Feeds and methods for controlling intestinal parasitic infections in mammals

Abstract

An oral animal feed and method for preventing and / or controlling parasites in a mammal in need of treatment by orally administering to a mammal, such as a canid, a feed or composition containing an effective amount of an anthelmintic drug, delivered daily or substantially daily, for an effective time to control parasites, thereby increasing and maintaining the amount of anthelmintic drug in the mammal's digestive tract to a therapeutically effective level.

Description

Related Applications

[0001] Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 407,146, filed September 15, 2022, which is incorporated herein by reference. [Technical Field]

[0002] FIELD OF THE DISCLOSURE

[0002] The teachings of the present disclosure relate generally to methods of administering active agents for controlling parasites in mammals. [Background technology]

[0003]

[0003] There are five main types of parasites, or helminths, that commonly infect domestic dogs and other mammals: ascarid worms, tapeworms, hookworms, whipworms, and heartworms. Helminths can cause serious health problems, including gastrointestinal problems, abdominal pain, weight loss, dehydration, anemia, and pneumonia, and in severe cases, can be fatal. Some of these intestinal helminth species are of zoonotic importance because they cause disease in humans. Therefore, it is essential that pet dogs and cats receive proper veterinary care, including treatment to prevent or treat infections with these various helminth parasites.

[0004]

[0004] Currently available treatments for controlling helminth infections in animals are known to have varying degrees of success. For example, in dogs and cats, problems contributing to ineffective parasite control include inadequate oral dosing, which can lead to further anthelmintic resistance, and vomiting caused by the high doses required for some anthelmintics to be effective. Summary of the Invention

[0005] Embodiment 1: A medicated animal feed for controlling intestinal helminths in a mammal, comprising: livestock feed; and (i) disrupt the cellular integrity of intestinal helminths and are selected from the group consisting of benzimidazoles, salicylanilides, and substituted phenols; and / or (ii) containing a dose of at least one anthelmintic drug that causes paralysis in intestinal helminths and is selected from the group consisting of tetrahydropyrimidines, emodepside, and monepantel; A medicated animal feed wherein at least one anthelmintic is an integral part of the medicated animal feed, and wherein the effective time for achieving a therapeutically effective level of the anthelmintic in the mammal's digestive tract is selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days, when the medicated animal feed is administered to the mammal daily or substantially daily.

[0006]

[0006] Embodiment 2: A medicated animal feed described in embodiment 1, wherein the livestock feed is selected from the group consisting of pet food, wet food, reward treats, and snacks.

[0007] Embodiment 3: A medicated animal feed according to embodiment 1 or 2, suitable for feeding to a mammal daily or substantially daily for said period.

[0007]

[0008] Embodiment 4: A medicated animal feed according to any one of embodiments 1 to 3, wherein the mammal is selected from the group consisting of canines and felines.

[0009] Embodiment 5: A medicated animal feed according to any one of embodiments 1 to 4, wherein the mammal is a dog.

[0008]

[0010] Embodiment 6: A medicated animal feed according to any one of embodiments 1 to 4, wherein the mammal is a cat.

[0011] Embodiment 7: A medicated animal feed according to any one of embodiments 1 to 6, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

[0009]

[0012] Embodiment 8: A medicated animal feed according to any one of embodiments 1 to 7, which reduces the intestinal helminth count in the mammal by at least 50%, at least 75%, at least 80%, at least 88%, at least 95%, or up to 100% compared to a mammal not administered the medicated feed.

[0010]

[0013] Embodiment 9: A medicated animal feed according to any one of embodiments 1 to 8, which protects the mammal from intestinal helminths for at least 7 days after the last administration of the medicated feed.

[0014] Embodiment 10: A medicated animal feed according to any one of embodiments 1 to 9, wherein the anthelmintic is pyrantel or a therapeutically acceptable derivative, salt, or metabolite thereof, and wherein the amount of pyrantel in the medicated feed is such that, when multiple administrations are given to the mammal within a period of about 30 days, the total therapeutic dose of pyrantel does not exceed about 50.0 mg of pyrantel per kg of body weight (mg / kg) of the mammal.

[0011]

[0015] Embodiment 11: A medicated animal feed according to embodiment 10, wherein the anthelmintic is pyrantel pamoate.

[0016] Embodiment 12: A medicated animal feed according to embodiment 10 or 11, wherein the daily amount of pyrantel in the medicated feed is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 1.0 mg / kg.

[0012]

[0017] Embodiment 13: A medicated animal feed according to any one of embodiments 10 to 12, wherein the cumulative dose of pyrantel administered to the mammal over a 30 day period is selected from the group consisting of about 3 mg / kg, about 7.5 mg / kg, about 15 mg / kg and about 30 mg / kg.

[0013]

[0018] Embodiment 14: A medicated animal feed according to any one of embodiments 1 to 9, wherein the anthelmintic is monepantel or a therapeutically acceptable derivative, salt, or metabolite thereof, and wherein the amount of monepantel in the medicated feed is such that, when multiple administrations are given to the mammal within a period of about 30 days, the total therapeutic dose of monepantel does not exceed about 25.0 mg of monepantel per kg of body weight of the mammal (mg / kg).

[0014]

[0019] Embodiment 15: A medicated animal feed according to embodiment 14, wherein the daily amount of monepantel in the medicated feed is selected from the group consisting of about 0.05 mg / kg, about 0.125 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 0.83 mg / kg.

[0015]

[0020] Embodiment 16: A medicated animal feed according to embodiment 14 or 15, wherein the cumulative dose of monepantel administered to the mammal over a 30 day period is selected from the group consisting of about 1.5 mg / kg, about 3.75 mg / kg, about 7.5 mg / kg and about 25.0 mg / kg.

[0016]

[0021] Embodiment 17: A medicated animal feed according to any one of embodiments 1 to 8, wherein the anthelmintic in the medicated feed that disrupts the cellular integrity of intestinal helminths is a benzimidazole.

[0022] Embodiment 18: A medicated animal feed according to embodiment 17, wherein the anthelmintic is fenbendazole or a therapeutically acceptable derivative, salt, or metabolite thereof, and wherein the amount of fenbendazole in the medicated feed is such that, when multiple doses are administered to the mammal within a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg of fenbendazole per kilogram of body weight of the mammal (mg / kg).

[0017]

[0023] Embodiment 19: A medicated animal feed according to embodiment 18, wherein the daily amount of fenbendazole in the medicated feed is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, and about 10 mg / kg.

[0018]

[0024] Embodiment 20: The medicated animal feed of embodiment 19, wherein the cumulative dose of fenbendazole administered to the mammal over 30 days is selected from the group consisting of about 3.0 mg / kg, about 7.5 mg / kg, about 15.0 mg / kg, about 30.0 mg / kg, about 75.0 mg / kg, about 150.0 mg / kg and about 300.0 mg / kg.

[0019]

[0025] Embodiment 21: A medicated animal feed according to any one of embodiments 1 to 20, further comprising a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt, or metabolite thereof.

[0020]

[0026] Embodiment 22: A method for controlling intestinal helminths in a mammal, comprising: providing a medicated feed according to any one of embodiments 1 to 21; administering said feed to the mammal daily or substantially daily.

[0021]

[0027] Embodiment 23: The method of embodiment 22, wherein the mammal is selected from the group consisting of canines and felines.

[0028] Embodiment 24: The method of embodiment 22 or 23, wherein the mammal is a dog.

[0022]

[0029] Embodiment 25: The method of any one of embodiments 22 to 24, wherein the mammal is a cat.

[0030] Embodiment 26: The method of any one of embodiments 22 to 25, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

[0023]

[0031] Embodiment 27: The method of any one of embodiments 22 to 26, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

[0024]

[0032] Embodiment 28: A composition for controlling intestinal helminths in a mammal, comprising: (i) disrupt the cellular integrity of intestinal helminths and are selected from the group consisting of benzimidazoles, salicylanilides, and substituted phenols; and / or (ii) containing at least one anthelmintic drug that causes paralysis in intestinal helminths and is selected from the group consisting of tetrahydropyrimidines, emodepside, and monepantel; The composition, when administered daily or substantially daily to a mammal, has a time period effective to achieve a therapeutically effective level of the anthelmintic in the gastrointestinal tract of the mammal selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

[0025]

[0033] Embodiment 29: The composition of embodiment 28, selected from the group consisting of pet food, wet feed, tablets, capsules, suspensions, solutions, ointments, pastes, reward treats, and snacks.

[0026]

[0034] Embodiment 30: The composition of embodiment 28 or 29, which is suitable for daily or substantially daily administration to a mammal over that period of time.

[0035] Embodiment 31: The composition of any one of embodiments 28 to 30, wherein the mammal is selected from the group consisting of canines and felines.

[0027]

[0036] Embodiment 32: The composition of any one of embodiments 28 to 31, wherein the mammal is a dog.

[0037] Embodiment 33: The composition of any one of embodiments 28 to 31, wherein the mammal is a cat.

[0028]

[0038] Embodiment 34: The composition of any one of embodiments 28 to 33, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

[0029]

[0039] Embodiment 35: The composition of any one of embodiments 28 to 34, which reduces the intestinal helminth count in a mammal by at least 50%, at least 75%, at least 80%, at least 88%, at least 95%, or 100% compared to a mammal not administered the composition.

[0030]

[0040] Embodiment 36: The composition of any one of embodiments 28 to 35, which protects a mammal against intestinal helminths for at least 7 days after the last administration.

[0041] Embodiment 37: The composition of any one of embodiments 28 to 36, wherein the anthelmintic is pyrantel or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of pyrantel in the composition is such that, when multiple administrations are administered to the mammal within a period of about 30 days, the total therapeutic dose of pyrantel does not exceed about 50.0 mg of pyrantel per kg of body weight (mg / kg) of the mammal.

[0031]

[0042] Embodiment 38: The composition of embodiment 37, wherein the anthelmintic is pyrantel pamoate.

[0043] Embodiment 39: The composition of embodiment 37 or 38, wherein the daily amount of pyrantel in the medicated feed is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 1.0 mg / kg.

[0032]

[0044] Embodiment 40: The composition of any one of embodiments 37 to 39, wherein the cumulative dose of pyrantel administered to the mammal over 30 days is selected from the group consisting of about 3.0 mg / kg, about 7.5 mg / kg, about 15 mg / kg, and about 30 mg / kg.

[0033]

[0045] Embodiment 41: A composition described in any one of embodiments 28 to 36, wherein the anthelmintic is monepantel or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of monepantel in the composition is such that when multiple administrations are given to a mammal within a period of about 30 days, the total therapeutic dose of monepantel does not exceed about 25.0 mg of monepantel per kg of body weight of the mammal (mg / kg).

[0034]

[0046] Embodiment 42: The composition of embodiment 41, wherein the daily amount of monepantel in the composition is selected from the group consisting of about 0.05 mg / kg, about 0.125 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 0.83 mg / kg.

[0035]

[0047] Embodiment 43: The composition of embodiment 41 or 42, wherein the cumulative dose of monepantel administered to the mammal over a 30 day period is selected from the group consisting of about 1.5 mg / kg, about 3.75 mg / kg, about 7.5 mg / kg, about 15 mg / kg and about 25.0 mg / kg.

[0036]

[0048] Embodiment 44: A composition according to any one of embodiments 28 to 36, wherein the anthelmintic in the composition that disrupts the cellular integrity of intestinal helminths is a benzimidazole.

[0049] Embodiment 45: The composition of embodiment 44, wherein the anthelmintic is fenbendazole or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of fenbendazole in the composition is such that, when multiple administrations are administered to the mammal within a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg of fenbendazole per kilogram of body weight of the mammal (mg / kg).

[0037]

[0050] Embodiment 46: The composition of embodiment 45, wherein the daily amount of fenbendazole in the composition is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, and about 10 mg / kg.

[0038]

[0051] Embodiment 47: The composition of embodiment 45 or 46, wherein the cumulative dose of fenbendazole administered to the mammal over 30 days is selected from the group consisting of about 3.0 mg / kg, about 7.5 mg / kg, about 15.0 mg / kg, about 30.0 mg / kg, about 75.0 mg / kg, about 150.0 mg / kg and 300.0 mg / kg.

[0039]

[0052] Embodiment 48: The composition of any one of embodiments 1 to 20, further comprising a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt, or metabolite thereof.

[0040]

[0053] Embodiment 49: A method for controlling intestinal helminths in a mammal, comprising: providing a composition according to any one of embodiments 28 to 48; A method comprising the step of administering said composition daily or substantially daily to a mammal.

[0041]

[0054] Embodiment 50: The method of embodiment 49, wherein the mammal is selected from the group consisting of canines and felines.

[0055] Embodiment 51: The method of embodiment 49 or 50, wherein the mammal is a dog.

[0042]

[0056] Embodiment 52: The method of any one of embodiments 49 to 51, wherein the mammal is a cat.

[0057] Embodiment 53: The method of any one of embodiments 49 to 52, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

[0043]

[0058] Embodiment 54: The method of any one of embodiments 49 to 53, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the composition is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

[0044]

[0059] Embodiment 55: A medicated feed according to any one of embodiments 1 to 21 for use in a method for controlling intestinal helminths in a mammal, wherein the method comprises: providing a medicated feed; administering said feed daily or substantially daily to a mammal.

[0045]

[0060] Embodiment 56: A medicated feed for use in the method of embodiment 55, wherein the mammal is selected from the group consisting of canines and felines.

[0061] Embodiment 57: A medicated feed for use in the method of embodiment 55 or 56, wherein the mammal is a dog.

[0046]

[0062] Embodiment 58: A medicated feed for use in the method of embodiment 55 or 56, wherein the mammal is a cat.

[0063] Embodiment 59: A medicated feed for use in the method of any one of embodiments 55 to 58, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipylidium spp., and Hydatid spp.

[0047]

[0064] Embodiment 60: The medicated animal feed for use in the method of any one of embodiments 55 to 59, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

[0048]

[0065] Embodiment 61: A composition according to any one of embodiments 28 to 48, for use in a method for controlling intestinal helminths in a mammal, wherein the method comprises: providing a composition; A composition comprising administering said composition daily or substantially daily to a mammal.

[0049]

[0066] Embodiment 62: A composition for use in the method of embodiment 61, wherein the mammal is selected from the group consisting of canines and felines.

[0067] Embodiment 63: A composition for use in the method of embodiment 61 or 62, wherein the mammal is a dog.

[0050]

[0068] Embodiment 64: A composition for use in the method of embodiment 61 or 62, wherein the mammal is a cat.

[0069] Embodiment 65: A composition for use in the method of any one of embodiments 61 to 64, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipylidium spp., and Hydatid spp.

[0051]

[0070] Embodiment 66: The composition for use in the method of any one of embodiments 61 to 65, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, it is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days. [Brief explanation of the drawings]

[0052] [Figure 1]

[0071] 1 is a bar graph showing percent efficacy, calculated as [parasite egg count in AM feces (control) - parasite egg count in AM feces (treated)] / parasite egg count in AM feces (control), 16, 19, 22, 25, 28, or 30 days after initial treatment with one of the following: 0.5 mg / kg pyrantel pamoate (horizontal stripes), 1.0 mg / kg pyrantel pamoate (right diagonal stripes), 5 mg / kg fenbendazole (small spots), and 10 mg / kg fenbendazole (vertical stripes). [Figure 2]

[0072] FIG. 1 is a bar graph showing percent efficacy, calculated as [AM fecal parasite egg count (control) - AM fecal parasite egg count (treated)] / AM fecal parasite egg count (control), 40, 45, 50, 52, or 60 days after initial treatment with one of the following: 0.25 mg / kg pyrantel pamoate (horizontal stripes), 0.5 mg / kg pyrantel pamoate (right diagonal stripes), 1.0 mg / kg pyrantel pamoate (small spots), 2.5 mg / kg fenbendazole (vertical stripes), 5 mg / kg fenbendazole (solid), or 10 mg / kg fenbendazole (left diagonal stripes). DETAILED DESCRIPTION OF THE INVENTION

[0053]

[0073] Surprisingly, the present disclosure teaches that in some cases, oral treatment with some anthelmintics can improve control of parasitic infections in mammals when the anthelmintic is orally administered to the mammal at smaller, more frequent / chronic doses than currently documented doses for monthly or quarterly administration. In some embodiments, administration is integrated with the feed, as discussed below. However, it is also anticipated that the anthelmintic can be administered by itself or in a form other than an integral part of the feed, such as a chew, tablet, liquid, gel, or other suitable form for oral administration. In some cases, using smaller, more frequent doses advantageously reduces the total amount of anthelmintic needed to control a parasitic infection over the same period of time.

[0054]

[0074] Advantageously, the total amount of anthelmintic required for a monthly therapeutically effective dose can be reduced by as much as 80 percent for some anthelmintics by switching to daily dosing. From a practical standpoint, formulating a medical feed product presents at least two problems: (1) creating a homogeneous feed; and (2) analytical control tests can be difficult to perform when testing is required for very small amounts of the more potent anthelmintic. The analytical matrix derived from the feed can be quite complex and difficult to assay. Assays can range from parts per million to parts per billion for some required doses and feed concentrations. Thus, one skilled in the art could choose to increase the daily dose of the more potent anthelmintic so that the total amount per day for a month is equal to the monthly dose of the prior art, or even higher, e.g., 200% of the monthly dose of the prior art. This can help ensure homogeneity and improve assay precision and reduce analytical variability when administered as part of the feed while still providing a net therapeutic dose several times less than the currently recommended monthly therapeutic dose.

[0055]

[0075] The method and composition taught herein has the additional advantage of promoting compliance, since a smaller amount of anthelmintic drug can be incorporated into the formulation administered as feed or chew treats, tablets, liquids, gels, or other suitable forms for oral administration.In some embodiments, a daily dose of anthelmintic drug is added.In either case, the owner naturally follows the daily feeding regimen, which reduces the possibility that the owner will forget or neglect to administer the anthelmintic drug.Therefore, the present disclosure provides a method for long-term parasite control in a safer and more effective manner than that achieved by known treatment methodologies.All the owner needs to remember is to feed their pet every day as usual and simultaneously add a daily dose of anthelmintic drug as described in this embodiment.

[0056]

[0076] Some classes of anthelmintic active compounds include macrocyclic lactones, such as abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole sulfoxide, cambindazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, triclabendazole, and the like; cyclooctadepsipeptides, such as emodepside, PF1022, and the like; aminoacetonitrile derivatives, such as monepantel, and the like; tetrahydropyrimidines, such as morantel, pyrantel, oxantel, and the like; imidazothiazoles, such as butamisole, lecithin, and the like. vamisole, tetramisole, etc.; salicylanilides, such as bromoxanide, brothianide, crioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, etc.; paraherquamides, such as delquantel, paraherquamide, etc.; aminophenylamidines, such as amidantel, deacylated amidantel (dAMD), tribendimidine, etc.; organophosphates, such as coumaphos, crufomate, dichlorvos, haloxone, naphthalofos, trichlorfon, etc.; substituted phenols, such as bithionol, disophenol, hexachlorophene, niclofolan, meniclofolan, nitroxynil, etc.; piperazinones, such as praziquantel, epsiprantel, etc.;and other classes including amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetid, dichlorophen, diethylcarbamazine, emetine, hetolin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omphalotin, oxamniquine, paromomycin, piperazine, and rezolantel;

[0057]

[0077] Anthelmintics that are particularly important in controlling parasitic infections as described in some embodiments of the present invention in mammals are benzimidazoles and aminoacetonitrile derivatives.

[0058]

[0078] Some benzimidazoles are anthelmintics that disrupt the cellular integrity of helminths. Benzimidazoles are bicyclic compounds with a fused ring of aromatic benzene and imidazole. An example of a benzimidazole is fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl)carbamate), shown below.

[0059] [ka]

[0060]

[0079] Pyrantel, a member of the tetrahydropyrimidine family of compounds, and its various salt forms are known veterinary anthelmintics that are also used in human medicine. Pyrantel pamoate, an example of a tetrahydropyrimidine, has been reported to have a mechanism of action involving nicotinic acetylcholine receptors, which are putative targets in several helminths.

[0061] [ka]

[0062]

[0080] Aminoacetonitrile derivatives, such as monepantel (N-[(2S)-2-cyano-1-[5-cyano-2-(trifluoromethyl)phenoxy]propan-2-yl]-4-(trifluoromethylsulfanyl)benzamide), are believed to act by interfering with parasite muscle function. Monepantel, its salts, derivatives, metabolites, and any of its biologically active enantiomers are aminoacetonitriles that may be suitable for use according to the present disclosure.

[0063] [ka]

[0064]

[0081] More particularly, anthelmintics with half-lives of at least about 1 day are particularly well suited for the methods and formulations of the present disclosure.

[0082] The formulations, feeds, and methods of the present disclosure can further include one or more other active pharmaceutical ingredients with therapeutic efficacy in combination with the anthelmintic. Such active agents include agents effective against parasites and / or related organisms that carry the parasites. Active agents can include, for example, praziquantel, isoxazolines, foramidines, spinosyns, macrocyclic lactones, and insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones).

[0065]

[0083] For example, praziquantel (2-(cyclohexanecarbonyl)-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one), shown below, or a therapeutically acceptable salt, metabolite, or derivative thereof, may be included in the formulations and compositions of the present invention.

[0066] [ka]

[0067]

[0084] The method of the present disclosure is carried out by administering small, frequent doses of an anthelmintic to a mammal. To facilitate routine dosing, the anthelmintic can be administered via feed or chew treats. Many different feeds are contemplated, provided that the manufacturing process and feed composition do not have adverse effects on the anthelmintic and, if applicable, other active substances in terms of chemical stability, efficacy, and safety. For example, feeds and snacks in the broad categories of dry feed, semi-moist feed, or canned-refrigerated feed, chew treats, reward treats, or supplemental feeds can be adapted for use according to the present disclosure. The mammal is administered a maintenance dose of the anthelmintic by consuming the feed product weekly, twice a week, or daily.

[0068]

[0085] By incorporating smaller amounts of anthelmintic into animal feed compositions and administering them at an effective rate (most preferably daily), the level of anthelmintic in the mammal's gastrointestinal tract can be maintained at a level effective for treating and preventing further parasitic infections. On the other hand, if the anthelmintic is orally administered in infrequent large doses, for example, administered only once as a single therapeutic treatment, the level of anthelmintic in the gastrointestinal tract may be sufficient to treat active infection but may not be effective for preventing subsequent infections. As disclosed herein, multiple small doses administered over a period of time are at least as effective as large doses administered in a single treatment, which constitute the current standard of care for treating parasitic infections in the gastrointestinal tract. Surprisingly, the cumulative dose of anthelmintic administered in multiple small doses is substantially lower, but is no less effective than a single large dose administered infrequently, for example, once a month.

[0069]

[0086] All ratios, percentages and parts discussed herein are "weight ratios," "weight percents" and "weight parts," respectively, unless otherwise specified.

[0087] Doses formulated for daily administration may include tablets, capsules, ointments, liquids, and pastes.

[0070]

[0088] The terms "controlling a parasitic infection" and "controlling a helminth infection" refer to the prevention, treatment, minimization or elimination of a parasitic or helminth infection in a mammal.

[0089] The term "controlling a parasitic infection" refers to the prevention, treatment, minimization or elimination of an infection by a parasite in a mammal.

[0071]

[0090] The terms "parasite" and "helminth" are used interchangeably to refer to members of the phyla Annelida, Platyhelminthes, Nematoda, and Acanthocephalina. The terms "parasite" and "helminth" include egg, larval, and adult developmental stages. For example, "parasites" or "helminths" include, but are not limited to, Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Ancylostoma braziliensis, Uncinaria stenocephala, Trichuris vulpis, Toxocara cati, Ancylostoma tubaeforme, Cestodes spp., Dipylidium spp., and Hydatid spp.

[0072]

[0091] The term "canid" refers to any member of the genus Canis, which includes species such as wolves, dogs, coyotes, and jackals.

[0092] The term "feline" refers to any member of the subfamily Felinae, and includes species such as the domestic cat, bobcat, wildcat, ocelot, members of the lynx genus, Pallas's cat, and cougar.

[0073]

[0093] In practicing the methods of the present disclosure, a "feed" refers to an animal feed, snack, reward treat, or other nutritional supplement that can be administered daily or substantially daily. By using different forms of feed, such as kibble and reward treats, pet owners can vary the mammal's diet and snacks from time to time while conveniently administering the daily dose of anthelmintic drug.

[0074]

[0094] The term "chew treat" refers to a reward treat that typically has flavor and aroma characteristics that are appealing to mammals, but generally lacks nutritional value. In practicing the methods of the present disclosure, "food" and / or "chew treat" may be used interchangeably.

[0075]

[0095] For purposes of this disclosure, the term "effective time," also referred to herein as "effective duration," includes at least the period of administration of the feed necessary to achieve a level of the anthelmintic in the mammalian gastrointestinal tract high enough to control the parasite, i.e., a "therapeutically effective" level. In some embodiments, the effective time can be as short as three days. In other cases, the effective time can be seven days, or fifteen days, or longer. As discussed below, the effective time will vary depending on how frequently the feed or anthelmintic is administered.

[0076]

[0096] As previously mentioned, "effective time" varies as a function of the frequency with which the feed is administered. As used herein, the term "effective frequency" refers to the number of feedings over a given period of time that will result in a therapeutically effective concentration of the anthelmintic drug in the mammal's gastrointestinal tract. In any case, as used herein, the term "effective frequency" contemplates multiple feedings per month that contain the anthelmintic drug. Those skilled in the art will understand that the anthelmintic drug can be administered at various frequencies. For example, the anthelmintic drug may be administered daily, every other day, every three days, once a week, or at irregular intervals.

[0077]

[0097] Furthermore, as discussed above, the frequency of effectiveness can affect the period of time required to achieve therapeutically effective levels of the anthelmintic in the mammal's gastrointestinal tract. For example, if a mammal is fed the anthelmintic composition daily, the period of feed administration required to achieve therapeutically effective levels of the anthelmintic in the mammal's gastrointestinal tract, and therefore the "effective time," will be relatively shorter than if the mammal were fed the anthelmintic composition only once or twice a week.

[0078]

[0098] Furthermore, the frequency of effectiveness is affected by the daily dose (mg / kg mammalian body weight), and missed doses have less impact on effectiveness, especially at slightly higher daily doses.

[0079]

[0099] Furthermore, the effective frequency is affected by the duration of treatment: for example, in the early stages before therapeutically effective levels of anthelmintic drug are reached in the mammal's gastrointestinal tract, the animal feed may need to be administered more frequently than is required after longer periods of use, i.e., after therapeutically effective levels are achieved.

[0080]

[0100] For purposes of this disclosure, "substantially daily" means sufficiently regularly that the concentration of the anthelmintic drug in the mammal's gastrointestinal tract rises to and is maintained at a therapeutically effective level. For example, a disclosed daily feed composition can preferably be given to a mammal daily indefinitely. However, as a practical matter, there are many reasons why doses may be periodically missed or omitted. For example, a mammal may become ill, or an owner may use up a day's supply of the medicated feed composition. The disclosed methods are robust enough to provide some degree of parasite protection to a mammal even with occasional interruptions in the daily feeding of the medicated animal feed composition. In practicing the methods of the present 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 three times per week, every other day, or daily, qualify as substantially daily if they facilitate the anthelmintic drug to reach and be maintained at a therapeutically effective level in the mammal's gastrointestinal tract.

[0081]

[0101] The term "therapeutically effective" means that the dose of the anthelmintic drug or its physiologically acceptable derivative or metabolite thereof is sufficient to control the helminth infection better than in the absence of the drug. The anthelmintic drug or its physiologically acceptable derivative or metabolite thereof may be naturally occurring or may be present together with one or more additional active substances. Preferably, the helminth infection is controlled by at least about 50% better than in the absence of the drug, and more preferably, the helminth infection is controlled by at least about 90% better than in the absence of the drug.

[0082]

[0102] In carrying out the method of the present disclosure, an effective amount or a therapeutically effective amount of an anthelmintic drug is orally administered to a mammal. The term "effective amount" or "therapeutically effective amount" refers to the amount necessary to control helminth infection. As can be understood by those skilled in the art, this amount will vary depending on many factors. These factors include, for example, the type and weight and general health of the mammal being treated.

[0083]

[0103] Anthelmintics vary in potency. Accordingly, an effective amount of an anthelmintic can be calculated for each particular anthelmintic used in some of the methods of the present disclosure. Generally, an effective daily dose of an anthelmintic can range from about 12.5% ​​to 90% of the approved label dose of the anthelmintic divided by the length of the dosing / retreatment interval (e.g., for a monthly product, the dose divided by 30). Those skilled in the art will recognize that higher doses, e.g., 90% to 200% of the approved label dose of the anthelmintic, can be selected for reasons including, but not limited to, ease of manufacturability, testing, and analysis. In some cases, the particular dose selected can be sufficient to raise the concentration of the anthelmintic in the mammalian gastrointestinal tract to a therapeutically effective level within about 7 days of substantially daily administration, more preferably within about 5 days of substantially daily administration, and most preferably within about 3 days of substantially daily administration.

[0084]

[0104] This disclosure describes the concentration of the anthelmintic in relation to feed, such as pet food, and also contemplates administration using other dosage forms, such as reward treats or chew treats. It is also contemplated that the anthelmintic may be administered by itself or in a tablet, liquid, gel, or other suitable form for oral administration. Those skilled in the art will understand that the concentration of the anthelmintic will vary depending on the particular dosage form. For example, if the animal feed is the reward treat, the concentration of the anthelmintic in the reward treat will be higher than the concentration of the anthelmintic in, for example, pet food. For example, if the daily dose of the anthelmintic relative to the mammal's body weight is 10 mg, a typical 5 g reward treat may contain about 0.002 percent anthelmintic (by weight). As the amount of pet food consumed per day exceeds 5 g, the percentage of the anthelmintic in the pet food will be smaller.

[0085]

[0105] For example, an effective amount of pyrantel pamoate can be a daily or substantially daily amount of about 0.1 to about 1.0 mg of pyrantel pamoate per kg of mammalian body weight. Alternatively, an effective amount of pyrantel pamoate can be a daily or substantially daily amount of about 0.1 to about 0.5 mg of pyrantel pamoate per kg of mammalian body weight. Alternatively, an effective amount of pyrantel pamoate can be a daily or substantially daily amount of about 0.25 to about 0.5 mg of pyrantel pamoate per kg of mammalian body weight. Alternatively, an effective amount of pyrantel pamoate can be a daily or substantially daily amount of about 0.1 to about 0.25 mg of pyrantel pamoate per kg of mammalian body weight.

[0086]

[0106] Animal feed typically contains about 0.0001 to about 0.09 weight percent pyrantel pamoate in the feed. Preferably, the pyrantel pamoate content in the feed is between about 0.0005 to about 0.06 weight percent. Most preferably, the content of one or more pyrantel pamoate components in the feed is between about 0.0009 to about 0.03 weight percent.

[0087]

[0107] In another example, an effective amount of fenbendazole can be a daily or substantially daily amount of about 0.5 to about 10.0 mg of fenbendazole per kg of mammalian body weight. Alternatively, an effective amount of fenbendazole can be a daily or substantially daily amount of about 1.0 to about 5.0 mg of fenbendazole per kg of mammalian body weight. Alternatively, an effective amount of fenbendazole can be a daily or substantially daily amount of about 2.5 to about 5.0 mg of fenbendazole per kg of mammalian body weight. Alternatively, an effective amount of fenbendazole can be a daily or substantially daily amount of about 0.5 to about 2.5 mg of fenbendazole per kg of mammalian body weight.

[0088]

[0108] Animal feed typically contains about 0.001 to about 0.12 percent fenbendazole by weight. Preferably, the fenbendazole content in the feed is between about 0.003 and about 0.09 percent by weight. Most preferably, the fenbendazole content in the feed is between about 0.008 and about 0.05 percent by weight.

[0089]

[0109] In another example, an effective amount of monepantel can be a daily or substantially daily amount of about 0.05 to about 0.83 mg of monepantel per kg of mammalian body weight. Alternatively, an effective amount of monepantel can be a daily or substantially daily amount of about 0.05 to about 0.5 mg of monepantel per kg of mammalian body weight. Alternatively, an effective amount of monepantel can be a daily or substantially daily amount of about 0.125 to about 0.5 mg of monepantel per kg of mammalian body weight. Alternatively, an effective amount of monepantel can be a daily or substantially daily amount of about 0.125 to about 0.25 mg of monepantel per kg of mammalian body weight.

[0090]

[0110] Animal feed typically contains about 0.00005 to about 0.0001 percent by weight of monepantel in the feed. Preferably, the monepantel content in the feed is between about 0.0001 and about 0.005 percent by weight. Most preferably, the monepantel content in the feed is between about 0.0005 and about 0.001 percent by weight.

[0091]

[0111] In one aspect, the present disclosure relates to a method of controlling parasitic infections in a mammal by administering a systemically active oral composition comprising an anthelmintic, or a physiologically acceptable derivative or salt thereof, and animal feed at least once a week, more preferably three times a week, and most preferably substantially daily.

[0092]

[0112] In another aspect, the present disclosure relates to a systemically active oral composition comprising an anthelmintic and an animal feed.

[0113] The present disclosure also relates to the use of an anthelmintic drug for the manufacture of animal feed for controlling parasitic infections in mammals.

[0093]

[0114] The present disclosure also relates to a method for long-term control of parasitic infections in a mammal, comprising orally administering to the mammal a daily or substantially daily amount of an effective amount of an anthelmintic drug in a daily feed. A daily feed is a feed intended to be administered daily, but which can be administered at an effective time, as described herein. The method comprises orally administering to the mammal an effective amount of an anthelmintic drug in a substantially daily amount, and is particularly useful for long-term control of parasites in a mammal.

[0094]

[0115] One aspect of the present disclosure is the oral administration of an amount of an anthelmintic drug that is ineffective or suboptimal for controlling parasitic infection in mammals when administered at longer intervals, such as once a month. However, as described herein, effective control of parasitic infection is achieved by repeated administration at shorter intervals, for example, substantially daily. By ineffective or suboptimal, we mean that a single administration as well as several administrations reduces parasitic infestation by less than 50%, including no reduction or substantial reduction compared to no administration of the drug at all. This reflects the chronic administration aspect, rather than the acute administration aspect, disclosed herein.

[0095]

[0116] In a first embodiment, a method for controlling parasites in a mammal by orally administering to the mammal a daily feed containing an effective amount of an anthelmintic drug for an effective period of time is disclosed.

[0096]

[0117] In a second embodiment, an anthelmintic drug is disclosed for use in controlling parasites in a mammal in need thereof. The anthelmintic drug may be present in an effective amount in a daily feed, the daily feed being administered to the mammal at an effective time to control the parasites.

[0097]

[0118] In a third embodiment, a daily feed for controlling parasites in a mammal is disclosed, the daily feed comprising an effective amount of an anthelmintic drug when administered at an effective time.

[0098]

[0119] In any aspect of the embodiment, the mammal can be a canine. More particularly, the canine can be a wolf, coyote, or dog.

[0120] In any aspect of the embodiment, the mammal can be a feline. More particularly, the feline can be a domestic cat, a bobcat, an ocelot, a member of the genus Lynx, a Pallas's cat, or a cougar.

[0099]

[0121] In any aspect of the various embodiments, the anthelmintic may be fenbendazole and / or pyrantel pamoate and / or monepantel, salts thereof, or mixtures thereof. In some aspects, other additional anthelmintic drugs may be included in the compositions and / or medicated feeds of the present invention.

[0100] Example

[0122] The following non-limiting examples illustrate some of the methods of the present disclosure. [Example]

[0101]

[0123] Efficacy of pyrantel pamoate and fenbendazole administered orally, i.e., via the mouth, to dogs for the treatment and control of canine hookworm.

[0124] Methods: A preliminary study of a group of 22 dogs is required to confirm suitability for this study. Dogs must be within the normal weight range for their breed, in good health with no history of serious illness, and not pregnant or lactating. A fecal examination can be performed between days -7 and -3 to confirm the absence of pre-existing infection with Nematode species. Dogs exposed to anthelmintics within the 30 days prior to day -7 will be excluded.

[0102]

[0125] Dogs are weighed on day -2 and randomized by weight into one of five treatment groups.

[0126] Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on Day 0. Dogs are then housed individually. Dogs should be fed a standard commercial dog food at the recommended rate and have free access to drinking water.

[0103]

[0127] A liquid formulation of anthelmintic will be administered orally to each dog in the treatment group (test groups 2-5). Each dog will be administered a dose on days 0-22 according to the test group shown in Table 1.

[0104] [Table 1]

[0105] *The selected doses represent 10% and 20% of the therapeutic doses of pyrantel pamoate (approximately 5 milligrams per kilogram (mg / kg) of mammalian body weight) and fenbendazole (approximately 50 milligrams per kilogram (mg / kg) of mammalian body weight) respectively, according to existing marketed drug labeling, for treating dogs with adult intestinal nematode infections. Current industry practice is to administer 50 mg / kg of fenbendazole in three divided doses over three days for the treatment of mammals with intestinal helminths; the current standard of care provides a total effective monthly dose of fenbendazole of approximately 150 mg / kg.

[0106]

[0128] Dogs in the control group are not administered any anthelmintic or any other parasite control treatment. The dogs are fasted overnight. Each dog in treatment groups 2-5 is given a fixed portion of dry food each morning, and an individual dose of the liquid formulation is administered after each dog has consumed approximately 25% of that morning's total food intake. After the anthelmintic dose is administered, the dog is allowed to continue eating. In this way, the anthelmintic is mixed in to resemble food.

[0107]

[0129] Dogs are inoculated orally with approximately 300 infective third-stage A. caninum larvae on day 0, approximately 8 hours after the first dose of anthelmintic. Fecal egg counts are performed on days 10, 13, 16, 19, and 22. A 7-day washout period should also be observed from days 23 to 30. During this washout period, fecal egg counts should also be performed on days 25, 28, and 30.

[0108]

[0130] The percent reduction in fecal parasite egg counts for the treatment groups is shown in the graph below. (It should be noted that in the fecal parasite egg counts on days 10 and 13, no parasite eggs were recovered in either group. Therefore, days 10 and 13 are omitted from the chart in Figure 1.) [Example]

[0109]

[0131] Efficacy of pyrantel pamoate and fenbendazole administered orally, i.e., via the mouth, to dogs for the treatment and control of dog roundworms.

[0132] Methods: A preliminary study of a group of 30 dogs is required to confirm suitability for this study. Dogs must be within the normal weight range for their breed, in good health with no history of serious illness, and not pregnant or lactating. On day 6, a fecal examination can be performed to confirm the absence of pre-existing infection with nematode species. Dogs exposed to anthelmintics within the 30 days prior to day 7 will be excluded.

[0110]

[0133] Twenty-eight dogs meeting the eligibility criteria will be weighed on day -1 and randomized by weight to one of seven treatment groups.

[0134] Dogs are housed indoors to promote prevention of naturally occurring parasite infections. Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on Day 0. Dogs are then housed individually. Dogs should be fed a standard commercial dog food at the recommended rate and have free access to water.

[0111]

[0135] A liquid formulation of anthelmintic will be administered orally to each dog in the treatment group (test groups 2-7). A dose will be administered to each dog on days 0-52 according to the test group. See Table 2.

[0112] [Table 2]

[0113]

[0136] Dogs in the control group were not administered any anthelmintic or other parasite control treatment. The dogs were fasted overnight. Each dog in treatment groups 2-7 was given a fixed portion of dry food each morning, and after each dog had consumed approximately 25% of its total food intake that morning, an individual dose of the liquid formulation was administered. After the anthelmintic dose was administered, the dogs were allowed to continue eating. In this way, the anthelmintic was mixed in to resemble food.

[0114]

[0137] Approximately 8 hours after the first dose of anthelmintic drug on day 0, dogs are orally inoculated with approximately 250 T. canis eggs containing infective larvae. Fecal parasite egg counts are performed on days 30, 35, 40, 45, 50, and 52. A 7-day drug-free period should also be observed from day 53 to day 60. Following this, fecal parasite egg counts should be performed on day 60.

[0115]

[0138] The percent reduction in fecal parasite egg counts for the treatment groups is shown in the graph below. (It should be noted that fecal parasite egg counts were not recovered on days 30 and 35.) Days 30 and 35 are omitted from the graph. Additionally, if more eggs were recovered in the fecal counts of a treatment group than in the fecal counts of the control group, efficacy data for that treatment group on that day is not shown in Figure 2. [Example]

[0116]

[0139] Efficacy of monepantel administered orally, i.e., via the mouth, to dogs for the treatment and control of canine hookworm.

[0140] Methods: A preliminary study of a group of 12 dogs is required to confirm suitability for this study. Dogs must be within the normal weight range for their breed, in good health with no history of serious illness, and not pregnant or lactating. A fecal examination can be performed between days -7 and -3 to confirm the absence of pre-existing infection with Nematode species. Dogs exposed to anthelmintics within the 30 days prior to day -7 will be excluded.

[0117]

[0141] Dogs are weighed on day -2 and randomized by weight into one of three treatment groups (control group 1 and treatment group 2).

[0142] Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on Day 0. Dogs are then housed individually. Dogs should be fed a standard commercial dog food at the recommended rate and have free access to drinking water.

[0118]

[0143] Each dog in the treatment group (test groups 2-3) will be administered a liquid formulation of monepantel by mouth. Each dog will be administered a dose according to test group on days 0-22. See Table 3.

[0119] [Table 3]

[0120]

[0144] Dogs in the control group are not administered any anthelmintic or any other parasite control treatment. The dogs are fasted overnight. Each morning, 2-3 dogs in each treatment group are given a fixed portion of dry food, and after each dog has consumed approximately 25% of its total food intake that morning, they are given an individual dose of the liquid formulation. After the anthelmintic dose is administered, the dogs are allowed to continue eating. In this way, the anthelmintic is mixed in to resemble food.

[0121]

[0145] Dogs are inoculated orally with approximately 300 infective third-stage A. caninum larvae on day 0, approximately 8 hours after the first dose of anthelmintic. Fecal egg counts are performed on days 10, 13, 16, 19, and 22. A 7-day washout period should also be observed from days 23 to 30. During this washout period, fecal egg counts should also be performed on days 25, 28, and 30.

[0122]

[0146] The percent reduction in fecal parasite egg counts in the treatment group is expected to reach 100% within approximately two weeks. [Example]

[0123]

[0147] Efficacy of monepantel administered orally, i.e., via the mouth, to dogs for the treatment and control of dog roundworms.

[0148] Methods: A preliminary screening of a group of dogs is required to confirm suitability for this study. Dogs must be within the normal weight range for their breed, in good health with no history of serious illness, and not pregnant or lactating. On day 6, a fecal examination can be performed to confirm the absence of pre-existing infection with nematode species. Dogs exposed to anthelmintics within the 30 days prior to day 7 will be excluded.

[0124]

[0149] Sixteen dogs meeting the eligibility criteria will be weighed on day -1 and randomized by weight to one of four treatment groups (one control group and three treatment groups).

[0150] Dogs are housed indoors to promote prevention of naturally occurring parasite infections. Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on Day 0. Dogs are then housed individually. Dogs should be fed a standard commercial dog food at the recommended rate and have free access to water.

[0125]

[0151] Each dog in each treatment group (test groups 2-4) will be administered a liquid formulation of monepantel by mouth. Each dog will be administered a dose according to test group on days 0-52. See Table 4.

[0126] [Table 4]

[0127]

[0152] Dogs in the control group are not administered any anthelmintic or any other parasite control treatment. The dogs are fasted overnight. Each dog in treatment groups 2-4 is given a fixed portion of dry food each morning, and an individual dose of the liquid formulation is administered after each dog has consumed approximately 25% of that morning's total food intake. After the anthelmintic dose is administered, the dog is allowed to continue eating. In this way, the anthelmintic is mixed in to resemble food.

[0128]

[0153] Approximately 8 hours after the first dose of anthelmintic drug on day 0, dogs are orally inoculated with approximately 250 T. canis eggs containing infective larvae. Fecal parasite egg counts are performed on days 30, 35, 40, 45, 50, and 52. A 7-day drug-free period should also be observed from day 53 to day 60. Following this, fecal parasite egg counts should be performed on day 60.

[0129]

[0154] 100% efficacy is expected across all treatment arms by the end of the study period. [Example]

[0130]

[0155] Efficacy of fenbendazole administered orally, i.e., via the mouth, to dogs for the treatment and control of dog roundworms.

[0156] Methods: A preliminary screening of a population of dogs is required to confirm suitability for this study. Dogs must be within the normal weight range for their breed, in good health with no history of serious illness, and not pregnant or lactating. A fecal examination can be performed between days -6 and -3 to confirm the absence of pre-existing infection with Nematode species. Dogs exposed to anthelmintics within the 30 days prior to day 7 will be excluded.

[0131]

[0157] Twenty dogs meeting the eligibility criteria will be weighed on day -2 or day -1 and randomized by weight to one of five treatment groups (one control group and four treatment groups).

[0132]

[0158] Dogs are housed indoors to promote prevention of naturally occurring parasite infections. Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on Day 0. Dogs are then housed individually. Dogs should be fed a standard commercial dog food at the recommended rate and have free access to water.

[0133]

[0159] A liquid formulation of fenbendazole will be administered orally to each dog in each treatment group (test groups 2-5). Each dog will receive a dose according to test group on days 0-52. See Table 5.

[0134] [Table 5]

[0135]

[0160] Dogs in the control group are not administered any anthelmintic or any other parasite control treatment. The dogs are fasted overnight. Each dog in treatment groups 2-5 is given a fixed portion of dry food each morning, and an individual dose of the liquid formulation is administered after each dog has consumed approximately 25% of that morning's total food intake. After the anthelmintic dose is administered, the dog is allowed to continue eating. In this way, the anthelmintic is mixed in to resemble food.

[0136]

[0161] Dogs are orally inoculated with approximately 250 infective T. canis eggs approximately 8 hours after the first dose of anthelmintic on day 0. Fecal egg counts are performed on days 30, 35, 40, 45, 50, and 53.

[0137]

[0162] By the end of the trial period, 100% efficacy is expected in at least two to four treatment arms.

[0163] While this invention has been described as having an exemplary design, the invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles.

Claims

1. 1. A medicated animal feed for controlling intestinal helminths in a mammal, comprising: livestock feed; and a dose of at least one anthelmintic drug, said at least one anthelmintic drug comprising: (i) disrupt the cellular integrity of intestinal helminths and are selected from the group consisting of benzimidazoles, salicylanilides, and substituted phenols; and / or (ii) causes paralysis in intestinal helminths and is selected from the group consisting of tetrahydropyrimidines, emodepside, and monepantel; 10. A medicated animal feed wherein the at least one anthelmintic is an integral part of the medicated animal feed, and wherein the effective time for achieving a therapeutically effective level of the anthelmintic in the digestive tract of the mammal is selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days, when the medicated animal feed is administered to the mammal daily or substantially daily.

2. 10. The medicated animal feed of claim 1, wherein the livestock feed is selected from the group consisting of pet food, wet food, reward treats, and snacks.

3. 3. A medicated animal feed according to claim 1 or 2, suitable for feeding to a mammal daily or substantially daily for said period.

4. 4. The medicated animal feed of claim 1, wherein the mammal is selected from the group consisting of canines and felines.

5. 5. A medicated animal feed according to any one of claims 1 to 4, wherein the mammal is a dog.

6. 5. The medicated animal feed of claim 1, wherein the mammal is a cat.

7. 7. The medicated animal feed of claim 1, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Cestodes spp., Dipyridium spp., and Hydatid spp.

8. 8. A medicated animal feed according to any one of claims 1 to 7, which reduces the intestinal helminth count in a mammal by at least 50%, at least 75%, at least 80%, at least 88%, at least 95%, or up to 100% compared to a mammal not administered the medicated feed.

9. 9. A medicated animal feed according to any one of claims 1 to 8, which protects a mammal against intestinal helminths for at least 7 days after the last administration of the medicated feed.

10. 10. The medicated animal feed of claim 1, wherein the anthelmintic is pyrantel or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of pyrantel in the medicated feed is such that, when multiple administrations are given to the mammal within a period of about 30 days, the total therapeutic amount of pyrantel does not exceed about 50.0 mg of pyrantel per kg of body weight of the mammal (mg / kg).

11. 11. The medicated animal feed of claim 10, wherein the anthelmintic is pyrantel pamoate.

12. 12. The medicated animal feed of claim 10 or 11, wherein the daily amount of pyrantel in the medicated feed is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 1.0 mg / kg.

13. 13. The medicated animal feed of any one of claims 10 to 12, wherein the cumulative dose of pyrantel administered to the mammal over a 30 day period is selected from the group consisting of about 3 mg / kg, about 7.5 mg / kg, about 15 mg / kg and about 30 mg / kg.

14. 10. A medicated animal feed according to any one of claims 1 to 9, wherein the anthelmintic is monepantel or a therapeutically acceptable derivative, salt or metabolite thereof, and the amount of monepantel in the medicated feed is such that when multiple administrations are given to the mammal within a period of about 30 days, the total therapeutic amount of monepantel does not exceed about 25.0 mg of monepantel per kg of mammal body weight (mg / kg).

15. 15. The medicated animal feed of claim 14, wherein the daily amount of monepantel in the medicated feed is selected from the group consisting of about 0.05 mg / kg, about 0.125 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 0.83 mg / kg.

16. 16. The medicated animal feed of claim 14 or 15, wherein the cumulative dose of monepantel administered to the mammal over a 30 day period is selected from the group consisting of about 1.5 mg / kg, about 3.75 mg / kg, about 7.5 mg / kg and about 25.0 mg / kg.

17. 9. A medicated animal feed according to any one of claims 1 to 8, wherein the anthelmintic in the medicated feed that disrupts the cellular integrity of intestinal helminths is a benzimidazole.

18. 18. The medicated animal feed of claim 17, wherein the anthelmintic is fenbendazole or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of fenbendazole in the medicated feed is such that, when multiple doses are administered to the mammal within a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg of fenbendazole per kg of body weight of the mammal (mg / kg).

19. 20. The medicated animal feed of claim 18, wherein the daily amount of fenbendazole in the medicated feed is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, and about 10 mg / kg.

20. 20. The medicated animal feed of claim 19, wherein the cumulative dose of fenbendazole administered to the mammal over a 30 day period is selected from the group consisting of about 3.0 mg / kg, about 7.5 mg / kg, about 15.0 mg / kg, about 30.0 mg / kg, about 75.0 mg / kg, about 150.0 mg / kg and about 300.0 mg / kg.

21. 21. A medicated animal feed according to any one of claims 1 to 20, further comprising a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt or metabolite thereof.

22. 1. A method for controlling intestinal helminths in a mammal, comprising: Providing a medicated feed according to any one of claims 1 to 21; administering said feed to the mammal daily or substantially daily; A method comprising:

23. 23. The method of claim 22, wherein the mammal is selected from the group consisting of canines and felines.

24. 24. The method of claim 22 or 23, wherein the mammal is a dog.

25. 25. The method of any one of claims 22 to 24, wherein the mammal is a cat.

26. 26. The method of any one of claims 22 to 25, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

27. 27. The method of any one of claims 22 to 26, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

28. 1. A composition for controlling intestinal helminths in a mammal, comprising: (i) disrupt the cellular integrity of intestinal helminths and are selected from the group consisting of benzimidazoles, salicylanilides, and substituted phenols; and / or (ii) containing at least one anthelmintic drug that causes paralysis in intestinal helminths and is selected from the group consisting of tetrahydropyrimidines, emodepside, and monepantel; The composition, when administered daily or substantially daily to a mammal, has a time period effective to achieve a therapeutically effective level of the anthelmintic in the gastrointestinal tract of the mammal selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

29. 29. The composition of claim 28, selected from the group consisting of pet food, wet feed, tablets, capsules, suspensions, solutions, ointments, pastes, reward treats, and snacks.

30. 30. A composition according to claim 28 or 29, suitable for daily or substantially daily administration to a mammal over said period.

31. 31. The composition of any one of claims 28 to 30, wherein the mammal is selected from the group consisting of canines and felines.

32. 32. The composition of any one of claims 28 to 31, wherein the mammal is a dog.

33. 32. The composition of any one of claims 28 to 31, wherein the mammal is a cat.

34. 34. The composition of any one of claims 28 to 33, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

35. 35. The composition of any one of claims 28 to 34, which reduces the number of intestinal helminths in a mammal by at least 50%, at least 75%, at least 80%, at least 88%, at least 95%, or up to 100% compared to a mammal not administered the composition.

36. 36. The composition of any one of claims 28 to 35, which protects a mammal against intestinal helminths for at least 7 days after the last administration.

37. 37. The composition of any one of claims 28 to 36, wherein the anthelmintic is pyrantel or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of pyrantel in the composition is such that when multiple administrations are given to a mammal within a period of about 30 days, the total therapeutic amount of pyrantel does not exceed about 50.0 mg of pyrantel per kg of body weight of the mammal (mg / kg).

38. 38. The composition of claim 37, wherein the anthelmintic is pyrantel pamoate.

39. 39. The composition of claim 37 or 38, wherein the daily amount of pyrantel in the medicated feed is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, and about 1.0 mg / kg.

40. 40. The composition of any one of claims 37 to 39, wherein the cumulative dose of pyrantel administered to the mammal over a 30 day period is selected from the group consisting of about 3.0 mg / kg, about 7.5 mg / kg, about 15 mg / kg and about 30 mg / kg.

41. A composition described in any one of claims 28 to 36, wherein the anthelmintic is monepantel or a therapeutically acceptable derivative, salt or metabolite thereof, and the amount of monepantel in the composition is such that when multiple administrations are given to a mammal within a period of about 30 days, the total therapeutic amount of monepantel does not exceed about 25.0 mg of monepantel per kg of mammal body weight (mg / kg).

42. The composition of claim 41, wherein the daily amount of monepantel in the composition is selected from the group consisting of about 0.05 mg / kg, about 0.125 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg and about 0.83 mg / kg.

43. The composition of claim 41 or 42, wherein the cumulative dose of monepantel administered to a mammal over a 30 day period is selected from the group consisting of about 1.5 mg / kg, about 3.75 mg / kg, about 7.5 mg / kg, about 15 mg / kg and about 25.0 mg / kg.

44. 37. The composition of any one of claims 28 to 36, wherein the anthelmintic in the composition that disrupts the cellular integrity of intestinal helminths is a benzimidazole.

45. 45. The composition of claim 44, wherein the anthelmintic is fenbendazole or a therapeutically acceptable derivative, salt, or metabolite thereof, and the amount of fenbendazole in the composition is such that, when multiple administrations are given to a mammal within a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg of fenbendazole per kg of body weight of the mammal (mg / kg).

46. 46. ​​The composition of claim 45, wherein the daily amount of fenbendazole in the composition is selected from the group consisting of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, and about 10 mg / kg.

47. 47. The composition of claim 45 or 46, wherein the cumulative dose of fenbendazole administered to the mammal over a 30 day period is selected from the group consisting of about 3.0 mg / kg, about 7.5 mg / kg, about 15.0 mg / kg, about 30.0 mg / kg, about 75.0 mg / kg, about 150.0 mg / kg and 300.0 mg / kg.

48. 21. The composition of any one of claims 1 to 20, further comprising a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt or metabolite thereof.

49. 1. A method for controlling intestinal helminths in a mammal, comprising: Providing a composition according to any one of claims 28 to 48; A method comprising the step of administering said composition daily or substantially daily to a mammal.

50. 50. The method of claim 49, wherein the mammal is selected from the group consisting of canines and felines.

51. 51. The method of claim 49 or 50, wherein the mammal is a dog.

52. 52. The method of any one of claims 49 to 51, wherein the mammal is a cat.

53. 53. The method of any one of claims 49 to 52, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipyridium spp., and Hydatid spp.

54. 54. The method of any one of claims 49 to 53, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the composition is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

55. 22. A medicated feed according to any one of claims 1 to 21 for use in a method for controlling intestinal helminths in a mammal, the method comprising: providing a medicated feed; administering said feed daily or substantially daily to a mammal.

56. 56. A medicated feed for use in the method of claim 55, wherein the mammal is selected from the group consisting of canines and felines.

57. 57. A medicated feed for use in the method of claim 55 or 56, wherein the mammal is a dog.

58. 57. A medicated feed for use in the method of claim 55 or 56, wherein the mammal is a cat.

59. 59. A medicated feed for use in the method of any one of claims 55 to 58, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Taenia spp., Dipylidium spp., and Hydatid spp.

60. 60. The medicated animal feed for use in the method of any one of claims 55 to 59, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

61. 50. A composition according to any one of claims 28 to 48 for use in a method for controlling intestinal helminths in a mammal, the method comprising: providing a composition; A composition comprising administering said composition daily or substantially daily to a mammal.

62. 62. The composition for use in the method of claim 61, wherein the mammal is selected from the group consisting of canines and felines.

63. 63. A composition for use in the method of claim 61 or 62, wherein the mammal is a dog.

64. 64. A composition for use in the method of any one of claims 61 to 63, wherein the mammal is a cat.

65. 65. A composition for use in the method of any one of claims 61 to 64, wherein the intestinal helminth is at least one intestinal helminth selected from the group consisting of Toxocara canis, Toxascaris leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris canis, Toxocara cati, Ancylostoma cati, Cestoda, Dipyridium, and Hydatid.

66. 66. The composition for use in the method of any one of claims 61 to 65, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, it is administered for a period selected from the group consisting of more than 1 day but less than 20 days, more than 20 days but less than 30 days, more than 30 days but less than 40 days, more than 40 days but less than 50 days, more than 50 days but less than 60 days, and more than 60 days.

Images