Bait and method for controlling tick infestations in mammals - Patents.com

Abstract

An oral animal feed and method for controlling mites in a mammal in need thereof by orally administering to the mammal an effective amount of a spinosyn for an effective period of time, thereby raising and maintaining the amount of spinosyn in the mammal's blood at a therapeutically effective level for controlling mites.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE

[0001] The teachings of this disclosure relate generally to spinosyns, baits containing spinosyns, and methods of administering spinosyns to control tick infestations in mammals. [Background technology]

[0002]

[0002] Ticks are vectors of a wide variety of pathogens in mammals. Examples of diseases caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia microti) and rickettsiosis (Rocky Mountain spotted fever). Ticks also release toxins that can cause inflammation or paralysis in the host.

[0003]

[0003] Tick infestations in wild animals, such as deer, elk, caribou, and moose, can result in the spread of disease from herd to herd, or from wild animals to domestic animals (eg, cattle, cats, and dogs) and humans.

[0004]

[0004] Livestock are also susceptible to infestations by various mites, such as those of the tick genus Rhipicephalus, especially those of the species microplus (cattle tick), decoloratus and annulatus. Ticks such as Rhipicephalus microplus are particularly difficult to control because they inhabit the pastures where the livestock graze. Besides cattle, Rhipicephalus spp. and other tick genera can infest buffalo, horses, donkeys, goats, sheep, deer, pigs, cats and dogs. Large tick loads on mammals can reduce production, damage hides and transmit diseases such as babesiosis ("cow fever") and anaplasmosis, which are caused by parasitic protozoa.

[0005] In addition to livestock, ticks also spread diseases to companion animals and humans, including, for example, Lyme disease, ascending paralysis, and Rocky Mountain spotted fever.

[0006] Of particular concern are the health-related risks of tick infestation in companion animals that extend to humans [Center for Disease Control and Prevention, Illnesses on the Rise, Vital Signs, May 2018, available at https: / / www.cdc.gov / vitalsigns / vector-borne / ]. Companion animals, such as dogs and cats, are becoming increasingly common in households worldwide. Globally, approximately 471 million dogs and 373 million cats are kept as household pets. In the United States alone, pet ownership has tripled since the 1970s. Unfortunately, ticks can infest these companion animals. Infested companion animals expose human owners to increased risk of disease. One way to control the risk to humans from ticks is to control the risk of infestation in companion animals.

[0006]

[0007] Treatments currently available to control tick infestations have achieved varying degrees of success. Many treatments involve chemicals applied to indoor and outdoor surfaces and to animals. Chemicals used include various carbamates, organophosphates, certain macrocyclic lactones, fiproles, pyrethrins and pyrethroids. These compounds often have adverse side effects that are problematic for both animals and animal owners. Furthermore, there is evidence that the use of these chemicals may be ineffective due to acaricide resistance and treatment shortages.

[0007]

[0008] Topical treatment is a well-known method for controlling tick infestation. There are numerous ways to deliver these therapeutic agents to the hair and skin of mammals, but many of these methods are ineffective and / or pose safety risks to the mammal or user during or after the dispensing operation. More specifically, when attaching the applicator tip to the applicator, a physical connection must be achieved between the applicator tip and the drug delivery device, and there is an inherent risk that the connection will be poor, causing some of the therapeutic agent to leak out of the device and come into physical contact with the user. For example, with a large dog, it can be difficult to operate the dispenser with one hand and keep the dog 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 dog's skin. This leakage is not only wasteful and messy, but also increases the risk that the user will suffer from skin irritation or other health concerns, especially if the user comes into direct contact with the agent.

[0008]

[0009] Oral treatments are also available for companion animals. However, to be effective, owners must administer the treatments, for example, once every 30 to 90 days. Long periods between treatments can create compliance issues if owners forget to administer the medication.

[0009]

[0010] Despite the availability of effective treatments, a recent study by Harris Poll found that 33% of pet owners do not routinely protect their pets against mites at all. Another study found that, on average, pet owners only purchase four months' worth of tick prevention products per pet per year, despite the fact that pets should be treated for tick prevention year-round. Thus, there is a continuing need for relatively safe and effective agents to prevent tick infestations in companion animals that owners can more easily remember to use. Summary of the Invention

[0010]

[0011] It has surprisingly been discovered by the inventors that spinosyns, such as spinosad, can provide improved control against tick infestations when administered orally in smaller, more frequent / chronic doses. Heretofore, spinosyns were generally thought to be ineffective for controlling ticks in pets, or more generally in mammals, because they are typically dosed on a monthly basis and the amount of spinosyn in the animal's blood declines too quickly to control tick infestations.

[0011]

[0012] The methods and compositions taught herein have the additional advantage of increasing compliance, since, at least in the case of companion animals, smaller doses of spinosyns can be incorporated into the daily feed that would be given to the companion animal anyway, making owners less likely to forget or neglect to administer treatment. Thus, the present disclosure provides a method for long-term control of mites in a safer and more effective manner than previously achieved with known treatments. Administration of spinosyns is described below as being combined with feed. However, it is also contemplated that spinosyns may be administered by themselves or in dosage forms other than feed, such as chews, tablets, liquids, gels, or other forms suitable for oral administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012]

[0013] Spinosyns are naturally occurring fermentation products. Spinosyns are a class of 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 consisting primarily of these two spinosyns are commercially available under the generic name "spinosad." The primary spinosyn factor, spinosyn A, is particularly known to have an excellent human and mammalian safety and toxicological profile.

[0013]

[0014] Each spinosyn has a macrocyclic 12-membered ring that is part of a rare 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 distinguishes the spinosyns from other macrocyclic compounds.

[0014]

[0015] Spinosyn A was the first spinosyn isolated and identified from the fermentation broth of S. spinosa. Subsequent examination of the fermentation broth revealed that S. spinosa produces several spinosyns, designated spinosyns A-J (A83543A-J). The major components are spinosyns A and D. Additional spinosyns, designated K through W, have been identified from mutant strains of S. spinosa. The various spinosyns are characterized by differences in the substitution patterns on the amino group of the forosamine, at selected sites on the tetracyclic ring system, and on the 2N,3N,4N-(tri-O-methyl)rhamnose group.

[0015]

[0016] Boeck et al., in U.S. Pat. Nos. 5,362,634 (issued Nov. 8, 1994); 5,496,932 (issued March 5, 1996); and 5,571,901 (issued Nov. 5, 1996), described spinosyns A through H and J (which Boeck et al. referred to as 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), described spinosyns L through N (which Mynderse et al. referred to as A83543 factors L, M and N), their N-demethyl 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), described spinosyns Q through T (which Turner et al. referred to as A83543 factors Q, R, S and T), their N-demethyl derivatives, and their salts. Spinosyns K, O, P, U, V, W and Y are described, for example, by Carl V. DeAmicis, James E. Dripps, Chris J. Hatton and Laura I. Karr in American Chemical Society's Symposium Series: Phytochemicals for Pest Control, Chapter 11, "Physical and Biological Properties of Spinosyns: Novel Macrolide Pest-Control Agents from Fermentation", pages 146-154 (1997).

[0016]

[0017] Spinosyns may react to form salts that 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 may be neutralized with a suitable 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, for example, 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, etc.

[0017]

[0018] The term "spinosyn", as used herein, 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.

[0018]

[0019] Spinosyns also offer advantages because when the dosages described herein are used according to the methods disclosed herein, they are highly effective against mites with residual protection after treatment. Furthermore, spinosyns do not have acaricidal cross-resistance to existing compounds. Thus, spinosyns are particularly useful against mammalian mite populations that have existing levels of resistance to currently used acaricidal products. Thus, spinosyns can be used in integrated pest management (IPM) programs to extend the life of commonly used products for which resistance has not been fully developed or has not yet been developed.

[0019]

[0020] Systemic efficacy (e.g., ingestion of spinosyn-containing blood by ticks) provides a different mode of exposure compared to topically applied formulations, where contact with the tick at the skin surface is the mode of exposure. The advantages of oral systemic treatment and killing of ticks by ingestion of their blood compared to killing by topical application and contact include: a) reduced exposure of human applicators and children and mammals to objects in the environment (e.g., floors, carpets, furniture); b) There is no concern about loss of mammals due to exposure to water (lakes, streams, beaches, etc.) or due to rubbing; c) there are no concerns regarding UV exposure and degradation; d) there are no problems with oxidation due to oils on the skin, etc.; and e) ensuring that the entire dose is administered (compared to topical applications where some of the dose may drip, be scraped off, and / or remain in the dispensing tube immediately following treatment).

[0020]

[0021] The formulations or baits and methods of the present disclosure may further comprise one or more other active substances having therapeutic efficacy in combination with spinosyn. Such active substances include agents that are effective against mites. The active substances may include, for example, isoxazolines, certain macrocyclic lactones, mite-specific chitin synthesis inhibitors, pyridines and pyrazoles or fiproles.

[0021]

[0022] The method of the present disclosure is carried out by administering small, frequent doses of spinosyns to the mammal. To facilitate routine dosing, spinosyn administration may be carried out using a daily feed. A wide variety of feeds are envisioned, provided that the manufacturing process(es) and feed composition are free of adverse effects related to efficacy, safety and stability of the spinosyns and, if applicable, other active substances. For example, a wide range of categories of food, including dry food, semi-moist food, wet food, retort canned food, fresh refrigerated food, and supplemental food, including treats, snacks and other supplemental foods, may be adapted for use with the present disclosure. The mammal receives a maintenance dose of spinosyns by consuming the food product once a week, twice a week or daily.

[0022]

[0023] By incorporating smaller doses of spinosyns into an animal's feed composition and administering them at an effective frequency (most likely daily), the blood level of spinosyns will rise over time until it reaches an optimal steady state that can be maintained by daily or substantially daily dosing. In contrast, if spinosyns are administered orally at larger doses and less frequently, such as a large single dose treatment administered via a "treat" once every 30 days, the level of spinosyns in the blood will spike at the time of dosing and then drop until the next dose is administered. Dosing at larger doses less frequently means that the animal must consume more spinosyns at each dose so that the blood level of spinosyns does not fall below the level required for effective protection before the next dose. The rapid and sudden drop in blood levels of spinosyns makes it impossible to maintain sufficient blood levels to control tick infestations using a monthly dosing strategy.

[0023]

[0024] All ratios, percentages, and parts set forth herein are "by weight" unless otherwise specified.

[0025] The term "controlling tick infestation" refers to preventing, treating, minimizing or eliminating tick infestation in a mammal.

[0024]

[0026] The term "tick" refers to any member of the order Ixodida. The term "tick" includes egg, larvae, nymphs, and adult stages of development. More specifically, the term tick includes the families Ixodidae and Argasidae. More specifically, the term "tick" includes species of the genera Africaniella, Amblyomma, Anomalohimalaya, Bothriocroton, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Margaropus, Nosomma, Rhipicentor, Rhipicephalus, Antricola, Argas, Nothoaspis, Ornithodoros, and Otobius.

[0025]

[0027] The term "mammal" refers to any member of the class Mammalia. In particular, the term "mammal" can refer to wild mammals, such as wolves, coyotes, jackals, deer, elk, moose, reindeer, and the like. The term "mammal" can also refer to domestic animals, such as cattle, sheep, pigs, bison, horses, and the like. The term "mammal" can also refer to companion animals. The term "mammal" can also refer to humans.

[0026]

[0028] The term "companion animal" refers to any domestic animal that may be kept as a pet, including, but not limited to, horses, dogs, wolves, coyotes, cats, hamsters, gerbils, mice, guinea pigs, ferrets, rabbits, and the like.

[0027]

[0029] The term "canine" refers to any member of the genus Canis, which includes species such as wolves, dogs, coyotes, and jackals.

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

[0028]

[0031] In practicing the methods of the present disclosure, a "food" is an animal's food, snack, treat or other supplemental food that may be provided daily or substantially daily. By using various forms of food, such as kibbles and treats or chews, a mammal's meals and snacks may be varied from time to time while still conveniently administering a daily dose of a spinosyn.

[0029]

[0032] The term "chew" refers to a treat that has flavor and aroma properties that are attractive to dogs, but typically has no nutritional value. In practicing the methods of the present disclosure, "bait" and / or "chew" may be used interchangeably.

[0030]

[0033] The term "effective time", also referred to herein as "effective duration", includes at least the duration of application of the bait required to bring the level of the spinosyn in the mammal's blood to a level high enough to control ticks, i.e., a "therapeutically effective" level. In some embodiments, the effective time may be as little as 3 days. In other examples, the effective time may be 7 or 15 days or longer. As described below, the effective time will vary based on how often the bait or spinosyn is administered.

[0031]

[0034] As mentioned above, the "effective time" varies as a function of how often the feed is administered. The term "effective frequency," as used herein, refers to the number of feedings over a given time period that results in a therapeutically effective concentration of the spinosyn in the mammal's blood. In any event, the term "effective frequency," as used herein, contemplates multiple feedings containing the spinosyn per month. It will be understood by those skilled in the art that the feed may be administered at various frequencies. For example, the spinosyn may be administered daily, every other day, every third day, once per week, or even at inconsistent time intervals.

[0032]

[0035] Furthermore, as discussed above, the effective frequency can affect the duration required to achieve a therapeutically effective level of a spinosyn in the mammal's blood. By way of example, if a mammal is fed the feed composition daily, the duration of feeding required to achieve a therapeutically effective level of a spinosyn in the mammal's blood, and therefore the "effective time," will be relatively shorter than if the mammal is fed the feed composition only once or twice per week.

[0033]

[0036] Furthermore, the frequency of efficacy is affected by the amount of the daily dose in mg / kg (body weight of the mammal). Particularly at slightly higher daily doses, e.g., greater than 1.0 mg / kg, missed doses have less effect on efficacy.

[0034]

[0037] Furthermore, effective frequency is affected by the duration of treatment: in the early stages, i.e., before the amount of spinosyn in the mammal's blood reaches therapeutically effective levels, the animal's feed may need to be fed more frequently than would be necessary if it were fed after longer periods of use, i.e., once therapeutically effective levels have been achieved.

[0035]

[0038] For purposes of this disclosure, "substantially daily" means sufficiently regular that the concentration of spinosyn in the mammal's blood rises to and remains at a therapeutically effective level. For example, the disclosed bait compositions can be preferably fed to the mammal daily indefinitely. However, as a practical matter, there are many reasons to forget or skip days periodically. For example, the mammal may be ill or the owner may run out of the bait composition. The disclosed methods are robust enough that even with an accidental interruption in the dosing of the spinosyn, the mammal is protected to some degree from mites. In practicing the methods of this disclosure, the term "substantially daily" includes at least 10 days per month, more preferably at least 15 days per month, and even more preferably at least 20 days per month. All of these feeding frequencies, whether they are, for example, three times per week, every other day, or daily, fall under the ambit of "substantially daily" as used in this disclosure, so long as they facilitate the spinosyn reaching and maintaining a therapeutically effective level of the spinosyn in the mammal's blood.

[0036]

[0039] The term "therapeutically effective" means that the dose of spinosyn in the bait or the concentration of spinosyn in the blood is sufficient to control tick infestation better than in the absence of the drug. The spinosyn may be present, for example, in the bait or in the blood of the mammal, alone or with one or more additional active agents. Preferably, the spinosyn controls tick infestation at least about 50% better than in the absence of the drug, and more preferably, the spinosyn controls tick infestation at least about 90% better than in the absence of the drug.

[0037]

[0040] In practicing the methods of the present disclosure, an effective or therapeutically effective amount of a spinosyn is orally administered to a mammal. The term "effective amount" or "therapeutically effective amount" refers to the amount needed to control tick infestation. As will be appreciated by those of skill in the art, this amount will vary depending on several factors. These factors include, for example, the type of mammal being treated, its weight and general physical condition.

[0038]

[0041] Although the present disclosure has described the concentration of spinosyns in terms of food such as kibbles, the present disclosure also contemplates administration using other dosage forms such as treats or chews. The present disclosure also contemplates that the spinosyns may be administered by themselves or in tablets, liquids, gels, or other suitable forms for oral administration. Those skilled in the art will appreciate that the concentration of the spinosyns will vary according to the particular dosage form. For example, if the dosage form is a treat or chew, the concentration of the spinosyns in the treat or chew will be higher than the concentration of the spinosyns in, for example, a kibble. For example, if the daily dose of spinosyns based on the weight of a dog is 10 mg, then typically 5 g of treat or chew will contain about 0.2 percent of the spinosyns (based on weight). Because the amount of kibble consumed in a day is greater than 5 g, the percentage of spinosyns in the kibble will be lower.

[0039]

[0042] In general, an effective dose refers to a dose of about 0.625 to about 10 mg of spinosyn / kg of mammalian body weight. More preferably, an effective dose refers to a dose of about 1 to about 4.5 mg of spinosyn / kg of mammalian body weight. More commonly, an effective amount is about 1 to about 3.75 mg / kg of mammalian body weight.

[0040]

[0043] The animal feed typically contains from about 0.005 to about 2 percent spinosyns (by weight) in the feed, preferably from about 0.01 to about 0.5 percent spinosyns (by weight) in the feed, and most preferably from about 0.03 to about 0.2 percent spinosyns (by weight) in the feed.

[0041]

[0044] In one aspect, the disclosure relates to a method of controlling tick infestation in a mammal by administering a systemically active oral composition comprising a spinosyn, or a physiologically acceptable derivative or salt thereof, and an animal feed at least once per week, more preferably three times per week, and most preferably substantially daily.

[0042]

[0045] In another aspect, the disclosure relates to a systemically active oral composition comprising a spinosyn and an animal feed.

[0046] The present disclosure also relates to the use of spinosyns for the manufacture of animal feed for controlling tick infestations in mammals.

[0043]

[0047] The present disclosure also relates to a method for controlling tick infestations in a mammal for an extended period of time, comprising orally administering to the mammal a daily or substantially daily dose of an effective amount of a spinosyn, for example in a bait. A daily bait is a bait that is intended to be administered daily, but may be administered less frequently than daily, as described herein. This method is particularly useful for controlling ticks in a mammal for an extended period of time, comprising orally administering to the mammal an effective amount of a substantially daily dose of a spinosyn.

[0044]

[0048] An embodiment of the present disclosure is the oral administration of an amount of spinosyn that is ineffective or suboptimal in controlling tick infestation in mammals in a single dose, for example once a month, but as described herein, over time with repeated administration, provides effective control of tick infestation. By ineffective or suboptimal, we mean that a single dose, as well as several doses, results in less than a 50% reduction in tick infestation, including no reduction or substantially no reduction, when compared to no drug administration at all. This reflects the chronic rather than acute administration aspects disclosed herein.

[0045]

[0049] Embodiment 1: A method of controlling tick infestation in a mammal in need thereof, comprising orally administering to said mammal an effective amount of a spinosyn for an effective period of time at least four times per month.

[0046]

[0050] Embodiment 2: The method of embodiment 1, wherein said mammal is selected from the group consisting of wild animals, livestock animals, companion animals and dogs.

[0051] Embodiment 3: The method of embodiment 1 or 2, wherein the spinosyn is spinosad.

[0047]

[0052] Embodiment 4: The method of any of embodiments 1-3, wherein the spinosyn is provided in a food selected from the group consisting of dry food and wet food.

[0053] Embodiment 5: The method of any of embodiments 1-3, wherein the spinosyn is present in an amount of about 0.005%-2% of the feed.

[0048]

[0054] Embodiment 6: The method of any of embodiments 1-5, wherein the spinosyn is administered to the mammal in an amount of about 0.625 mg / kg to 10 mg / kg of weight of the mammal.

[0049]

[0055] Embodiment 7: The method of any of embodiments 1-6, wherein said frequency is selected from the group consisting of at least three times per week, substantially daily, and daily.

[0056] Embodiment 8: The method of any of embodiments 1-7, wherein the effective time period is selected from the group consisting of at least 1 week and at least 2 weeks.

[0050]

[0057] 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 mammal within a period of time selected from the group consisting of one week after the first administration of the spinosyn and two days after the first administration of the spinosyn.

[0051]

[0058] 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 mammal 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.

[0052]

[0059] Embodiment 11: The method of any of embodiments 1-10, wherein said administration provides a concentration of spinosyn in the blood of said mammal greater than about 300 ng / mL and less than about 6000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0053]

[0060] 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 out of 30 days and at least 20 days out of 30 days.

[0054]

[0061] Embodiment 13: The method of any of embodiments 1-12, wherein the spinosyn is provided as a component of a feed that includes one or more other active agents.

[0062] Embodiment 14: The method of any of embodiments 1-13, further comprising discontinuing administration of the spinosyn for a period selected from the group consisting of at least 3 days and at least 7 days, wherein the blood concentration of the spinosyn in the mammal is maintained at a therapeutically effective level during that period.

[0055]

[0063] Embodiment 15: The method of embodiment 14, further comprising resuming administration of the spinosyn after a cessation of administration of the spinosyn, thereby continuing to maintain blood levels of the spinosyn in the mammal at a therapeutically effective level.

[0056]

[0064] Embodiment 16: The method of embodiment 1, wherein the spinosyn is a component of a chew.

[0065] Embodiment 17: The method of embodiment 16, wherein the oral administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0057]

[0066] Embodiment 18: A spinosyn for use in controlling ticks in a mammal in need thereof, wherein the spinosyn is orally administered to the mammal in an effective amount for an effective period of time at least four times per month.

[0058]

[0067] Embodiment 19: The spinosyn of embodiment 18, wherein said mammal is selected from the group consisting of wild animals, livestock animals, companion animals, and dogs.

[0068] Embodiment 20: The spinosyn of any of embodiments 18-19, wherein the spinosyn is spinosad.

[0059]

[0069] Embodiment 21: The spinosyn of any of embodiments 18-20 provided in a food selected from the group consisting of dry food and wet food.

[0070] Embodiment 22: The spinosyn of any of embodiments 18-21, present in an amount of about 0.005%-2% of the feed.

[0060]

[0071] Embodiment 23: The spinosyn of any of embodiments 18-22, administered to the mammal in an amount of about 0.625 mg / kg to 10 mg / kg of weight of the mammal.

[0072] Embodiment 24: The spinosyn of any of embodiments 18-23, wherein said administering step comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0061]

[0073] Embodiment 25: The spinosyn of any of embodiments 18-24, wherein said effective time period is selected from the group consisting of at least 1 week and at least 2 weeks.

[0074] 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 mammal within a period of time selected from the group consisting of one week after the first administration of the spinosyn and two days after the first administration of the spinosyn.

[0062]

[0075] 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 mammal 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.

[0063]

[0076] Embodiment 28: The spinosyn of any of embodiments 18-27, wherein said administration provides a concentration of the spinosyn in the blood of the mammal of greater than about 300 ng / mL and less than about 6000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0064]

[0077] Embodiment 29: The spinosyn of any of embodiments 18-28, wherein the feed is administered for a number of days in a 30 day period selected from the group consisting of at least 15 days and at least 20 days.

[0065]

[0078] Embodiment 30: The spinosyn of any of embodiments 18-29, which is a bait component comprising one or more additional active agents.

[0079] Embodiment 31: The spinosyn of any of embodiments 18-30, further comprising discontinuing administration of the spinosyn for a period of time selected from the group consisting of at least 3 days and at least 7 days, wherein the blood concentration of the spinosyn in the mammal is maintained at a therapeutically effective level.

[0066]

[0080] Embodiment 32: The spinosyn of embodiment 31, further comprising resuming administration of the spinosyn after a cessation of administration of the spinosyn, thereby maintaining a blood concentration of the spinosyn in the mammal at a therapeutically effective level.

[0067]

[0081] Embodiment 33: A spinosyn of any one of embodiments 18-32 that is a component of a chew.

[0082] Embodiment 34: The spinosyn of embodiment 33, wherein said administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0068]

[0083] Embodiment 35: A bait or chew for controlling mites in a mammal comprising an amount of a spinosyn effective to control a mite infestation when orally administered at least four times per month for an effective period of time.

[0069]

[0084] Embodiment 36: The feed or chew of embodiment 35, wherein said mammal is selected from the group consisting of wild animals, livestock, companion animals and dogs.

[0085] Embodiment 37: The bait or chew of any of embodiments 35-36, wherein the spinosyn is spinosad.

[0070]

[0086] Embodiment 38: The food or chew of any of embodiments 35-37, wherein said food or chew is a food selected from the group consisting of dry food and wet food.

[0087] Embodiment 39: The feed or chew of any of embodiments 35-38, wherein the spinosyn is present in an amount of about 0.005% to 2% of the feed.

[0071]

[0088] Embodiment 40: The feed or chew of any of embodiments 35-39, wherein the spinosyn is administered to the mammal in an amount of about 0.625 mg / kg to 10 mg / kg of weight of the mammal.

[0072]

[0089] Embodiment 41: The feed or chew of any of embodiments 35-40, wherein said administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

[0073]

[0090] Embodiment 42: The feed or chew of 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.

[0074]

[0091] Embodiment 43: The feed or chew of any of embodiments 35-42, wherein said administration provides a therapeutically effective level of a spinosyn in the blood of said mammal within a period of time selected from the group consisting of one week after the first administration of said feed or chew and two days after the first administration of said feed or chew.

[0075]

[0092] 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 said mammal 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.

[0076]

[0093] Embodiment 45: The feed or chew of any of embodiments 35-44, wherein said administration provides a concentration of spinosyn in the blood of said mammal of greater than about 300 ng / mL and less than about 6000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

[0077]

[0094] Embodiment 46: The feed or chew of any of embodiments 35-45, which is administered for a number of days out of 30 days selected from the group consisting of at least 15 days and at least 20 days.

[0078]

[0095] Embodiment 47: The bait or chew of any of embodiments 35-46, comprising one or more other active substances.

[0096] Embodiment 48: The feed or chew of any of embodiments 35-47, further comprising a step of discontinuing administration of the feed or chew for a period of time selected from the group consisting of at least 3 days and at least 7 days, wherein the blood concentration of the spinosyn in the mammal is maintained at a therapeutically effective level.

[0079]

[0097] Embodiment 49: The feed or chew of embodiment 48, further comprising the step of resuming administration of the feed or chew after a cessation of administration of the feed or chew, thereby maintaining a blood concentration of the spinosyn in the mammal at a therapeutically effective level.

[0080]

[0098] In any aspect of the embodiment, administration provides a concentration of spinosyn in the blood of the mammal greater than about 300 ng / mL and less than about 6000 ng / mL for at least 30 days. More preferably, administration provides a concentration of spinosyn in the blood of the mammal greater than about 300 ng / mL and less than about 2500 ng / mL for at least 30 days. Even more preferably, administration provides a concentration of spinosyn in the blood of the mammal greater than about 300 ng / mL and less than about 2000 ng / mL for at least 30 days. Even more preferably, administration provides a concentration of spinosyn in the blood of the mammal greater than about 400 ng / mL and less than about 1500 ng / mL for at least 30 days.

[0081]

[0099] In any aspect of the embodiment, administration provides a concentration of spinosyn in the blood of the mammal greater than about 300 ng / mL and less than about 6000 ng / mL for at least 365 days. More preferably, administration provides a concentration of spinosyn in the blood of the mammal greater than about 300 ng / mL and less than about 2500 ng / mL for at least 365 days. Even more preferably, administration provides a concentration of spinosyn in the blood of the mammal greater than about 300 ng / mL and less than about 2000 ng / mL for at least 365 days. Even more preferably, administration provides a concentration of spinosyn in the blood of the mammal greater than about 400 ng / mL and less than about 1500 ng / mL for at least 365 days. EXAMPLES

[0082]

[0100] The following examples illustrate the methods of the present disclosure: Example 1

[0101] Efficacy of spinosyns administered orally, i.e., by mouth, to dogs for the treatment and control of brown dog ticks (Rhipicephalus sanguineus)

[0102] Methods: To generate a pool of dogs that can adequately maintain a reliable infestation rate of approximately 50% live fleas over a 48-hour period, a pool of 40 dogs can be screened prior to inclusion in this example by pre-infestation with approximately 100 unfed adult cat fleas (Ctenocephalides felis). Dogs with the highest live flea counts are randomly assigned to two treatment groups (6 dogs per group) based on the pre-treatment flea counts of the dogs from the experimental infestation. The first treatment group is the control group and the second treatment group is the test group.

[0083]

[0103] The dogs are individually housed and fed a commercial dry dog ​​food ration and have access to water ad libitum for the duration of the study. Each dog in the test group receives a liquid formulation of a spinosyn, preferably spinosad, by mouth. A dose of 2.5 mg / kg (dog's body weight) is administered to the dogs on each of days 0-29, and a dose of 5 mg / kg (dog's body weight) is administered on days 30-50.

[0084]

[0104] Dogs in the control group do not receive spinosyns or any other tick control treatment. Each dog in the test group is provided with its daily ration (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily ration. After receiving the spinosyn dosage, the dog continues to eat. This mimics the incorporation of spinosyns in the diet. Dogs in the test and control groups are each experimentally infested with 50 unfed adult ticks (approximately 50% male / 50% female) on test days 12, 19, 28, 35, 42, 49, and 56. Combined counts of live and moribund adult ticks are taken on days 14, 21, 30, 37, 44, 51, and 58. Note that the dosage is increased on day 30 with the final dose administered on day 50.

[0085]

[0105] Results: The percent reduction in combined live and moribund adult tick counts for the test groups compared to the control groups is shown in the graph below using spinosad.

[0086] [ka]

[0087]

[0106] Using the same study methodology described above, blood is collected at 72, 120, 168, 336, 504, 720 and 888 hours after the first dose of spinosyn is administered. The average concentrations of spinosyn in the blood at various dosage levels can then be determined.

[0088]

[0107] Sample results of mean plasma concentrations of spinosad in dog blood at various dosage levels are shown in the following table and chart. For comparison, mean plasma concentrations of spinosad from administration of a single dose given monthly are also shown in the following table and chart:

[0089] [Table 1]

[0090] [ka]

[0091]

[0108] While the invention has been described as having an exemplary design, 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. 1. A method for controlling mite infestation in a mammal other than a human in need thereof, comprising orally administering to said mammal an effective amount of a spinosyn for an effective period of time at least four times per month.

2. 2. The method of claim 1, wherein the spinosyn is spinosad.

3. 10. The method of claim 1, wherein the spinosyn is provided in a food selected from the group consisting of dry food and wet food.

4. 10. The method of claim 1, wherein the spinosyn is present in an amount of about 0.005% to 2% of the feed.

5. 10. The method of claim 1, wherein the spinosyn is administered to the mammal in an amount of about 0.625 mg / kg to 10 mg / kg of the mammal's weight.

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

7. 10. The method of claim 1, wherein the effective time period is selected from the group consisting of at least 1 week and at least 2 weeks.

8. The method of claim 1, wherein said administration provides a therapeutically effective level of the spinosyn in the blood of said mammal within a period selected from the group consisting of one week after the first administration of said spinosyn and two days after the first administration of said spinosyn.

9. 2. The method of claim 1, wherein said administration provides a therapeutically effective level of a spinosyn in the blood of said mammal 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.

10. The method of claim 1, wherein said administration provides a concentration of spinosyn in the blood of the mammal selected from the group consisting of: in the blood of said mammal, greater than about 300 ng / mL and less than about 6000 ng / mL for at least 30 days; greater than about 300 ng / mL and less than about 2500 ng / mL; greater than about 300 ng / mL and less than about 2000 ng / mL; and greater than about 400 ng / mL and less than about 1500 ng / mL in the blood of said mammal for at least 30 days.

11. 11. The method of claim 10, wherein said administration provides a concentration of spinosyn in the blood of said mammal of greater than about 300 ng / mL and less than about 6000 ng / mL for a period selected from the group consisting of at least 30 days and at least 365 days.

12. 10. The method of claim 1, wherein the spinosyn is administered for a number of days selected from the group consisting of at least 15 days out of 30 days and at least 20 days out of 30 days.

13. 10. The method of claim 1, wherein the spinosyn is provided as a component of a bait that includes one or more other active agents.

14. 10. The method of claim 1, further comprising the step of discontinuing administration of the spinosyn for a period selected from the group consisting of at least 3 days and at least 7 days, wherein the mammal's blood concentration of the spinosyn is maintained at a therapeutically effective level during that period.

15. 15. The method of claim 14, further comprising the step of resuming administration of a spinosyn after said discontinuation of administration of the spinosyn, thereby continuing to maintain blood levels of a spinosyn in said mammal at said therapeutically effective levels.

16. 10. The method of claim 1, wherein said oral administration comprises a feeding frequency selected from the group consisting of at least three times per week, substantially daily, and daily.

17. A food selected from the group consisting of dry food and wet food; and A mammalian food or chew comprising at least one spinosyn.

18. The bait or chew of claim 17, wherein the spinosyn is present in an amount of about 0.005% to 2% by weight of the bait or chew.

19. The feed or chew of claim 17, wherein the spinosyn in the feed or chew is administered to the mammal in an amount of about 0.625 mg / kg to 10 mg / kg of the weight of the mammal.

20. The bait or chew of claim 17, wherein the spinosyn is spinosad.

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