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 a spinosyn for an effective period of time, thereby raising and maintaining the amount of spinosyn 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 spinosyns, feline feeds containing spinosyns, and methods of administering spinosyns 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, isoxazolines, 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 infestations 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 present inventors have found that spinosyns, such as spinosad, can provide improved control of flea infestations 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 the spinosyns may be administered alone or in dosage forms other than feed, such as chews, tablets, liquids, gels, or other forms suitable for oral administration. Advantageously, by using lower, more frequent doses, less total active material is required over the same period to control flea infestation. For example, assume that to reach and maintain a therapeutically effective concentration of spinosyn for continuous flea control in the blood of a feline, according to conventional approaches, 51 mg of spinosyn per kg of feline body weight is required for a single administration over a period of 30 days (one month). The smaller, more frequent dosing approach of the present invention results in only 0.21 to 1.4 mg of spinosyn per kg of feline body weight, or 6.375 to 42 mg of spinosyn per kg of feline body weight accumulated over the same 30 day period.

[0009] Advantageously, the total amount of spinosyns required for a therapeutically effective monthly dose can be reduced by 10-87.5% by converting to daily dosing. 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 spinosyns 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. Thus, it is possible for one 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 spinosyns can be incorporated into the feed. Owners are less likely to forget or neglect to administer spinosyns 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011]

[0011] Spinosyns are naturally occurring fermentation products. They are macrolides produced by the culture of Saccharopolyspora spinosa. Fermentation of S. spinosa produces a number of factors, including spinosyn A and spinosyn D (also called A83543A and A8354D). Spinosyn A and spinosyn D are the two most active spinosyns as insecticides. Products based primarily on these two spinosyns are commercially available under the generic name "spinosad." The major spinosyn factor, spinosyn A, is particularly known to have an excellent human and feline safety and toxicity profile.

[0012] Each spinosyn has a macrocyclic 12-membered ring that is part of a unique tetracyclic ring system to which two different sugars, the amino-sugar forosamine and the neutral sugar 2N,3N,4N-(tri-O-methyl)rhamnose, are attached. This unique structure sets the spinosyns apart from other macrocyclic compounds.

[0013] Spinosyn A was the first spinosyn isolated and identified from the fermentation broth of S. spinosa. Subsequent studies of the fermentation broth revealed that S. spinosa produces many spinosyns, designated spinosyns A-J (A83543A-J). The major components are spinosyn A and spinosyn D. Additional spinosyns, designated K-W, have been identified from mutant strains of S. spinosa. The various spinosyns are characterized by differences in the substitution patterns of the amino group of the phorosamine at selected positions in the tetracyclic ring system, and of the 2N,3N,4N-(tri-O-methyl)rhamnose group.

[0014]

[0014] Boeck et al., in U.S. Pat. Nos. 5,362,634 (issued Nov. 8, 1994), 5,496,932 (issued Mar. 5, 1996), and 5,571,901 (issued Nov. 5, 1996), describe spinosyns A through H and J (which they called A83543 factors A, B, C, D, E, F, G, H and J), and salts thereof. Mynderse et al., in U.S. Pat. No. 5,202,242 (issued April 13, 1993), describe spinosyns L through N (which they referred to as A83543 factors L, M and N), their N-demethylated derivatives, and their salts, and Turner et al., in U.S. Pat. Nos. 5,591,606 (issued January 7, 1997) and 5,631,155 (issued May 29, 1997), describe spinosyns Q through T (which they referred to as A83543 factors Q, R, S and T), their N-demethylated derivatives, and their salts. For example, spinosyns K, O, P, U, V, W and Y are described by Carl V. DeAmicis, James E. Dripps, Chris J. Hatton and Laura I. Karr, "Physical and Biological Properties of Spinosyns: Novel Macrolide Pest-Control Agents from Fermentation," in Chapter 11 of the American Chemical Society Symposium Series: Phytochemicals for Pest Control, pp. 146-154 (1997).

[0015]

[0015] Spinosyns can react to form salts which are also useful in the methods and formulations of the present disclosure. The salts are prepared using standard procedures for salt preparation. For example, spinosyn A can be neutralized with an appropriate acid to form an acid addition salt. Acid addition salts of spinosyns are particularly useful. Representative suitable acid addition salts include salts formed by reaction with either organic or inorganic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, cholic acid, pamoic acid, mucic acid, glutamic acid, camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, formic acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, sorbic acid, picric acid, benzoic acid, cinnamic acid, and the like.

[0016]

[0016] As used herein, the term "spinosyn" refers to an individual spinosyn factor (spinosyn A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y), an N-demethyl derivative of an individual spinosyn factor, a chemically modified spinosyn, such as spinetoram, a salt of any of the above, a metabolite of any of the above, a physiologically acceptable derivative thereof, or a combination thereof.

[0017]

[0017] Spinosyns also provide advantages because when used in the dosages described herein, they are highly effective against fleas and provide residual protection after treatment. Furthermore, spinosyns have no insecticidal cross-resistance to existing compounds. Thus, they are particularly beneficial against flea populations in felines that have existing levels of resistance to currently used products. Thus, spinosyns 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.

[0018] Systemic efficacy (e.g., ingestion of spinosyn-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).

[0019] 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 spinosyns. Such active agents include agents that are effective against fleas. The active agents may include, for example, isoxazolines, certain macrocyclic lactones, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines, and pyrazoles.

[0020] The method of the present disclosure is carried out by administering small, frequent doses of spinosyns to the feline. To facilitate habitual administration, spinosyn 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 chemical stability, efficacy, and safety of the spinosyns and, if applicable, other active substances. For example, feeds in the broad categories of dry, semi-moist, canned, retorted feeds, treats, chews, snacks, or other supplemental feeds or fresh refrigerated feeds can be adapted for use according to the present disclosure. The feline is provided with a controlled amount of spinosyns by consuming the feed or chew product weekly, approximately weekly, or daily.

[0021] By incorporating smaller doses of spinosyns into an animal's feed composition and administering them at an effective rate (most preferably daily), the blood concentration of the spinosyns will rise over time until an optimal steady state is reached that can be maintained by daily or substantially daily administration. In contrast, if the spinosyns are 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 via a "treat," the level of the spinosyn 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 must consume more spinosyns with each dose, thereby preventing the blood level of the spinosyns from dropping below the level required for effective prevention before the next dose is administered.

[0022] All ratios, percentages, and parts discussed herein are "by weight" unless otherwise specified.

[0023] The term "controlling flea infestation" refers to preventing, treating, minimizing or eliminating flea infestation in felines.

[0023]

[0024] The term "flea" refers to any member of the order Siphonaptera. The term "flea" includes the egg, larva, pupae, and adult stages of development.

[0025] The term "feline" refers to any member of the subfamily Felidae, and includes species such as the domestic cat, bobcat, wild cat, ocelot, members of the genus Lynx, the Pallas's cat, and the cougar.

[0024]

[0026] In carrying out the methods of the present disclosure, a "feed" is an animal's feed or treats, snacks, or other supplemental feed that may 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 spinosyn.

[0025]

[0027] The term "chew" refers to a treat that has flavors and aromatic properties that are 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.

[0026]

[0028] 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 bring the level of spinosyn in the feline's blood to a level 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 spinosyn is administered.

[0027]

[0029] As alluded to above, the "effective time" varies depending on how often the feed is administered. As used herein, the term "effective frequency" refers to the number of servings over a given time period that will result in a therapeutically effective concentration of the spinosyn in the blood of the feline. In all cases, as used herein, "effective frequency" contemplates servings that include multiple spinosyns per month. Those skilled in the art will appreciate that spinosyns can be administered at a wide range of frequencies. For example, spinosyns can be administered daily, every other day, every third day, once per week, or even at inconsistent time intervals.

[0028]

[0030] Additionally, as discussed above, the frequency of effect can affect the period of time required to achieve a therapeutically effective level of the spinosyn in the feline's blood. By way of example, if a feline is fed a spinosyn composition daily, the feeding period, and thus the "effective time," required to achieve a therapeutically effective level of the spinosyn in the feline's blood will be relatively shorter than if the feline is fed the spinosyn composition only once or twice per week.

[0029]

[0031] Furthermore, the frequency of effectiveness is affected by the daily dose in mg / kg of feline body weight, with missed doses having less effect on efficacy, especially at slightly higher daily doses.

[0030]

[0032] Furthermore, the frequency of effectiveness is affected by the duration of treatment: in the early stages, e.g., before the amount of spinosyn in the feline's blood reaches a therapeutically effective level, the animal feed may need to be administered more frequently than is required after a longer period of use, i.e., once a therapeutically effective level has been achieved.

[0031]

[0033] For purposes of this disclosure, "substantially daily" means sufficiently regular that the concentration of the spinosyn in the feline's blood rises to and remains at a therapeutically effective level. For example, the disclosed feed compositions can preferably be fed 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 strong enough that even if the daily feeding of the medicated animal feed composition is occasionally interrupted, the feline will still be protected from fleas to some degree. In carrying out the methods of the present disclosure, 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 feeding frequencies, whether they are, for example, three times per week, every other day, or daily, qualify as substantially daily, so long as they facilitate the spinosyn reaching and maintaining a therapeutically effective level of the spinosyn in the feline's blood.

[0032]

[0034] The term "therapeutically effective" means that the dose or blood level of a spinosyn or a physiologically acceptable derivative thereof or a metabolite thereof is sufficient to control a flea infestation more than if the drug were not present. The spinosyn or a physiologically acceptable derivative thereof or a metabolite thereof may be present alone or with one or more additional active agents. Preferably, it controls the flea infestation by approximately at least 50% more than if the drug were not present, and more preferably, it controls the flea infestation by approximately at least 90% more than if the drug were not present.

[0033]

[0035] In carrying out the methods of the present disclosure, an effective or therapeutically effective amount of a spinosyn is orally administered to a 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.

[0034]

[0036] Generally, an effective amount refers to a dose of about 0.18 to about 17 mg of spinosyn per kg of feline body weight. More preferably, an effective amount refers to a dose of about 0.3 to about 7.65 mg of spinosyn per kg of feline body weight. More commonly, an effective amount is a dose of about 0.3 to about 6.375 mg of spinosyn per kg of feline body weight.

[0035]

[0037] Animal feeds typically contain from about 0.0008 to about 0.34 percent spinosyns by weight in the feed, preferably between about 0.04 to about 0.2 percent spinosyns by weight in the feed, and most preferably between about 0.0045 to about 0.1 percent spinosyns by weight in the feed.

[0036]

[0038] Although the present disclosure describes the concentration of spinosyns in terms of feed, e.g., kibbles, administration using other dosage forms, e.g., treats or chews, is also contemplated. It is also contemplated that the spinosyns may be administered alone or in tablets, liquids, gels, or other suitable forms for oral administration. One of skill in the art will appreciate that the concentration of the spinosyns will vary depending on the specific dosage form. For example, if the animal feed is a treat, the concentration of the spinosyns in the treat will be greater than the concentration of the spinosyns in, e.g., a kibble. For example, if the daily dose of spinosyns by weight for a feline is 20 mg, a typical 5 g treat may contain about 0.4 percent of the spinosyns (by weight). Because the amount of kibble consumed per day is greater than 5 g, the percentage of the spinosyns in the kibble will be less.

[0037]

[0039] In one aspect, the disclosure relates to a method of controlling flea infestations in felines by administering a systemically active oral composition comprising a spinosyn, or a physiologically acceptable derivative or salt thereof, and an animal feed or chew at least once per week, more preferably three times per week, and most preferably substantially daily.

[0038]

[0040] In another aspect, the disclosure relates to a systemically active oral composition comprising a spinosyn and an animal feed or chew.

[0041] The present disclosure also relates to the use of spinosyns for the manufacture of animal feeds or chews for controlling flea infestations in felines.

[0039]

[0042] The present disclosure also relates to a method of controlling flea infestations in felines over an extended period of time, comprising orally administering to the feline daily or substantially daily an effective amount of a dose of a spinosyn. A daily feed is a feed that is intended to be administered daily, but may be administered for an effective time period as described herein. The method is particularly useful for controlling fleas in felines over an extended period of time, and comprises orally administering to the feline daily an effective amount of a dose of a spinosyn.

[0040]

[0043] One embodiment of the present disclosure is the oral administration of an amount of a spinosyn that is by itself ineffective or suboptimal for controlling flea infestation in felines 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 a 50% reduction in flea infestation compared to no drug administered at all, including no or substantially no reduction. This reflects the chronic rather than acute administration aspects of the present disclosure.

[0041]

[0044] Embodiment 1: A method of controlling flea infestation in a feline in need thereof, comprising orally administering to said feline an effective amount of a spinosyn for an effective period of time at least four times per month.

[0042]

[0045] Embodiment 2: The method of embodiment 1, wherein the feline is a domestic cat.

[0046] Embodiment 3: The method of any one of embodiments 1 or 2, wherein the spinosyn is spinosad.

[0043]

[0047] Embodiment 4: The method of any of embodiments 1-3, wherein the spinosyn is provided in a feed selected from the group consisting of dry cat food and wet cat food.

[0044]

[0048] Embodiment 5: The method of any one of embodiments 1-3, wherein the spinosyn is present in an amount between about 7.5 mg / kg and 2400 mg / kg of feed.

[0049] Embodiment 6: The method of any one of embodiments 1-5, wherein the spinosyn is administered to the feline in an amount of between about 0.18 mg / kg and 17 mg / kg of the feline's body weight.

[0045]

[0050] Embodiment 7: The method of any one of embodiments 1-6, wherein said oral administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0046]

[0051] Embodiment 8: The method of any one of embodiments 1 to 7, wherein the effective time is selected from the group consisting of at least 1 week and at least 2 weeks.

[0052] Embodiment 9: The method of any of embodiments 1-8, wherein said administration provides a therapeutically effective level of the spinosyn in the blood of the feline within a period of time selected from the group consisting of within one week of a first administration of the spinosyn and within two days of a first administration of the spinosyn.

[0047]

[0053] Embodiment 10: The method of any of embodiments 1-9, wherein said administration provides a therapeutically effective level of a spinosyn in the blood of said feline for a period selected from the group consisting of at least 45 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days.

[0048]

[0054] Embodiment 11: The method of any of embodiments 1-10, wherein said administration provides a concentration of spinosyn between 7.5 ng / mL and 1020 ng / mL in the blood of said feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0049]

[0055] Embodiment 12: The method of any of embodiments 1-11, wherein the spinosyn is administered for a number of days selected from the group consisting of at least 15 days and at least 20 days out of a 30 day period.

[0050]

[0056] Embodiment 13: The method of any one of embodiments 1-12, wherein the spinosyn is a component of a feed that contains one or more other active agents.

[0057] Embodiment 14: The method of any of embodiments 1-13, further comprising discontinuing said administration of a spinosyn for a number of days selected from the group consisting of at least 3 days and at least 7 days, wherein the feline's blood concentration of spinosyn is maintained at a therapeutically effective level.

[0051]

[0058] Embodiment 15: The method of embodiment 14, further comprising discontinuing said administration of a spinosyn, thereby maintaining said feline's blood concentration of a spinosyn at said therapeutically effective level, and then resuming said administration of a spinosyn.

[0052]

[0059] Embodiment 16: The method of embodiment 1, wherein the spinosyn is a component of a chew.

[0060] Embodiment 17: The method of embodiment 16, wherein said oral administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0053]

[0061] Embodiment 18: A spinosyn for use in controlling fleas in a feline in need thereof, wherein said spinosyn is administered to said feline in an effective amount for an effective period of time at least four times per month.

[0054]

[0062] Embodiment 19: The spinosyn of embodiment 18, wherein the feline is a domestic cat.

[0063] Embodiment 20: The spinosyn of any of embodiments 18-19, wherein the spinosyn is spinosad.

[0055]

[0064] Embodiment 21: The spinosyn of any of embodiments 18-20, wherein the spinosyn is provided in a feed selected from the group consisting of dry cat food and wet cat food.

[0056]

[0065] Embodiment 22: The spinosyn of any of embodiments 18-21, wherein the spinosyn is present in an amount between about 7.5 mg / kg and 2400 mg / kg of feed.

[0066] Embodiment 23: The spinosyn of any of embodiments 18-22, wherein the spinosyn is administered to the feline in an amount of between about 0.18 mg / kg and 17 mg / kg of the feline's body weight.

[0057]

[0067] Embodiment 24: The spinosyn of any of embodiments 18-23, wherein said administration comprises a delivery frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0058]

[0068] Embodiment 25: The spinosyn of any of embodiments 18-24, wherein the effective time is selected from the group consisting of at least 1 week and at least 2 weeks.

[0069] Embodiment 26: The spinosyn of any of embodiments 18-25, wherein said administration provides a therapeutically effective level of the spinosyn in the blood of the feline within a period of time selected from the group consisting of within one week of a first administration of the spinosyn and within two days of a first administration of the spinosyn.

[0059]

[0070] Embodiment 27: The spinosyn of any of embodiments 18-26, wherein said administration provides a therapeutically effective level of the spinosyn in the blood of the feline for a period selected from the group consisting of at least 45 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days.

[0060]

[0071] Embodiment 28: The spinosyn of any of embodiments 18-27, wherein said administration provides a spinosyn concentration of between 7.5 ng / mL and 1020 ng / mL in the blood of said feline for a period selected from the group consisting of at least 30 days and at least 365 days.

[0061]

[0072] Embodiment 29: The spinosyn of any of embodiments 18-28, wherein the spinosyn is administered for a number of days selected from the group consisting of at least 15 days and at least 20 days out of a 30 day period.

[0062]

[0073] Embodiment 30: The spinosyn of any of embodiments 18-29, wherein the spinosyn is a component of a feed containing one or more other active agents.

[0074] Embodiment 31: The spinosyn of any of embodiments 18-30, further comprising discontinuing administration of the spinosyn for a number of days selected from the group consisting of at least 3 days and at least 7 days, wherein the feline's blood concentration of the spinosyn is maintained at a therapeutically effective level.

[0063]

[0075] Embodiment 32: The spinosyn of embodiment 31, further comprising discontinuing administration of the spinosyn, thereby maintaining the feline's blood concentration of the spinosyn at a therapeutically effective level, followed by resuming administration of the spinosyn.

[0064]

[0076] Embodiment 33: The spinosyn of any one of embodiments 18-32, wherein the spinosyn is a component of a chew.

[0077] Embodiment 34: The spinosyn of embodiment 33, wherein said administration comprises a delivery frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0065]

[0078] Embodiment 35: A feed or chew for controlling fleas in a feline, said feed or chew comprising a therapeutically effective amount of a spinosyn to control a flea infestation when administered to said feline for an effective time, at least four times per month.

[0066]

[0079] Embodiment 36: The feed or chew of embodiment 35, wherein the feline is a domestic cat.

[0080] Embodiment 37: A feed or chew according to any of embodiments 35 or 36, wherein the spinosyn is spinosad.

[0067]

[0081] Embodiment 38: A feed or chew according to any of embodiments 35-37, wherein the spinosyn is provided in a feed selected from the group consisting of dry cat food and wet cat food.

[0068]

[0082] Embodiment 39: A feed or chew according to any of embodiments 35-38, wherein the spinosyn is present in an amount of between about 7.5 mg / kg and 2400 mg / kg of feed.

[0083] Embodiment 40: The feed or chew of any of embodiments 35-39, wherein the spinosyn is administered to the feline in an amount of between about 0.18 mg / kg and 17 mg / kg of the feline's body weight.

[0069]

[0084] Embodiment 41: A feed or chew according to any of embodiments 35 to 40, wherein said administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily and daily.

[0070]

[0085] Embodiment 42: A feed or chew according to any of embodiments 35-41, 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.

[0071]

[0086] Embodiment 43: A feed or chew according to any of embodiments 35-42, wherein said administration provides a therapeutically effective level of a spinosyn in the blood of the feline within a period of time selected from the group consisting of within one week of the first administration of said feed or chew and within two days of the first administration of said feed or chew.

[0072]

[0087] Embodiment 44: The feed or chew of any of embodiments 35-43, wherein said administration provides a therapeutically effective level of a spinosyn in the blood of the feline for a period selected from the group consisting of at least 45 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days.

[0073]

[0088] Embodiment 45: The feed or chew of any of embodiments 35-44, wherein said administration provides a concentration of spinosyn between 7.5 ng / mL and 1020 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.

[0074]

[0089] Embodiment 46: A feed or chew according to any of embodiments 35 to 45, 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.

[0075]

[0090] Embodiment 47: A feed or chew according to any of embodiments 35 to 46, wherein the feed or chew comprises one or more other active substances.

[0091] Embodiment 48: The feed or chew of any of embodiments 35-47, further comprising the step of discontinuing administration of the feed or chew for a number of days selected from the group consisting of at least 3 days and at least 7 days, wherein the feline's blood concentration of the spinosyn is maintained at a therapeutically effective level.

[0076]

[0092] Embodiment 49: The feed or chew of embodiment 48, further comprising the step of discontinuing administration of the feed or chew, thereby maintaining the feline's blood concentration of the spinosyn at a therapeutically effective level, followed by resuming administration of the feed or chew.

[0077]

[0093] In some aspects of any of the embodiments, administration for controlling flea infestation maintains a concentration of spinosyns in the blood of said feline of at least 7.5 ng / ml and no more than 1020 ng / ml for at least 30 days. More preferably, administration maintains a concentration of spinosyns in the blood of said feline of at least 7.5 ng / ml and no more than 510 ng / ml for at least 30 days. More preferably, administration maintains a concentration of spinosyns in the blood of said feline of at least 15 ng / ml and no more than 383 ng / ml for at least 30 days. Even more preferably, administration maintains a concentration of spinosyns in the blood of said feline of at least 37.5 ng / ml and no more than 340 ng / ml for at least 30 days.

[0078]

[0094] In some aspects of any of the embodiments, administration to control flea infestation maintains a concentration of spinosyns in the blood of said feline of at least 7.5 ng / ml and no more than 1020 ng / ml for at least 365 days. More preferably, administration maintains a concentration of spinosyns in the blood of said feline of at least 7.5 ng / ml and no more than 510 ng / ml for at least 365 days. More preferably, administration maintains a concentration of spinosyns in the blood of said feline of at least 15 ng / ml and no more than 383 ng / ml for at least 365 days. Even more preferably, administration maintains a concentration of spinosyns in the blood of said feline of at least 37.5 ng / ml and no more than 340 ng / ml for at least 365 days. EXAMPLES

[0079]

[0095] 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.

[0080] Example 1

[0096] Efficacy of spinosyns administered orally, i.e. by mouth, to cats for the treatment and control of Ctenocephalides felis

[0097] Methods: A pool of 40 cats was pre-infested with approximately 100 unfed adult C. felis to generate a group of cats capable of adequately maintaining a reliable infestation rate of approximately 50% live fleas over a 48-hour period. Cats with the highest live flea counts were randomly assigned to four treatment groups (six cats per group) based on their pre-treatment flea counts from the trial infestation. The first treatment group was the control group and groups 2-4 were the test groups.

[0081]

[0098] Cats are individually housed for the duration of the study, fed a commercial dry cat food diet and allowed free access to water.

[0099] Cats in each of test groups 2-4 are given a liquid formulation of a spinosyn, preferably spinosad, by mouth. The doses administered to cats on each of days 0-29 according to test group are shown in the table below.

[0082] [Table 1]

[0083]

[0100] Cats in the control group receive no Spinosyn or any other flea control treatment. Each cat in test groups 2-4 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 Spinosyn is administered, the cat is allowed to continue eating. This is similar to incorporating Spinosyn in the diet. Each cat in test groups 2-4 and the control group is challenge infested 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, with day 0 being the start of daily dosing. The final challenge infestation is allowed to occur approximately 5 days after the last daily dose of Spinosyn.

[0084]

[0101] Test group 2 and 3 dose levels are predicted to show greater than 90% flea reduction efficacy compared to the control group with 2 days of substantially daily administration, and greater than 98% efficacy after one week of substantially daily administration. Test group 4 dose level is predicted to show greater than 98% flea reduction efficacy compared to the control group with 2 days of substantially daily administration.

[0085]

[0102] Additionally, all test groups are expected to show greater than 85% efficacy one week after substantially daily dosing has ceased, e.g., by combined count on day 37. At higher dose levels, e.g., test group 4, no significant decline in efficacy may be seen one week after substantially daily dosing has ceased.

[0086]

[0103] Using the same study methodology described above, blood is drawn at 72, 120, 168, 336, 504, 720 and 888 hours after the initial dose of Spinosyn is administered. The average blood concentrations of Spinosyn can then be determined for the different dose levels.

[0087]

[0104] The mean plasma concentrations of all spinosyns in feline blood with substantially daily dosing at the dose level of Test Group 2 are predicted to range from about 20 ng / ml at 72 hours to about 58 ng / ml at 336 hours. For Test Group 3, the predicted range is from about 56 ng / ml at 72 hours to about 143 ng / ml at 504 hours. For Test Group 4, the predicted range is from about 118 ng / ml at 72 hours to about 372 ng / ml at 504 hours. In comparison, plasma concentrations of spinosad in feline blood with a typical monthly single dose have a predicted range of from about 878 ng / ml one hour after dosing to about 6107 ng / ml 12 hours after dosing.

[0088] Example 2

[0105] Efficacy of spinosyns in cats when administered in medicated feed at a dose of 0.85 mg / kg of cat body weight

[0106] Methods: A pool of cats was pre-infested with approximately 100 unfed adult C. felis to create a group of 18 cats capable of adequately maintaining a reliable infestation rate of approximately 50% live fleas over a 48-hour period. Cats with the highest live flea counts were randomly assigned to three groups (six cats per group) based on their pre-treatment flea counts from the trial infestation. The first treatment group was the control group and groups 2-3 were the test groups.

[0089]

[0107] Cats are individually housed for the duration of the study with water available ad libitum.

[0108] There is an initial acclimation period of at least 4 days during which cats in test groups 2 and 3 are transitioned from the standard certified commercial cat chow to a non-medicated version of the daily cat chow. During the acclimation period, cats are allowed to consume the chow for 1 hour, after which the cats' acceptance of the chow is observed and recorded.

[0090]

[0109] Each cat in test groups 2 and 3 is orally fed a daily feed formulation containing a spinosyn, preferably spinosad. The doses and formulations administered to the cats on each of days 0-29 according to test group are shown in the table below.

[0091] [Table 2]

[0092]

[0110] Cats in the control group will not receive Spinosyn or will receive any other flea control treatment. On days 0-29, each cat in treatment groups 2 and 3 will be fed its daily food containing Spinosyn for one hour. On days 30-37, all cats will be fed regular cat food without Spinosyn.

[0093]

[0111] Each cat in test groups 2 and 3 and the control group is challenge infested with 100 unfed adult fleas on test days -1, 5, 12, 28 and 35. Combined live adult flea counts are taken on days 2, 7, 14, 30 and 37, with day 0 being the start of the daily feeding of medicated food.

[0094]

[0112] Assuming that all cats in groups 2 and 3 consume all of the food required for the daily 0.85 mg / kg dose within a one-hour period without regurgitation, the percent reduction in live adult flea counts for test groups 2 and 3 is expected to reach greater than 90% within 14 days. Some feed formulations may achieve 90% efficacy sooner than 14 days. Additionally, the percent reduction in live adult flea counts for test groups 2 and 3 is expected to remain greater than 80% 7 days after the last administered dose. Differences in feed formulations are not expected to significantly affect the rate of decline in efficacy after dosing is discontinued.

[0095]

[0113] By comparing the two examples, it can be seen that, on average, an effective amount of spinosyn can be administered to a cat via the medicated feed. Example 3

[0114] Efficacy of spinosyns when administered in medicated feed for the treatment and control of Ctenocephalides felis.

[0115] 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 Spinosyn.

[0096]

[0116] Cats are individually housed for the duration of the study with water available ad libitum.

[0117] 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.

[0097] [Table 3]

[0098]

[0118] Cats are fasted overnight prior to each daily treatment. The daily dose volume of Spinosyn 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.

[0099]

[0119] Control cats receive no spinosyn 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.

[0100]

[0120] 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]

[0101]

[0121] While the invention has been described in an illustrative manner, the invention may be further modified within the spirit and scope of the disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles.

Claims

1. A composition for use in controlling flea infestation in felines in need of controlling flea infestation, comprising spinosin, 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.

2. The composition according to claim 1, wherein the spinosin is spinosad.

3. The composition according to claim 1, wherein the spinosin is administered to the feline in an amount between about 0.18 mg / kg and 17 mg / kg based on the body weight of the feline.

4. The composition according to claim 1, which is a feed, preferably moist or dry cat food, or a chew.

5. The composition according to claim 4, wherein the spinosin is present in an amount between about 7.5 mg / kg and 2400 mg / kg of the feed.

6. The composition according to claim 3, wherein the administration for flea control provides a concentration of spinosin in the blood of the feline within a range selected from the group consisting of at least 7.5 ng / mL and 1020 ng / mL or less, and at least 15 ng / mL and 383 ng / mL or less for at least 30 days.

7. The composition according to claim 1, wherein the feline is a cat.

8. The composition according to claim 1, wherein the administration includes a feeding frequency selected from the group consisting of at least 3 times per week, substantially daily, and daily.

9. The composition according to claim 1, wherein the effective period of time is selected from the group consisting of at least 1 week and at least 2 weeks.

10. The composition according to claim 1, wherein the administration supplies a therapeutically effective level of spinosin in the blood of the feline within a period selected from the group consisting of within 1 week from the first administration of the spinosin and within 2 days from the first administration of the spinosin. **Claim 11**: The composition according to claim 1, wherein the administration supplies a therapeutically effective level of spinosin in the blood of the feline for a period selected from the group consisting of at least 45 days, at least 60 days, at least 90 days, at least 180 days, and at least 365 days. **Claim 12**: The composition according to claim 1, wherein the administration supplies a concentration of spinosin between 15 ng / mL and 383 ng / mL 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. **Claim 13**: The composition according to claim 1, which is administered for a number of days selected from the group consisting of at least 15 days and at least 20 days out of 30 days. **Claim 14**: The composition according to claim 1, wherein the administration further comprises a step of suspending the administration for a number of days selected from the group consisting of at least 3 days and at least 7 days, and the blood concentration of spinosin in the feline is maintained at a therapeutically effective level. **Claim 15**: The composition according to claim 1, wherein the administration further comprises a step of resuming the administration after suspending the administration, thereby maintaining the blood concentration of spinosin in the feline at the therapeutically effective level.