than about 3 ng / mL and less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0177]

[0214] In certain aspects of any of the above embodiments, administration provides a therapeutically effective concentration of the particular isoxazoline in the blood of the feline 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 60 ng / mL and less than about 18,000 ng / mL in the blood of the feline for at least 30 days. More preferably, administration of mivoliraner provides an isoxazoline concentration of greater than about 60 ng / mL and less than about 3750 ng / mL in the blood of the feline for at least 30 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 3 ng / mL and less than about 1800 ng / mL in the blood of the feline for at least 30 days. More preferably, afoxolaner provides an isoxazoline concentration of greater than about 3 ng / mL and less than about 900 ng / mL in the blood of the feline for at least 30 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 6 ng / mL and less than about 4500 ng / mL in the blood of the feline for at least 30 days. More preferably, fluralaner provides an isoxazoline concentration of greater than about 6 ng / mL and less than about 2250 ng / mL in the blood of the feline for at least 30 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 1200 ng / mL in the blood of the feline for at least 30 days. More preferably, sarolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 600 ng / mL in the blood of the feline for at least 30 days. In another example, lotilaner provides an isoxazoline concentration of greater than about 12 ng / mL and less than about 4500 ng / mL in the blood of the feline for at least 30 days. More preferably, Lotilaner provides an isoxazoline concentration in the blood of said feline of greater than about 12 ng / mL and less than about 3000 ng / mL for at least 30 days. In another example, Tigolaner provides an isoxazoline concentration in the blood of said feline of greater than about 1.5 ng / mL and less than about 1200 ng / mL for at least 30 days.More preferably, tigolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 450 ng / mL in the blood of said feline for at least 30 days. In another example, umifoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of said feline for at least 30 days. More preferably, umifoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 450 ng / mL in the blood of said feline for at least 30 days. In another example, esafoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of said feline for at least 30 days. More preferably, esafoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 450 ng / mL in the blood of said feline for at least 30 days.

[0178]

[0215] In certain aspects of any of the above embodiments, administration provides a therapeutically effective concentration of the particular isoxazoline in the blood of the feline 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 60 ng / mL and less than about 18,000 ng / mL in the blood of the feline for at least 365 days. More preferably, administration of mivoliraner provides an isoxazoline concentration of greater than about 60 ng / mL and less than about 3750 ng / mL in the blood of the feline for at least 365 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 3 ng / mL and less than about 1800 ng / mL in the blood of the feline for at least 365 days. More preferably, afoxolaner provides an isoxazoline concentration of greater than about 3 ng / mL and less than about 900 ng / mL in the blood of the feline for at least 365 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 6 ng / mL and less than about 4500 ng / mL in the blood of the feline for at least 365 days. More preferably, fluralaner provides an isoxazoline concentration of greater than about 6 ng / mL and less than about 2250 ng / mL in the blood of the feline for at least 365 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 1200 ng / mL in the blood of the feline for at least 365 days. More preferably, sarolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 600 ng / mL in the blood of the feline for at least 365 days. In another example, lotilaner provides an isoxazoline concentration of greater than about 12 ng / mL and less than about 4500 ng / mL in the blood of the feline for at least 365 days. More preferably, the lotilaner provides an isoxazoline concentration in the blood of the feline of greater than about 12 ng / mL and less than about 3000 ng / mL for at least 365 days. In another example, the tigolaner provides an isoxazoline concentration in the blood of the feline of greater than about 1.5 ng / mL and less than about 1200 ng / mL for at least 365 days.More preferably, tigolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 450 ng / mL in the blood of said feline for at least 365 days. In another example, umifoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of said feline for at least 365 days. More preferably, umifoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 450 ng / mL in the blood of said feline for at least 365 days. In another example, esafoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 900 ng / mL in the blood of said feline for at least 365 days. More preferably, esafoxolaner provides an isoxazoline concentration of greater than about 1.5 ng / mL and less than about 450 ng / mL in the blood of said feline for at least 365 days. EXAMPLES

[0179]

[0216] The following examples illustrate the method of the present disclosure. As the term is understood by those skilled in the art, it should be understood that two of the following three examples are prophetic examples. In other words, two of the following three examples are based on predicted results, not actual experiments. However, the predicted results are based on the experiments carried out by other animals, and are considered sufficient for those skilled in the art to practice the present disclosure.

[0180] Example 1

[0217] Efficacy of isoxazolines administered orally, i.e. by mouth, to cats for the treatment and control of Ctenocephalides felis.

[0218] Methods: A pool of 14 cats is pre-infested with approximately 100 unfed adult C. felis to identify cats capable of adequately maintaining a reliable infestation rate defined by approximately 50% fleas alive at the end of 48 hours. The 12 cats with the highest live flea counts are selected for inclusion in the study. Cats are randomly selected and divided into control and treatment groups with 6 cats per group.

[0181]

[0219] Cats are individually housed for the duration of the study, fed a commercial dry cat food diet and allowed free access to water.

[0220] Each cat in the isoxazoline treatment group is given a liquid formulation of isoxazoline by mouth. A dose of 1.125 mg / kg of isoxazoline is administered to the cat on each of days 0-29.

[0182]

[0221] Cats in the control group receive no isoxazoline or any other flea control treatment. Each cat in the treatment group is fed its daily diet (dry food) and each cat is administered an individual dose of the liquid formulation after eating at least 25% of its total daily diet. After the dose of isoxazoline is administered, the cat is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each cat in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, 12, 20 and 35. Combined live adult flea counts are taken on days 2, 7, 14, 22 and 37. The combined flea count on day 37 is after a washout period of approximately 8 days.

[0183]

[0222] The expected outcome in such studies conducted with various isoxazolines, such as mivorilaner, is at least a 95 percent reduction in live flea counts relative to controls.

[0184]

[0223] 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 concentration of isoxazoline can then be determined.

[0185]

[0224] The mean plasma concentration of the isoxazoline in feline blood in such studies conducted with various isoxazolines, e.g., mivorilaner, at a dose level of 1.125 mg / kg, is predicted to range between about 1011 ng / mL at 72 hours to about 4088 at 504 hours. Furthermore, the mean concentration is predicted to decrease to about 3025 ng / mL at 888 hours, about 8 days after the final dose was administered.

[0186] Example 2

[0225] Efficacy of various doses of isoxazolines administered orally, i.e. by mouth, to cats for the treatment and control of Ctenocephalides felis

[0226] Methods: A pool of 46 cats is pre-infested with approximately 100 unfed adult C. felis to identify cats capable of adequately maintaining a reliable infestation rate defined by approximately 50% of fleas alive at the end of 48 hours. The 40 cats with the highest flea counts are selected for inclusion in the study. Cats are randomly assigned to one control group and four treatment groups with 8 cats per group.

[0187]

[0227] Cats are individually housed for the duration of the study, fed a commercial dry cat food diet and allowed free access to water.

[0228] Each cat in the treatment group (test groups 2-5) will be given a liquid formulation of isoxazoline by mouth. The dose will be administered to the cat on each of days 0-29 according to the test group in the table below.

[0188] [Table 1]

[0189]

[0229] Cats in the control group receive no isoxazoline or any other flea control treatment. Each cat in treatment groups 2-5 is fed its daily diet (dry food) and administered an individual dose of the liquid formulation after each cat has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the cat is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each cat in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, 12, 19, 28, and 35. Combined live adult flea counts are taken on days 2, 7, 14, 21, 30, and 37. The combined flea count on day 37 is after a washout period of approximately 8 days.

[0190]

[0230] The dose level for arm 2 is expected to achieve 95% efficacy within 14 days. The dose level for arm 3 is expected to achieve 95% efficacy within 7 days. The dose levels for arms 4 and 5 are expected to achieve 95% efficacy within 2 days.

[0191]

[0231] Using the same study methodology described above, blood is drawn at 0, 72, 120, 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.

[0192]

[0232] The mean plasma concentrations of isoxazoline in feline blood from substantially daily administration at the dose level of Test Group 2 are predicted to range from about 203 ng / ml at 72 hours to about 630 ng / ml at 720 hours. For Test Group 3, the predicted range is from about 424 ng / ml at 72 hours to about 1524 ng / ml at 720 hours. For Test Group 4, the predicted range is from about 711 ng / ml at 72 hours to about 2811 ng / ml at 720 hours. For Test Group 5, the predicted range is from about 1427 ng / ml at 72 hours to about 5635 ng / ml at 720 hours. At 888 hours, approximately 8 days after the last daily dose of isoxazoline on Day 29, the predicted mean plasma concentration of the isoxazoline in the blood of the felines in Test Group 2 is about 500 ng / ml, in Test Group 3 the predicted mean plasma concentration of the isoxazoline in the blood of the felines is about 1000 ng / ml, in Test Group 4 the predicted mean plasma concentration of the isoxazoline in the blood of the felines is about 2000 ng / ml, and in Test Group 5 the predicted mean plasma concentration of the isoxazoline in the blood of the felines is about 4000 ng / ml.

[0193] Example 3

[0233] Efficacy of various liquid formulations of isoxazolines administered orally, i.e. by mouth, to cats for the treatment and control of Ctenocephalides felis.

[0234] Methods: A pool of 36 cats is pre-infested with approximately 100 unfed adult C. felis to identify cats capable of adequately maintaining a reliable infestation rate defined by approximately 50% fleas alive at the end of 48 hours. The 30 cats with the highest live attached flea counts are selected for inclusion in the study. Cats are randomly assigned to one control group and four treatment groups with six cats per group.

[0194]

[0235] Cats are individually housed for the duration of the study, fed a commercial dry cat food diet and allowed free access to water.

[0236] Each cat 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 cat on each of days 0-29.

[0195] [Table 2]

[0196]

[0237] Cats in the control group receive no isoxazoline or any other flea control treatment. Each cat in the test group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each cat has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the cat is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each cat 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.

[0197]

[0238] At the dose levels described in this example, all treatment groups are expected to reach greater than 95% efficacy by day 7. Example 4

[0239] Plasma concentrations of isoxazolines in cats when administered in medicated food at a dose of 1.5 mg / kg of cat weight

[0240] Methods: A pool of 30 cats were assigned by weight into 5 groups to minimize between- and within-group variability. Each group was fed a different feed formulation containing the isoxazoline, and blood levels of the isoxazoline were determined over a 1-month period after a single oral dose in the drugged feed.

[0198]

[0241] Cats are individually housed for the duration of the study with water available ad libitum.

[0242] There is an initial acclimation period of at least 4 days during which cats are transitioned from the standard certified commercial diet to a non-medicated version of the daily diet. During the acclimation period, cats are allowed 15 min / day to consume food.

[0199]

[0243] Each drugged food formulation should provide approximately 14.1 g / kg of isoxazoline-containing food daily. The amount of drugged food for each cat will be determined according to the cat's most recent body weight prior to the first day of the study (day 0). Each drugged food will be offered for 15 minutes daily from days 0 through 30 (inclusive). After each daily 15 minute feeding period, any remaining drugged food will be removed, weighed, and the amount recorded. An amount of undrugged food equivalent to the amount of remaining drugged food will be offered at the time of the first blood draw 10 hours later.

[0200]

[0244] Blood samples are collected at the following times: 0 hours (time of first feeding of medicated feed) on day 0, 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.

[0201]

[0245] Mean plasma concentrations in such studies conducted with various isoxazolines, such as mivorilaner, are expected to produce plasma concentrations consistent with those obtained in Examples 1 and 2 above, regardless of the different feed formulations.

[0202] Example 5

[0246] Plasma concentrations of isoxazolines when administered in medicated diets at different dose levels

[0247] Methods: A pool of cats is randomly assigned to one control group and two treatment groups with six cats per group.

[0203]

[0248] Cats are individually housed for the duration of the study with water available ad libitum.

[0249] Each cat in the treatment groups (Groups 2 and 3) will be fed one of two medicated daily chows on study days 0 through 14. Depending on the study group, the medicated daily chows will be delivered to the cats for 1 h on each of days 0 through 14.

[0204] [Table 3]

[0205]

[0250] After the initial dose of isoxazoline is administered, blood is drawn on day 0 (the day of first administration of medicated feed) and days 2, 4, 7, 10, 14, 21, and 30. The average blood concentration of isoxazoline can then be determined for each of the medicated feed formulations (treatment groups 2 and 3).

[0206]

[0251] Plasma concentrations of isoxazolines in such studies conducted with various isoxazolines, for example mivorilaner, are expected to be consistent between treatment groups 2 and 3 regardless of differences in feed formulation.

[0207] Example 6

[0252] Efficacy of isoxazolines administered in medicated feed for the treatment and control of Ctenocephalides felis.

[0253] Methods: Pools of cats are pre-infested with approximately 100 unfed adult C. felis fleas to generate cats capable of adequately maintaining a reliable infestation rate defined as approximately 50% live fleas maintained at the end of 48 hours. Cats with the highest live flea counts are randomly assigned to one control group (Group 1) and two medicated diet treatment groups (Groups 2 and 3) with four cats per group. Cats in Groups 2 and 3 are given mivorilaner.

[0208]

[0254] Cats are individually housed for the duration of the study with water available ad libitum.

[0255] Each cat in the treatment groups (Groups 2 and 3) will receive daily medicated food on study days 0-29 according to the table below.

[0209] [Table 4]

[0210]

[0256] Cats are fasted overnight prior to each daily treatment. The daily dose of mivolilaner is mixed into a small portion of moist canned cat food (approximately 25% of the cat's daily dietary requirements). Approximately 4 hours after the medicated food is first served, if any, the medicated food is mixed with 75% of the non-medicated daily food for each cat. The resulting food supply is available for consumption by the cat until the food bowl is removed for the daily overnight fast.

[0211]

[0257] Control cats receive no isoxazoline or any other flea control treatment. Each cat in treatment groups 2 and 3 and the control group is challenged with 100 unfed adult C. felis on days 1, 7, 14, and 28 during the treatment phase, and on test day 35 during the washout period after the last daily feeding of medicated food. Combined live and moribund flea counts are taken on days 2, 9, 16, 30, and 37.

[0212]

[0258] Results: The percent reduction in live and moribund flea counts for treatment groups 2 and 3 according to this example is shown in the graph below. [ka]

[0213]

[0259] 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

**Claim 1**: A composition for use in controlling flea infestation in felines in need of controlling flea infestation, comprising isoxazoline, wherein the composition is orally administered to the feline in an effective amount at a frequency of at least 4 times per month for an effective period of time. **Claim 2** The composition according to claim 1, wherein the feline is a domestic cat. **Claim 3** The composition according to claim 1 or 2, wherein the isoxazoline is milbemyral or a salt thereof. **Claim 4** The composition according to claim 3, wherein the milbemyral is supplied in an amount selected from the group consisting of between about 0.0002 and about 0.12 weight percent of the feed and between about 0.0003 and about 0.075 weight percent of the feed in the feed. **Claim 5** The composition according to claim 3, wherein the milbemyral is administered to the feline in an amount selected from the group consisting of between about 0.06 mg / kg and about 5 mg / kg relative to the body weight of the feline and between about 0.1 mg / kg and about 2.25 mg / kg relative to the body weight of the feline. **Claim 6** The composition according to claim 3, wherein the administration supplies a milbemyral concentration in the blood of the feline of greater than about 60 ng / mL and less than about 18,000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days. **Claim 7** The composition according to claim 1, wherein the isoxazoline is selected from the group consisting of fluralaner, sarolaner, afoxolaner, and lotilaner or a salt of any of the foregoing. **Claim 8**: The composition according to claim 7, wherein the isoxazoline is fluralaner or a salt thereof, and the fluralaner is supplied in an amount selected from the group consisting of between about 0.00003 and about 0.045 weight percent of the feed and between about 0.00006 and about 0.03 weight percent of the feed in the feed. **Claim 9**: The composition according to claim 7, wherein the isoxazoline is fluralaner or a salt thereof, and the fluralaner is administered to the feline in an amount selected from the group consisting of between about 0.012 mg / kg and about 0.1 mg / kg relative to the body weight of the feline and between about 0.019 mg / kg and about 0.45 mg / kg relative to the body weight of the feline. **Claim 10**: The isoxazoline is fluralaner or a salt thereof, and the administration provides a fluralaner concentration in the blood of the felid animal that exceeds about 6 ng / mL and is less than about 4500 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days. The composition according to claim 7. **Claim 11**: The isoxazoline is sarolaner or a salt thereof, and the sarolaner is supplied in an amount selected from the group consisting of between about 0.000003 and about 0.045 weight percent of the feed and between about 0.000006 and about 0.03 weight percent of the feed in the feed. The composition according to claim 7. **Claim 12**: The isoxazoline is sarolaner or a salt thereof, and the sarolaner is administered to the felid animal in an amount selected from the group consisting of between about 0.0015 mg / kg and about 0.12 mg / kg based on the body weight of the felid animal and between about 0.0024 mg / kg and about 0.054 mg / kg based on the body weight of the felid animal. The composition according to claim 7. **Claim 13**: The isoxazoline is sarolaner or a salt thereof, and the administration provides a sarolaner concentration in the blood of the felid animal that exceeds about 1.5 ng / mL and is less than about 1200 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days. The composition according to claim 7. **Claim 14**: The isoxazoline is afoxolaner or a salt thereof, and the afoxolaner is supplied in an amount selected from the group consisting of between about 0.0000075 and about 0.045 weight percent of the feed and between about 0.000015 and about 0.03 weight percent of the feed in the feed. The composition according to claim 7. **Claim 15**: The isoxazoline is afoxolaner or a salt thereof, and the afoxolaner is administered to the felid animal in an amount selected from the group consisting of between about 0.003 mg / kg and about 0.25 mg / kg based on the body weight of the felid animal and between about 0.0045 mg / kg and about 0.113 mg / kg based on the body weight of the felid animal. The composition according to claim 7. **Claim 16**: The isoxazoline is afoxolaner or a salt thereof, and the administration supplies a concentration of afoxolaner in the blood of the felid animal that exceeds about 3 ng / mL and is less than about 1800 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days. The composition according to claim 7. **Claim 17**: The isoxazoline is lotilaner or a salt thereof, and the lotilaner is supplied in an amount selected from the group consisting of between about 0.00006 and about 0.045 weight percent of the feed and between about 0.00012 and about 0.03 weight percent of the feed in the feed. The composition according to claim 7. **Claim 18**: The isoxazoline is lotilaner or a salt thereof, and the lotilaner is administered to the felid animal in an amount selected from the group consisting of between about 0.026 mg / kg and about 2 mg / kg based on the body weight of the felid animal and between about 0.04 mg / kg and about 0.9 mg / kg based on the body weight of the felid animal. The composition according to claim 7. **Claim 19**: The isoxazoline is lotilaner or a salt thereof, and the administration supplies a concentration of lotilaner in the blood of the felid animal that exceeds about 12 ng / mL and is less than about 4500 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days. The composition according to claim 7. **Claim 20**: The isoxazoline is administered as a component of feed, preferably wet or dry cat food, or treats, more preferably dry cat food. The composition according to claim 1. **Claim 21**: The frequency is selected from the group consisting of at least 3 times per week, substantially daily, and daily. The composition according to claim 1. **Claim 22**: The effective time includes administering the isoxazoline for a period selected from the group consisting of at least 1 week and at least 2 weeks. The composition according to claim 1. **Claim 23**: The administration supplies a therapeutically effective level of isoxazoline in the blood of the felid animal within a period selected from the group consisting of 1 week from the first administration of the isoxazoline and 2 days from the first administration of the isoxazoline. The composition according to claim 1. **Claim 24**: The composition according to claim 1, wherein the administration supplies a therapeutically effective level of isoxazoline in the blood of the felid 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. **Claim 25**: The composition according to 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. **Claim 26**: The composition according to claim 1, wherein the administration further comprises a step of stopping the administration for a period selected from the group consisting of at least 3 days and at least 7 days, and the blood concentration of isoxazoline in the felid is maintained at a therapeutically effective level. **Claim 27**: The composition according to claim 26, wherein the administration further comprises a step of restarting the administration after stopping the administration, thereby maintaining the blood concentration of isoxazoline in the felid at the therapeutically effective level.