Feed and method for controlling intestinal parasite infection in mammals

Abstract

An oral animal feed and a method of preventing and / or controlling parasites in a mammal in need thereof by orally administering a feed or a composition comprising an effective amount of an anthelmintic to a mammal, such as a dog, the anthelmintic being delivered everyday or substantially everyday for an effective time, this results in an increase in the amount of anthelmintic in the alimentary canal of the mammal and maintained at a therapeutically effective level for controlling parasites.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 407,146, filed on September 15, 2022, which is hereby incorporated by reference herein. Field of the Invention

[0003] The teachings of the present disclosure are generally directed to methods of administering active substances to control parasites in mammals.

[0004] background

[0005] There are five major types of parasites or helminths that commonly infect domestic dogs and other mammals: roundworms, tapeworms, hookworms, whipworms, and heartworms. Helminths can cause serious health problems, including gastrointestinal problems, abdominal pain, weight loss, dehydration, anemia, pneumonia, and in severe cases, death. Some of these intestinal helminth species are also of zoonotic importance by causing disease in humans. Therefore, dogs and cats kept as pets must receive appropriate veterinary care, including treatment to prevent or treat these various helminth parasite infections.

[0006] Therapies currently available for controlling helminth infections in animals are known to achieve varying degrees of success. Problems leading to ineffective control of parasites in, for example, dogs and cats include improper oral dosing, which can lead to further anthelmintic resistance, and vomiting caused by the high doses required by some anthelmintics to achieve effectiveness.

[0007] Overview

[0008] Embodiment 1: A medicated animal feed for controlling intestinal worms in mammals, comprising:

[0009] feedstuff; and

[0010] A dosage of at least one anthelmintic that:

[0011] (i) disrupts cellular integrity in intestinal worms and is selected from the group consisting of benzimidazoles, salicylanilides and substituted phenols, and / or

[0012] (ii) causing intestinal helminth paralysis and selected from the group consisting of ectoine, emodepside and monepantel;

[0013] wherein the at least one anthelmintic is a component of the medicated animal feed and when the medicated animal feed is administered to the mammal daily or substantially daily, 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.

[0014] Embodiment 2: The medicated animal feed according to embodiment 1, wherein the feed raw material is selected from the group consisting of: kibble, wet formula, treats and snacks.

[0015] Embodiment 3: The medicated animal feed according to embodiments 1-2, wherein the medicated feed is suitable for feeding to the mammal every day or substantially every day over a certain period of time.

[0016] Embodiment 4: The medicated animal feed according to embodiments 1-3, wherein the mammal is selected from the group consisting of canines and felines.

[0017] Embodiment 5: The medicated animal feed according to embodiments 1-4, wherein the mammal is a dog.

[0018] Embodiment 6: The medicated animal feed according to embodiments 1-4, wherein the mammal is a cat.

[0019] Embodiment 7: The medicated animal feed according to embodiments 1-6, wherein the intestinal worm is at least one intestinal worm selected from the group consisting of: oxocara canis, Toxascaris leonina, Ancylostoma caninum, Ancylostomabraziliensis, Uncinaria stenocephala, Trichuris vulpis, Toxocara cati, Ancylostoma tubaeforme, Taenia spp., Dipylidium spp., and Echinococcus spp.

[0020] Embodiment 8: The medicated animal feed of embodiments 1-7, wherein the medicated feed reduces the intestinal worm 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 receiving the medicated feed.

[0021] Embodiment 9: The medicated animal feed of embodiments 1-8, wherein the medicated feed protects the mammal from intestinal worms for a period of at least 7 days after the last administration of the medicated feed.

[0022] Embodiment 10: The medicated animal feed of Embodiments 1-9, 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 administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of pyrantel does not exceed about 50.0 mg pyrantel / kg body weight (mg / kg) of the mammal.

[0023] Embodiment 11: The medicated animal feed according to Embodiment 10, wherein the anthelmintic is pyrantel pamoate.

[0024] Embodiment 12: The medicated animal feed according to embodiments 10-11, wherein the daily dose 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.

[0025] Embodiment 13: The medicated animal feed according to embodiments 10-12, wherein the cumulative dose of pyrantel administered to the mammal over 30 days 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.

[0026] Embodiment 14: The medicated animal feed of Embodiments 1-9, 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 administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of monepantel does not exceed about 25.0 mg monepantel / kg body weight (mg / kg) of the mammal.

[0027] Embodiment 15: The medicated animal feed according to Embodiment 14, wherein the daily dose 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.

[0028] Embodiment 16: The medicated animal feed according to embodiments 14-15, wherein the cumulative dose of monepantel administered to the mammal over 30 days 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.

[0029] Embodiment 17: The medicated animal feed according to embodiments 1-8, wherein the anthelmintic drug in the medicated feed that destroys the cell integrity in the intestinal worms is a benzimidazole.

[0030] Embodiment 18: The medicated animal feed of 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 administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg fenbendazole / kg body weight (mg / kg) of the mammal.

[0031] Embodiment 19: The medicated animal feed according to Embodiment 18, wherein the daily dose 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.

[0032] Embodiment 20: The medicated animal feed according to 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.

[0033] Embodiment 21: The medicated animal feed according to Embodiments 1-20, wherein the medicated animal feed further comprises a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt or metabolite thereof.

[0034] Embodiment 22: A method for controlling intestinal worms in a mammal comprising the steps of:

[0035] Providing a medicated feed according to embodiments 1-21; and

[0036] The feed is administered to the mammal daily or substantially daily.

[0037] Embodiment 23: The method of Embodiment 22, wherein the mammal is selected from the group consisting of canines and felines.

[0038] Embodiment 24: The method of embodiments 22-23, wherein the mammal is a dog.

[0039] Embodiment 25: The method of embodiments 22-24, wherein the mammal is a cat.

[0040] Embodiment 26: The method according to embodiments 22-25, wherein the intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma caninum, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris caninum, Toxocara felis, Ancylostoma tubuliformis, Taenia species, Dipylidium species and Echinococcus species.

[0041] Embodiment 27: A method according to embodiments 22-26, wherein the medicated feed is administered over a time 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 when the medicated animal feed is administered to the mammal daily or substantially daily.

[0042] Embodiment 28: A composition for controlling intestinal worms in a mammal, comprising:

[0043] At least one anthelmintic agent, said anthelmintic agent:

[0044] (i) disrupts cellular integrity in intestinal worms and is selected from the group consisting of benzimidazoles, salicylanilides and substituted phenols, and / or

[0045] (ii) causes intestinal helminth paralysis and is selected from the group consisting of ectoine, emodepside and monepantel;

[0046] wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the effective time to achieve 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.

[0047] Embodiment 29: The composition of embodiment 28, wherein the composition is selected from the group consisting of kibble, wet feed, tablet, capsule, suspension, solution, ointment, paste, treat, and snack.

[0048] Embodiment 30: The composition of embodiments 28-29, wherein the composition is suitable for daily or substantially daily administration to the mammal over a period of time.

[0049] Embodiment 31: The composition of embodiments 28-30, wherein the mammal is selected from the group consisting of canines and felines.

[0050] Embodiment 32: The composition of embodiments 28-31, wherein the mammal is a canine.

[0051] Embodiment 33: The composition of embodiments 28-31, wherein the mammal is a cat.

[0052] Embodiment 34: The composition according to embodiments 28-33, wherein the intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma caninum, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris caninum, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

[0053] Embodiment 35: The composition of embodiments 28-34, wherein the composition reduces the intestinal worm count in the mammal by at least 50%, at least 75%, at least 80%, at least 88%, at least 95%, or 100% compared to a mammal not receiving the composition.

[0054] Embodiment 36: The composition of Embodiments 28-35, wherein the composition protects the mammal from intestinal worms for a period of at least 7 days after the last administration.

[0055] Embodiment 37: A composition according to embodiments 28-36, wherein the anthelmintic is pyrantel or a therapeutically acceptable derivative, salt or metabolite thereof, and wherein the amount of pyrantel in the composition is such that when administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of pyrantel does not exceed about 50.0 mg pyrantel / kg body weight (mg / kg) of the mammal.

[0056] Embodiment 38: The composition of Embodiment 37, wherein the anthelmintic is pyrantel pamoate.

[0057] Embodiment 39: The composition according to embodiments 37-38, wherein the daily dose 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.

[0058] Embodiment 40: The composition of Embodiments 37-39, 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.

[0059] Embodiment 41: A composition according to embodiments 28-36, wherein the anthelmintic is monepantel or a therapeutically acceptable derivative, salt or metabolite thereof, and wherein the amount of monepantel in the composition is such that when administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of monepantel does not exceed about 25.0 mg monepantel / kg body weight (mg / kg) of the mammal.

[0060] Embodiment 42: The composition of Embodiment 41, wherein the daily dose 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.

[0061] Embodiment 43: The composition of embodiments 41-42, wherein the cumulative dose of monepantel administered to the mammal over 30 days 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.

[0062] Embodiment 44: The composition of embodiments 28-36, wherein the anthelmintic in the composition that disrupts the cellular integrity of the intestinal worms is a benzimidazole.

[0063] Embodiment 45: A composition according to embodiment 44, wherein the anthelmintic is fenbendazole or a therapeutically acceptable derivative, salt or metabolite thereof, and wherein the amount of fenbendazole in the composition is such that when administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg fenbendazole / kg body weight (mg / kg) of the mammal.

[0064] Embodiment 46: The composition according to Embodiment 45, wherein the daily dose 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.

[0065] Embodiment 47: The composition of embodiments 45-46, 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 about 300.0 mg / kg.

[0066] Embodiment 48: The composition according to Embodiments 1-20, wherein the composition further comprises a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt or metabolite thereof.

[0067] Embodiment 49: A method for controlling intestinal worms in a mammal comprising the steps of:

[0068] Providing a composition according to embodiments 28-48; and

[0069] The composition is administered to the mammal daily or substantially daily.

[0070] Embodiment 50: The method of Embodiment 49, wherein the mammal is selected from the group consisting of canines and felines.

[0071] Embodiment 51: The method of embodiments 49-50, wherein the mammal is a dog.

[0072] Embodiment 52: A method according to embodiments 49-51, wherein the mammal is a cat.

[0073] Embodiment 53: The method according to embodiments 49-52, wherein the intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma caninum, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris caninum, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

[0074] Embodiment 54: A method according to embodiments 49-53, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the composition is administered over a time 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.

[0075] Embodiment 55: The medicated feed according to embodiments 1-21 is used in a method for controlling intestinal worms in mammals, the method comprising the following steps:

[0076] providing the medicated feed; and

[0077] The feed is administered to the mammal daily or substantially daily.

[0078] Embodiment 56: The medicated feed for use in the method according to Embodiment 55, wherein the mammal is selected from the group consisting of canines and felines.

[0079] Embodiment 57: The medicated feed for use in the method according to embodiments 55-56, wherein the mammal is a dog.

[0080] Embodiment 58: The medicated feed for use in the method according to embodiments 55-56, wherein the mammal is a cat.

[0081] Embodiment 59: The medicated feed used in the method according to embodiments 55-58, wherein the intestinal worms are at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma caninum, Ancylostoma brasiliensis, Ancylostoma stenocephalus, Trichuris caninum, Toxocara felis, Ancylostoma tubuli, Taenia species, Dipylidium species and Echinococcus species.

[0082] Embodiment 60: The medicated feed for use in the method according to embodiments 55-59, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered over a period of time 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.

[0083] Embodiment 61: The composition of embodiments 28-48 is used in a method for controlling intestinal worms in a mammal, the method comprising the steps of:

[0084] providing the composition; and

[0085] The composition is administered to the mammal daily or substantially daily.

[0086] Embodiment 62: The composition for use in the method of Embodiment 61, wherein the mammal is selected from the group consisting of canines and felines.

[0087] Embodiment 63: The composition for use in the method of Embodiments 61-62, wherein the mammal is a canine.

[0088] Embodiment 64: The composition for use in the method of embodiments 61-62, wherein the mammal is a cat.

[0089] Embodiment 65: The composition for use in the method according to embodiments 61-64, wherein the intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma caninum, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris caninum, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp., and Echinococcus spp.

[0090] Embodiment 66: The composition for use in the method of embodiments 61-65, wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the composition is administered over a period of time 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 DESCRIPTION OF THE DRAWINGS

[0092] Figure 1. Histogram showing the percent power calculated as follows:

[0093] [AM fecal egg control-AM fecal egg treatment] / AM fecal egg control

[0094] On day 16, 19, 22, 25, 28 or 30 after initial treatment with one of the following: 0.5 mg / kg pyrantel pamoate (horizontal hash), 1.0 mg / kg pyrantel pamoate (right hash), 5 mg / kg fenbendazole (dots) and 10 mg / kg fenbendazole (vertical hash).

[0095] Figure 2. Histogram showing the percent power calculated as follows:

[0096] [AM fecal egg control-AM fecal egg treatment] / AM fecal egg control

[0097] On day 40, 45, 50, 52, or 60 after initial treatment with one of the following; 0.25 mg / kg pyrantel pamoate (horizontally hashed), 0.5 mg / kg pyrantel pamoate (right hashed), 1.0 mg / kg pyrantel pamoate (dotted), 2.5 mg / kg fenbendazole (vertically hashed), 5 mg / kg fenbendazole (solid), or 10 mg / kg fenbendazole (left hashed).

[0098] illustrate

[0099] Surprisingly, the present disclosure teaches that oral treatment with some anthelmintics can provide improved control of parasitic infections in mammals when the anthelmintics are orally administered to mammals in smaller, more frequent / chronic doses than currently recorded monthly or quarterly administrations. In some embodiments, administration is discussed below as being integrally combined with feed. However, it is also contemplated that the anthelmintics may be administered alone or in a dosage form other than as a component of feed, such as a chew, tablet, liquid, gel, or other suitable form for oral administration. Advantageously, in some cases, less total anthelmintics are needed to control parasitic infections in the same time period by using smaller, more frequent doses.

[0100] Advantageously, for some anthelmintics, the total amount of anthelmintic required for a therapeutically effective monthly dose can be reduced by up to 80% by switching to daily administration. From a practical perspective, formulating pharmaceutical feeds creates at least two problems: (1) producing a uniform feed; and (2) analytical control, as it requires testing very small doses of the more potent anthelmintic, which can be difficult to achieve. The analytical matrix from the feed can be very complex and difficult to assay. For some desired doses and feed concentrations, the assays can be in the parts per million to parts per billion range. Thus, it is possible that one skilled in the art could choose to increase the daily dose of the more potent anthelmintic so that the sum of the daily doses over the course of a month is equal to the prior art monthly dose or even higher, e.g., 200% of the prior art monthly dose. Doing so can help ensure uniformity as well as increase assay accuracy and reduce analytical variability when the dose is administered as part of the feed, while still producing a net therapeutic dose that is several times smaller than the currently recommended monthly therapeutic dose.

[0101] The methods and compositions taught herein have the additional advantage of promoting compliance, since smaller doses of anthelmintics can be incorporated into feed or formulations administered as chews, tablets, liquids, gels, or other suitable forms for oral administration. In some embodiments, a daily dose of anthelmintics is added. Since the owner naturally follows a daily feeding regimen in any case, this makes it less likely that the owner will forget or neglect to administer the anthelmintics. Therefore, the present disclosure provides methods for controlling parasites for an extended period of time in a safer and more effective manner than achieved with previously known treatment methods. All the owner needs to remember is to feed their pet every day as they normally would and as described in this embodiment, concomitantly adding a daily dose of anthelmintics.

[0102] Several classes of compounds with anthelmintic activity are known, including, for example: macrolides, such as avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin, moxidectin, nemaketin, selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole-sulfoxide, canbendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, triclabendazole ; cyclooctadepsipeptides, such as emodepside, PF1022; aminoacetonitrile derivatives, such as monepantel; tetrahydropyrimidines, such as morantel, pyrantel, octadal; imidazothiazoles, such as butamidazole, levamisole, tetramisole; salicylanilides, such as bromoxanide, brotianide, chloramphenicol ... Iosanil, closantel, niclosamide, hydroxychlorosanilide, clobeniosamide, tribromosalan; paraherquamides, such as dequinol, paraherquamide; aminophenylamidines, such as amitrail, deacylated amitrail (dAMD), triphenamide; organophosphates, such as coumaphos, fusophate, dichlorvos, haloxone, naphthalofos, trichlorfon; substituted phenols, such as thiobisdichlorophenol, diiodonitrophenol, hexachlorophene, Nitrochlorophenol, meniclopholan, nitroiodine; piperazinones such as praziquantel, ezetimibe; and other classes, which include such examples as nitrothiocyanamide, benzylphenidate, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitrothiocyanate, oltipraz, omphalotin, oxamidine, paromomycin, piperazine and resortel.

[0103] As discussed in some embodiments of the present invention, anthelmintics of particular interest for use in controlling parasitic infections in mammals are benzimidazoles and aminoacetonitrile derivatives.

[0104] Some benzimidazoles are anthelmintics that destroy cell integrity in worms. They are bicyclic compounds with fused rings of the aromatic compounds benzene and imidazole. An example of a benzimidazole is fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl)carbamate), as shown below:

[0105]

[0106] Pyrantel and its various salt forms, members of the ectoine family of compounds, are known veterinary anthelmintics that are also used in human medicine. Pyrantel pamoate is an example of an ectoine reported to have a mode of action involving the nicotinic acetylcholine receptor, which is a putative target for some helminths, as shown below:

[0107]

[0108] 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 biologically active enantiomers thereof are aminoacetonitriles that may be suitable for use in the present disclosure.

[0109]

[0110] More particularly, anthelmintics having a half-life of about at least 1 day may be particularly well suited for use in the methods and formulations of the present disclosure.

[0111] The formulations, feeds and methods disclosed herein may further include one or more other active pharmaceutical substances with therapeutic efficacy in combination with an anthelmintic. Such active substances include agents effective against parasites and / or associated carriers of parasites. Active substances may include, for example, praziquantel, isoxazolines, foramidines, spinosad, macrolides and insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs and juvenile hormone).

[0112] 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.

[0113]

[0114] The method of the present disclosure is carried out by administering the anthelmintic to the mammal in small, frequent doses. For ease of conventional dosing, the anthelmintic administration can be carried out using feed or chews. Many different feeds are contemplated, provided that one or more manufacturing methods and feed compositions have no adverse effects on the chemical stability, efficacy and safety of the anthelmintic and (if applicable) other active substances. For example, feeds and snacks, chews, treats or supplementary feeds in the broad categories of dry, semi-wet, canned cooked feeds or fresh refrigerated feeds may be suitable for the present disclosure. Mammals receive a maintenance amount of anthelmintics by consuming feed products weekly, semi-weekly or daily.

[0115] By incorporating smaller doses of anthelmintics into animal feed compositions and administering them at an effective rate (most preferably daily), the level of anthelmintics in the digestive tract of mammals can be maintained at a level that is effective in treating and preventing further worm infections. In contrast, when anthelmintics are orally administered in larger doses at a lower frequency, for example, a single treatment of a large dose that is only administered once as a single therapeutic treatment, the level of anthelmintics in the digestive tract may be sufficient to treat active infections, but may not be effective in preventing subsequent infections. As disclosed herein, multiple small doses administered over a period of time are at least as effective as the large doses administered in a single treatment that constitutes the current standard of care for treating worm infections in the gastrointestinal tract. Surprisingly, the cumulative amount of anthelmintics administered in multiple small doses can be significantly lower, but still as effective as a single large dose administered less frequently (e.g., monthly).

[0116] Unless otherwise indicated, all ratios, percentages and parts discussed herein are "by weight."

[0117] Doses formulated for daily administration may include tablets, capsules, ointments, liquids and pastes.

[0118] The terms "controlling parasitic infections" and "controlling helminth infections" refer to preventing, treating, minimizing or eliminating an infection with parasites or helminths in mammals.

[0119] The term "controlling parasitic infections" refers to preventing, treating, minimizing or eliminating parasitic infections in mammals.

[0120] The terms "parasite" and "worm" are used interchangeably and refer to members of the phyla Annelida, Platyhelminthes, Nematodes, and Acanthocephala. The terms "parasite" and "worm" include egg, larval, and adult developmental stages. For example, "parasite" or "worm" may include, but are not limited to, the following: Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Tapeworm species, Dipylidium species, and Echinococcus species.

[0121] The term "canid" refers to any member of the genus Canis, which includes species such as wolves, dogs, coyotes, and jackals.

[0122] The term "feline" refers to any member of the subfamily Felinae, which includes species such as domestic cats, bobcats, wildcats, ocelots, members of the genus Lynx, Pallas's cats, and cougars.

[0123] In practicing the methods of the present disclosure, "feed" is animal feed, snacks, treats or other supplemental feed that can be administered daily or substantially daily. By using different forms of feed, e.g., kibble and treats, pet owners can vary the diet and snacks of mammals from time to time while still conveniently administering a daily dose of an anthelmintic.

[0124] The term "chew" refers to a treat that generally has flavor and aroma properties that are attractive to mammals but typically has no nutritional value. In practicing the methods of the present disclosure, "feed" and / or "chew" may be used interchangeably.

[0125] For purposes of this disclosure, the term "effective time", also referred to herein as "effective duration", includes at least the duration of feed administration required to achieve a sufficiently high level of anthelmintic in the digestive tract of a mammal for controlling parasites (i.e., a "therapeutically effective" level). In some embodiments, the effective time may be as short as three days. In other cases, the effective time may be seven days or fifteen days or longer. As discussed below, the effective time will vary based on the frequency of administration of the feed or anthelmintic.

[0126] As just mentioned, the "effective time" will vary as a function of the frequency of administration of the feed. The term "effective frequency" as used herein means the number of feedings that produce a therapeutically effective concentration of the anthelmintic in the gastrointestinal tract of a mammal over a given period of time. In all cases, the term "effective frequency" as used herein contemplates feedings that include the anthelmintic multiple times per month. Those skilled in the art will appreciate that the anthelmintic can be administered over a range of frequencies. For example, the anthelmintic can be administered daily, every other day, every three days, once a week, or even at inconsistent time intervals.

[0127] In addition, as discussed above, the effective frequency can affect the duration required to achieve therapeutically effective levels of the anthelmintic in the digestive tract of a mammal. For example, if a mammal is fed an anthelmintic composition daily, the duration of feed administration required to achieve therapeutically effective levels of the anthelmintic in the gastrointestinal tract of the mammal, and therefore the "effective time", will be relatively less than if the mammal is only fed the anthelmintic composition once or twice per week.

[0128] In addition, the effective frequency is affected by the amount of the daily dose in mg / kg mammal body weight. In particular, at slightly higher daily doses, the effect of missed doses on efficacy is smaller.

[0129] Furthermore, the effective frequency is affected by the duration of treatment. In the initial phase, e.g., before the amount of anthelmintic in the digestive tract of the mammal has reached therapeutically effective levels, the animal feed may need to be administered more frequently than would be required after a longer period of use (i.e., once therapeutically effective levels are achieved).

[0130] For the purposes of this disclosure, "substantially daily" means a sufficiently regular basis that the concentration of the anthelmintic in the digestive tract of a mammal rises and remains at a therapeutically effective level. For example, the disclosed daily feed composition can preferably be fed to a mammal every day indefinitely. However, as a practical matter, there are many reasons why a dose may be missed or skipped for a few days on a regular basis. For example, a mammal may be sick or the owner may have run out of the daily medicated feed composition. The disclosed method is sufficiently robust that even if the daily feeding of the medicated animal feed composition is occasionally interrupted, the mammal will still be protected to a certain extent from parasites. When implementing the method of the present disclosure, the term "substantially daily" includes at least 10 days / month, more preferably at least 15 days / month, and even more preferably at least 20 days / month. All of these feeding frequencies, whether they are, for example, three times a week, every other day or every day, are suitable for being classified within the scope of substantially every day as long as they promote the anthelmintic to reach and maintain therapeutically effective levels in the gastrointestinal tract of a mammal.

[0131] The term "therapeutically effective" means that the dosage of the anthelmintic or its physiologically acceptable derivative or metabolite thereof is sufficient to control helminth infection better than if the drug were not present. The anthelmintic or its physiologically acceptable derivative or metabolite thereof may be present by itself or together with one or more additional active substances. Preferably it controls helminth infection by about at least 50% better than if the drug were not present, and more preferably it controls helminth infection by about at least 90% better than if the drug were not present.

[0132] In practicing the methods of the present disclosure, an effective amount or therapeutically effective amount of an anthelmintic is orally administered to a mammal. The term "effective amount" or "therapeutically effective amount" refers to the amount required to control a helminth infection. As will be appreciated by those skilled in the art, this amount will vary depending on a number of factors. These factors include, for example, the type of mammal being treated and its weight and general physical condition.

[0133] The effectiveness of anthelmintics varies. Therefore, the effective amount of each specific anthelmintic used in some of the methods according to the present disclosure can be calculated. Typically, the effective amount of the daily dose of the anthelmintic can be in the range of about 12.5%-90% of the approved label dose of the anthelmintic divided by the length of the dosing / retreatment interval (e.g., for a product administered once a month, the dose is divided by 30). Those skilled in the art will recognize that for reasons such as, but not limited to, manufacturability, ease of testing and analysis, a higher dose of, for example, 90%-200% of the approved label dose of the anthelmintic can be selected. In some cases, the specific dose selected can be sufficient to increase the concentration of the anthelmintic in the digestive tract of a mammal 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.

[0134] Although the present disclosure describes the concentration of anthelmintics in terms of feed such as kibble, it is also contemplated that the anthelmintics may be administered alone or in tablets, liquids, gels, or other suitable forms for oral administration. It will be appreciated by those skilled in the art that the concentration of the anthelmintics will vary depending on the particular dosage form. For example, in the case where the animal feed is a treat, the concentration of the anthelmintic in the treat will be greater than the concentration of the anthelmintic in the kibble. For example, if the daily dose of the anthelmintic based on the weight of the mammal is 10 mg, a typical 5 g treat may contain about 0.002% anthelmintic (by weight). Since the amount of kibble consumed in a day exceeds 5 g, the percentage of anthelmintics in the kibble will be smaller.

[0135] For example, the effective amount of pyrantel pamoate can be a daily dose or substantially a daily dose of about 0.1 to about 1.0 mg pyrantel pamoate / kg mammal body weight. Alternatively, the effective amount of pyrantel pamoate can be a daily dose or substantially a daily dose of about 0.1 to about 0.5 mg pyrantel pamoate / kg mammal body weight. Alternatively, the effective amount of pyrantel pamoate can be a daily dose or substantially a daily dose of about 0.25 to about 0.5 mg / kg mammal body weight. Alternatively, the effective amount of pyrantel pamoate can be a daily dose or substantially a daily dose of about 0.1 to about 0.25 mg pyrantel pamoate / kg mammal body weight.

[0136] Animal feed will typically contain about 0.0001% to about 0.09% pyrantel pamoate (by weight) in the feed. Preferably about 0.0005% to about 0.06% pyrantel pamoate (by weight) in the feed. More preferably about 0.0009% to about 0.03% of one or more pyrantel pamoate components (by weight) in the feed.

[0137] In another example, the effective amount of fenbendazole can be a daily dose of about 0.5 to about 10.0mg fenbendazole / kg mammal body weight or a daily dose substantially. Alternatively, the effective amount of fenbendazole can be a daily dose of about 1.0 to about 5.0mg fenbendazole / kg mammal body weight or a daily dose substantially. Alternatively, the effective amount of fenbendazole can be a daily dose of about 2.5 to about 5.0mg fenbendazole / kg mammal body weight or a daily dose substantially. Alternatively, the effective amount of fenbendazole can be a daily dose of about 0.5 to about 2.5mg fenbendazole / kg mammal body weight or a daily dose substantially.

[0138] Animal feed will typically contain about 0.001% to about 0.12% fenbendazole (by weight) in the feed. Preferably about 0.003% to about 0.09% fenbendazole (by weight) in the feed. More preferably about 0.008% to about 0.05% of one or more fenbendazole components (by weight) in the feed.

[0139] In another example, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.05 to about 0.83 mg monepantel / kg mammal body weight. Alternatively, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.05 to about 0.5 mg monepantel / kg mammal body weight. Alternatively, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.125 to about 0.5 mg / kg mammal body weight. Alternatively, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.125 to about 0.25 mg monepantel / kg mammal body weight.

[0140] Animal feed will typically contain 0.00005% to about 0.0001% monepantel by weight in the feed. Preferably about 0.0001% to about 0.005% monepantel by weight in the feed. More preferably about 0.0005% to about 0.001% of one or more monepantel components by weight in the feed.

[0141] In one aspect, the present disclosure relates to a method of controlling parasitic infections in mammals by administering a systemically active oral composition comprising an anthelmintic or a physiologically acceptable derivative or salt thereof and an animal feed at least once a week, more preferably three times a week, and most preferably substantially daily.

[0142] In another aspect, the present disclosure relates to a systemically active oral composition comprising an anthelmintic and an animal feed.

[0143] The present disclosure also relates to the use of an anthelmintic for the preparation of an animal feed for controlling parasitic infections in mammals.

[0144] The present disclosure also relates to a method for controlling parasitic infections in mammals over an extended period of time, comprising orally administering to the mammal a daily dose or substantially a daily dose of an effective amount of an anthelmintic in a daily feed. A daily feed is a feed that is intended to be administered daily, but as described herein, it may be administered for an effective period of time. The method is particularly useful for controlling parasites in mammals over an extended period of time, comprising orally administering to the mammal a substantially daily dose of an effective amount of an anthelmintic.

[0145] An aspect of the present disclosure is oral administration of an amount of an anthelmintic that is ineffective or suboptimal for controlling parasitic infections in mammals if administered at longer intervals, such as once a month. However, as described herein, by repeated administration at shorter intervals, such as substantially daily, effective control of parasitic infections is achieved. Ineffective or suboptimal means that a single administration, as well as multiple administrations, results in less than a 50% reduction in parasitic infections, including no or substantially no reduction, compared to administration of no drug at all. This reflects the chronic rather than acute administration aspect disclosed herein.

[0146] In a first embodiment, a method for controlling parasites in a mammal by orally administering to the mammal a daily feed comprising an effective amount of an anthelmintic for an effective period of time is disclosed.

[0147] In a second embodiment, an anthelmintic for use in controlling parasites in a mammal in need thereof is disclosed. The anthelmintic may be present in an effective amount in a daily feed that is to be administered to the mammal for an effective period of time to control parasites.

[0148] In a third embodiment, a daily feed for controlling parasites in a mammal is disclosed comprising an effective amount of an anthelmintic when administered for an effective period of time.

[0149] In aspects of any one of the embodiments, the mammal can be a canine. More particularly, the canine can be a wolf, a coyote or a dog.

[0150] In aspects of any one of the embodiments, the mammal can be a feline. More particularly, the feline can be a domestic cat, a bobcat, a wild cat, an ocelot, a member of the genus Lynx, a Pallas's cat, or a puma.

[0151] In aspects of any 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 anthelmintics may be included in the compositions and / or medicated feeds of the present invention. Example

[0152] The following non-limiting examples illustrate some of the methods of the present disclosure:

[0153] Example 1

[0154] Efficacy of pyrantel pamoate and fenbendazole administered orally (ie, by the mouth) to dogs for the treatment and control of Ancylostoma caninum.

[0155] Methods: A group of 22 dogs will be initially examined to ensure suitability for this example. Dogs must be within the normal weight range for breeding, in good health, with no known history of serious illness, and neither pregnant nor lactating. Between Days -7 and -3, a fecal examination may be performed to confirm the absence of pre-existing infection with any nematode species. Dogs exposed to anthelmintics within 30 days prior to Day -7 will be excluded.

[0156] On Day -2, dogs will be weighed and randomized by weight to 1 of 5 treatment groups.

[0157] Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on day 0. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercial dog diet at the recommended rate and should be allowed ad libitum access to drinking water.

[0158] Each dog in the treatment group (Test Groups 2-5) will receive a liquid formulation of the anthelmintic drug orally. The dogs will be administered a dose daily on Days 0-22 according to the test group shown in Table 1.

[0159] Table 1

[0160]

[0161] * The doses selected represent 10% and 20% of the therapeutic doses of pyrantel pamoate (approximately 5 milligrams of anthelmintic per kilogram of mammal body weight (mg / kg)) and fenbendazole (approximately 50 milligrams of anthelmintic per kilogram of mammal body weight (mg / kg)), respectively, for treating canine adult intestinal nematode infections, according to label instructions for existing commercial drug products. Current practice in the industry is to administer three separate 50 mg / kg doses of fenbendazole over a three-day period to treat mammals with intestinal worms; therefore, under the current standard of care, the total effective monthly dose of fenbendazole is approximately 150 mg / kg.

[0162] The dogs in the control group will not receive any anthelmintics or any other worm control treatment. The dogs will be fasted overnight. Each dog in treatment groups 2-5 will be provided with its daily morning ration (dry food) and a single dose of the liquid formulation will be administered after each dog has eaten approximately 25% of its total morning ration. After receiving the dose of anthelmintics, the dogs will be allowed to continue eating. This simulates the incorporation of anthelmintics in the feed.

[0163] On day 0, approximately 8 hours after the initial dose of anthelmintics, dogs will be orally inoculated with approximately 300 infective third-stage Ancylostoma caninum larvae. Fecal egg counts will be performed on days 10, 13, 16, 19, and 22. There should also be a 7-day washout period from day 23-30. During the washout period, fecal egg counts should be performed on days 25, 28, and 30.

[0164] The percent reduction in fecal egg counts for the treatment groups is shown in the following graphs. (Note that for fecal egg counts on Days 10 and 13, no eggs were recovered in any group. Therefore, these days were omitted from the graphs in Figure 1.

[0165]

[0166] Example 2

[0167] Efficacy of pyrantel pamoate and fenbendazole administered orally (ie, by the mouth) to dogs for the treatment and control of Toxocara canis.

[0168] Methods: A group of 30 dogs will be initially examined to ensure suitability for this example. Dogs must be within the normal weight range for breeding, in good health, with no known history of serious illness, and neither pregnant nor lactating. On Day -6, a fecal examination may be performed to confirm the absence of pre-existing infection with any nematode species. Dogs exposed to anthelmintics within 30 days prior to Day -7 will be excluded.

[0169] On Day -1, 28 eligible dogs will be weighed and randomized by weight to 1 of 7 treatment groups.

[0170] The dogs will be housed indoors to help prevent naturally occurring parasitic infections. Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on Day 0. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercially available dog diet at the recommended rate and should be allowed ad libitum access to drinking water.

[0171] Each dog in the treatment group (Test Groups 2-7) will receive a liquid formulation of the anthelmintic drug orally. Referring to Table 2, the dogs will be administered a dose daily on Days 0-52, depending on the test group.

[0172] Table 2

[0173]

[0174]

[0175] The dogs in the control group will not receive any anthelmintics or any other worm control treatment. The dogs will be fasted overnight. Each dog in treatment groups 2-7 will be provided with its daily morning ration (dry food) and a single dose of the liquid formulation will be administered after each dog has eaten approximately 25% of its total morning ration. After receiving the dose of anthelmintics, the dogs will be allowed to continue eating. This simulates the incorporation of anthelmintics in the feed.

[0176] On day 0, approximately 8 hours after the initial dose of anthelmintics, dogs will be orally inoculated with approximately 250 infective larval eggs of Toxocara canis. Fecal egg counts will be performed on days 30, 35, 40, 45, 50, and 52. There should also be a 7-day washout period from day 53 to day 60. Following the washout period, fecal egg counts should be performed on day 60.

[0177] The percent reduction in fecal egg counts for the treatment groups is shown in the following graph. (Note that no fecal eggs were recovered on counts on Days 30 and 35. These days have been omitted from the graph. In addition, in cases where more eggs were recovered in the fecal counts of a treatment group than in the fecal counts of the control group, the efficacy data for that treatment group on that day is not shown in FIG. 2 .

[0178]

[0179] Example 3

[0180] Efficacy of monepantel administered orally (ie, by the mouth) to dogs for the treatment and control of Ancylostoma caninum.

[0181] Methods: A group of 12 dogs will be initially examined to ensure suitability for this example. Dogs must be within the normal weight range for breeding, in good health, with no known history of serious illness, and neither pregnant nor lactating. Between Days -7 and -3, a fecal examination may be performed to confirm the absence of pre-existing infection with any nematode species. Dogs exposed to anthelmintics within 30 days prior to Day -7 will be excluded.

[0182] On Day -2, dogs will be weighed and randomized by weight to 1 of 3 groups (1 control group and 2 treatment groups).

[0183] Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on day 0. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercial dog diet at the recommended rate and should be allowed ad libitum access to drinking water.

[0184] Each dog in the treatment group (Test Groups 2-3) will receive a liquid formulation of monepantel orally. Referring to Table 3, the dogs will be administered doses daily on Days 0-22 according to the test group.

[0185] Table 3

[0186]

[0187] The dogs in the control group will not receive any anthelmintics or any other worm control treatment. The dogs will be fasted overnight. Each dog in treatment groups 2-3 will be provided with its daily morning ration (dry food) and a single dose of the liquid formulation will be administered after each dog has eaten approximately 25% of its total morning ration. After receiving the dose of anthelmintics, the dogs will be allowed to continue eating. This simulates the incorporation of anthelmintics in the feed.

[0188] On day 0, approximately 8 hours after the initial dose of anthelmintics, dogs will be orally inoculated with approximately 300 infective third-stage Ancylostoma caninum larvae. Fecal egg counts will be performed on days 10, 13, 16, 19, and 22. There should also be a 7-day washout period from day 23-30. During the washout period, fecal egg counts should be performed on days 25, 28, and 30.

[0189] The percent reduction in fecal egg counts for the treatment groups is expected to reach 100% in approximately 2 weeks.

[0190] Example 4

[0191] Efficacy of monepantel administered orally (ie, by the mouth) to dogs for the treatment and control of Toxocara canis.

[0192] Methods: A cohort of dogs will be initially examined to ensure suitability for this example. Dogs must be within the normal weight range for breeding, in good health, with no known history of serious illness, and neither pregnant nor lactating. On Day -6, a fecal examination may be performed to confirm the absence of pre-existing infection with any nematode species. Dogs exposed to anthelmintics within 30 days prior to Day -7 will be excluded.

[0193] On Day -1, 16 eligible dogs will be weighed and randomly assigned by weight to 1 of 4 groups (1 control group and 3 treatment groups).

[0194] The dogs will be housed indoors to help prevent naturally occurring parasitic infections. Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on Day 0. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercially available dog diet at the recommended rate and should be allowed ad libitum access to drinking water.

[0195] Each dog in the treatment group (Test Groups 2-4) will receive a liquid formulation of monepantel orally. Referring to Table 4, the dogs will be administered a dose daily on Days 0-52 according to the test group.

[0196] Table 4

[0197]

[0198] The dogs in the control group will not receive any anthelmintics or any other worm control treatment. The dogs will be fasted overnight. Each dog in treatment groups 2-4 will be provided with its daily morning ration (dry food) and a single dose of the liquid formulation will be administered after each dog has eaten approximately 25% of its total morning ration. After receiving the dose of anthelmintics, the dogs will be allowed to continue eating. This simulates the incorporation of anthelmintics in the feed.

[0199] On day 0, approximately 8 hours after the initial dose of anthelmintics, dogs will be orally inoculated with approximately 250 infective larval eggs of Toxocara canis. Fecal egg counts will be performed on days 30, 35, 40, 45, 50, and 52. There should also be a 7-day washout period from day 53 to day 60. Following the washout period, fecal egg counts should be performed on day 60.

[0200] Efficacy for all treatment groups was expected to be 100% by the end of the study period.

[0201] Example 5

[0202] Efficacy of fenbendazole administered orally (ie, by the mouth) to dogs for the treatment and control of Toxocara canis infections.

[0203] Methods: A cohort of dogs will be initially examined to ensure suitability for this example. Dogs must be within the normal weight range for breeding, in good health, with no known history of serious illness, and neither pregnant nor lactating. Between Days -6 and -3, a fecal examination may be performed to confirm the absence of pre-existing infection with any nematode species. Dogs exposed to anthelmintics within 30 days prior to Day -7 will be excluded.

[0204] On Day -2 or Day -1, 20 eligible dogs will be weighed and randomly assigned by weight to 1 of 5 groups (1 control group and 4 treatment groups).

[0205] The dogs will be housed indoors to help prevent naturally occurring parasitic infections. Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on Day 0. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercially available dog diet at the recommended rate and should be allowed ad libitum access to drinking water.

[0206] Each dog in the treatment group (Test Groups 2-5) will receive a liquid formulation of fenbendazole orally. Referring to Table 5, the dogs will be administered a dose daily on Days 0-52, depending on the test group.

[0207] Table 5

[0208]

[0209]

[0210] The dogs in the control group will not receive any anthelmintics or any other worm control treatment. The dogs will be fasted overnight. Each dog in treatment groups 2-5 will be provided with its daily morning ration (dry food) and a single dose of the liquid formulation will be administered after each dog has eaten approximately 25% of its total morning ration. After receiving the dose of anthelmintics, the dogs will be allowed to continue eating. This simulates the incorporation of anthelmintics in the feed.

[0211] On day 0, approximately 8 hours after the initial dose of anthelmintics, dogs will be orally inoculated with approximately 250 infective eggs of Toxocara canis. Fecal egg counts will be performed on days 30, 35, 40, 45, 50, and 53.

[0212] It is expected that by the end of the study period, efficacy for at least treatment groups 2-4 will be 100%.

[0213] Although the present invention has been described as having an exemplary design, the present invention can be further modified within the spirit and scope of the present disclosure. Therefore, this application is intended to cover any changes, uses, or adaptations of the present invention using its general principles.

Claims

1. A medicated animal feed for controlling intestinal worms in mammals, comprising: Feed ingredients; and A dosage of at least one anthelmintic agent that: (i) disrupts cellular integrity in intestinal worms and is selected from the group consisting of benzimidazoles, salicylanilides and substituted phenols, and / or (ii) causes intestinal helminth paralysis and is selected from the group consisting of ectoine, emodepside and monepantel; wherein the at least one anthelmintic is a component of the medicated animal feed and when the medicated animal feed is administered to the mammal daily or substantially daily, 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.

2. The medicated animal feed according to claim 1, wherein: The feed raw material is selected from the group consisting of: Kibbles, wet formula, treats and snacks.

3. The medicated animal feed according to claim 1-2, wherein: The medicated feed is suitable for feeding to the mammal daily or substantially daily over a period of time.

4. The medicated animal feed according to claims 1-3, wherein: The mammal is selected from the group consisting of canines and felines.

5. The medicated animal feed according to claims 1-4, wherein: The mammal is a canine.

6. The medicated animal feed according to claims 1-4, wherein: The mammal is a cat.

7. The medicated animal feed according to claims 1-6, wherein: The intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

8. The medicated animal feed according to claims 1-7, wherein: The medicated feed reduces the intestinal worm 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 receiving the medicated feed.

9. The medicated animal feed according to claims 1-8, wherein: The medicated feed protects the mammal from intestinal worms for a period of at least 7 days after the last administration of the medicated feed.

10. The medicated animal feed according to claims 1-9, 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 administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of pyrantel does not exceed about 50.0 mg pyrantel / kg body weight (mg / kg) of the mammal.

11. The medicated animal feed according to claim 10, wherein: The anthelmintic drug is pyrantel pamoate.

12. The medicated animal feed according to claims 10-11, wherein: The daily dose 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. The medicated animal feed according to claims 10-12, wherein: The cumulative dose of pyrantel administered to the mammal over 30 days 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. The medicated animal feed according to claims 1-9, 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 administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of monepantel does not exceed about 25.0 mg monepantel / kg body weight (mg / kg) of the mammal.

15. The medicated animal feed according to claim 14, wherein: The daily dose 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. The medicated animal feed according to claims 14-15, wherein: The cumulative dose of monepantel administered to the mammal over 30 days 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. The medicated animal feed according to claims 1-8, wherein: The anthelmintic in the medicated feed that disrupts the cellular integrity in the intestinal worms is a benzimidazole.

18. The medicated animal feed according to claim 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 administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of fenbendazole does not exceed about 300 mg fenbendazole / kg body weight (mg / kg) of the mammal.

19. The medicated animal feed according to claim 18, wherein: The daily dose 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. The medicated animal feed according to claim 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.

21. The medicated animal feed according to claims 1-20, wherein: The medicated animal feed further comprises a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt or metabolite thereof.

22. A method for controlling intestinal worms in a mammal comprising the steps of: Providing a medicated feed according to claims 1-21; and The feed is administered to the mammal daily or substantially daily.

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

24. The method according to claims 22-23, wherein: The mammal is a canine.

25. The method according to claims 22-24, wherein: The mammal is a cat.

26. The method according to claims 22-25, wherein: The intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

27. The method according to claims 22-26, wherein: When the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered over a period of time 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. A composition for controlling intestinal worms in a mammal, comprising: At least one anthelmintic agent, said anthelmintic agent: (i) disrupts cellular integrity in intestinal worms and is selected from the group consisting of benzimidazoles, salicylanilides and substituted phenols, and / or (ii) causes intestinal helminth paralysis and is selected from the group consisting of ectoine, emodepside and monepantel; wherein when the medicated animal feed is administered to the mammal daily or substantially daily, the effective time to achieve 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.

29. The composition according to claim 28, wherein The composition is selected from the group consisting of kibble, wet feed, tablet, capsule, suspension, solution, ointment, paste, treat and snack.

30. The composition according to claims 28-29, wherein The composition is suitable for daily or substantially daily administration to the mammal over a period of time.

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

32. The composition according to claims 28-31, wherein The mammal is a canine.

33. The composition according to claims 28-31, wherein The mammal is a cat.

34. The composition according to claims 28-33, wherein The intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

35. The composition according to claims 28-34, wherein The composition reduces the intestinal worm count in the mammal by at least 50%, at least 75%, at least 80%, at least 88%, at least 95%, or 100% compared to a mammal not receiving the composition.

36. The composition according to claims 28-35, wherein After the last administration, the composition protects the mammal from intestinal worms for a period of at least 7 days.

37. The composition according to claims 28-36, wherein The anthelmintic is pyrantel or a therapeutically acceptable derivative, salt or metabolite thereof, and wherein the amount of pyrantel in the composition is such that when administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of pyrantel does not exceed about 50.0 mg pyrantel / kg body weight (mg / kg) of the mammal.

38. The composition according to claim 37, wherein The anthelmintic drug is pyrantel pamoate.

39. The composition according to claims 37-38, wherein The daily dose 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. The composition according to claims 37-39, 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.

41. The composition according to claims 28-36, wherein The anthelmintic is monepantel or a therapeutically acceptable derivative, salt or metabolite thereof, and wherein the amount of monepantel in the composition is such that when administered to the mammal in multiple doses over a period of about 30 days, the total therapeutic dose of monepantel does not exceed about 25.0 mg monepantel / kg body weight (mg / kg) of the mammal.

42. The composition according to claim 41, wherein The daily dose 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 according to claims 41-42, wherein The cumulative dose of monepantel administered to the mammal over 30 days 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. The composition according to claims 28-36, wherein The anthelmintic in the composition that disrupts the cellular integrity of the intestinal worms is a benzimidazole.

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

46. ​​The composition according to claim 45, wherein The daily dose 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. The composition according to claims 45-46, 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 about 300.0 mg / kg.

48. The composition of claims 1-20, wherein The composition further comprises a therapeutically effective amount of praziquantel or a therapeutically acceptable derivative, salt or metabolite thereof.

49. A method for controlling intestinal worms in a mammal comprising the steps of: Providing a composition according to claims 28-48; and The composition is administered to the mammal daily or substantially daily.

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

51. The method according to claims 49-50, wherein: The mammal is a canine.

52. The method of claims 49-51, wherein: The mammal is a cat.

53. The method of claims 49-52, wherein: The intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

54. The method of claims 49-53, wherein: When the medicated animal feed is administered to the mammal daily or substantially daily, the composition is administered over a period of time 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. The medicated feed according to claims 1-21 for use in a method of controlling intestinal worms in a mammal, the method comprising the steps of: providing the medicated feed; and The feed is administered to the mammal daily or substantially daily.

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

57. The medicated feed for use in the method according to claims 55-56, wherein The mammal is a canine.

58. The medicated feed for use in the method according to claims 55-56, wherein The mammal is a cat.

59. The medicated feed for use in the method according to claims 55-58, wherein The intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

60. The medicated feed for use in the method according to claims 55-59, wherein: When the medicated animal feed is administered to the mammal daily or substantially daily, the medicated feed is administered over a period of time 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. A composition according to claims 28-48 for use in a method of controlling intestinal worms in a mammal, the method comprising the steps of: providing the composition; and The composition is administered to the mammal daily or substantially daily.

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. The composition for use in the method according to claims 61-62, wherein The mammal is a canine.

64. The composition for use in the method according to claims 61-63, wherein The mammal is a cat.

65. The composition for use in the method according to claims 61-64, wherein The intestinal worm is at least one intestinal worm selected from the group consisting of Toxocara canis, Toxocara leonina, Ancylostoma canis, Ancylostoma brasiliensis, Ancylostoma stenocephalum, Trichuris canis, Toxocara felis, Ancylostoma tubuliformis, Taenia spp., Dipylidium spp. and Echinococcus spp.

66. The composition for use in the method according to claims 61-65, wherein When the medicated animal feed is administered to the mammal daily or substantially daily, the composition is administered over a period of time 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.

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