Palatable animal compositions

Abstract

The present invention relates to a stable, effective, palatable composition for chewing animals which comprises an isoxazoline compound of formula (I) as an active ingredient, a stabilized macrocyclic lactone, pyrantel and an excipient.

Description

[Technical field]

[0001] This application relates to a palatable, chewable animal dosage form comprising an isoxazoline parasiticidal compound, a bioactive macrocyclic lactone compound and pyrantel pamoate, a method for making the animal dosage form, and uses thereof. [Background technology]

[0002] A number of parasites can infest domestic animals, particularly companion animals such as cats and dogs. These pests and parasites are a great nuisance to both the animals and their owners.

[0003] Isoxazoline compounds are known in the art and these compounds and their use as parasiticides have been described, for example, in U.S. Patent Application US2007 / 0066617 and International Patent Applications WO2005 / 085216, WO2007 / 079162, WO2009 / 002809, WO2009 / 024541, WO2009 / 003075, WO2009 / 080250, WO2010 / 070068 and WO2010 / 079077.

[0004] Compounds of this type are known to have excellent activity against ectoparasites, i.e. parasites that live permanently or temporarily on the outer surface of animals, such as parasitic insects and mites, such as ticks and fleas, as well as endoparasites that live inside the body of animals, and are, for example, anthelmintics active against parasitic nematodes.

[0005] One known and convenient method of administering isoxazoline compounds to animals is orally via a solid oral dosage form.

[0006] Furthermore, macrocyclic lactones are known to act as very powerful parasiticides, particularly as acaricides, anthelmintics and / or insecticides, and therefore are useful in the treatment of ectoparasites as well as endoparasites in animals.

[0007] In view of the above, it would be desirable to have a solid oral dosage form further comprising one or more active agents from different classes, such as macrocyclic lactones and pyrantel pamoate, to enhance / improve the therapeutic efficacy of the isoxazoline compounds, thereby broadening the range of parasites controlled by the same dosage form. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US2007 / 0066617 [Patent Document 2] WO2005 / 085216 [Patent Document 3] WO2007 / 079162 [Patent Document 4] WO2009 / 002809 [Patent Document 5] WO2009 / 024541 [Patent Document 6] WO2009 / 003075 [Patent Document 7] WO2009 / 080250 [Patent Document 8] WO2010 / 070068 [Patent Document 9] WO2010 / 079077 Summary of the Invention [Problem to be solved by the invention]

[0009] However, the active macrocyclic lactones have been found to form significant amounts of degradation products, i.e., when added to typical palatable chewing animal formulations, the macrocyclic lactones are often not stable enough to reliably provide an effective amount of such macrocyclic lactone compounds in the resulting dosage form.

[0010] EP 329460 discloses that the stability of the compound may be enhanced in the presence of certain antioxidants. In particular, EP 329460 discloses the stabilization of moxidectin. The antioxidants described in EP 329460 as being useful for stabilization are gallic acid C, 1-2 Alkyl;Hydroxybenzoic acid C 1-6 benzyl hydroxybenzoate or a salt thereof; butylated hydroxyanisole (BHA); butylated hydroxytoluene (BHT); quinones or a salt thereof; nordihydroguaiaretic acid; and tocopherols such as alpha-tocopherol.

[0011] AU2006 / 203347 discloses a composition comprising moxidectin and a stabilizer selected from the group consisting of dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine ​​or a salt thereof; ethoxyquin; isoascorbic acid; ethylenediaminetetraacetic acid or a salt thereof, potassium hydrogen sulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; and mixtures thereof.

[0012] Therefore, there remains a need for a chewing animal dosage form comprising a combination of agents from the groups of isoxazoline compounds, pyrantel pamoate and biologically active macrocyclic lactone compounds, which ensures stability of the biologically active agent and advantageously reduces degradation products of the biologically active agent.

[0013] This advantageously allows for an extended shelf life of the resulting product, allowing for storage of the product under more extreme conditions. Additionally, the stability of the biologically active macrocyclic lactone should be improved without adversely affecting the bioavailability of the biologically active macrocyclic lactone or the isoxazoline or pyrantel pamoate.

[0014] Another important consideration is that macrocyclic lactone compounds are generally present in very small amounts in palatable chewable animal dosage forms, which creates problems in ensuring content uniformity, i.e., that the macrocyclic lactone is evenly distributed throughout the tablet.

[0015] It is therefore an object of the present invention to overcome one or more of the disadvantages of the above-mentioned dosage forms.

[0016] In particular, it is an object of the present invention to provide a dosage form for chewing animals which contains, inter alia, a uniform content of physiologically active macrocyclic lactones in a stabilized form such that degradation is advantageously reduced or preferably even prevented.

[0017] Another object is to provide a chewable animal dosage form containing a combination of these three active agents that is effective in the treatment of endoparasites and ectoparasites in non-human animals, particularly fleas and ticks in small mammals such as dogs and cats, which is highly palatable to companion animals, particularly dogs. [Means for solving the problem]

[0018] The present invention unexpectedly overcomes at least one of the above objectives by providing a novel palatable dosage form for chewing animals.

[0019] Thus, in one embodiment, the subject of the present invention is a) an isoxazoline compound of formula (I): [ka] [In the formula, R 1 are halogens, CF3, OCF3, CN, n is an integer from 0 to a maximum of 3, preferably 1, 2 or 3; R 2 is C1-C3-haloalkyl, preferably CF3 or CF2Cl, T is a 5-12 membered monocyclic or bicyclic ring system, which is optionally substituted by one or more groups Y; Y is methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent groups Y together form a chain, in particular a 3- to 4-membered chain; Q is X-NR 3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more groups; X is CH2, CH(CH3), CH(CN), CO, or CS; R 3 is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanyl, alkylsulfinealkyl, alkylsulfonealkyl, cycloalkyl [ka] and; Z A is hydrogen, halogen, cyano, halomethyl, preferably CF3; R 4is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; R 5 is hydrogen, alkyl or haloalkyl; R 6 is hydrogen, alkyl or haloalkyl; Or R 3 and R 4 Together, [ka] or a salt or solvate thereof, pyrantel pamoate and a macrocyclic lactone compound, and a carrier comprising at least one flavoring and a stabilizing component comprising an inorganic alkalizing agent, porous silica, or a mixture thereof.

[0020] In yet a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a. isoxazoline and pyrantel pamoate granules are prepared by 1) dry blending the isoxazoline compound and pyrantel pamoate with disintegrants, fillers, colorants and surfactants; 2) preparing a solution of solvent and cellulosic polymer; 3) blending the isoxazoline and pyrantel pamoate and dry blending with the solution in a high shear mixer granulator to prepare isoxazoline-pyrantel granules; 4) drying and grinding the isoxazoline-pyrantel granules; b. Moxidectin granules are prepared by 1) dry blending porous silica, a filler and an alkalizing agent; 2) dissolving moxidectin in a solvent along with a non-cellulosic polymer and an antioxidant; 4) mixing the dry blend with the moxidectin solution in a high shear mixer granulator to prepare moxidectin granules; 4) drying and grinding the moxidectin granules; c.1) preparing a blend by mixing at least one flavoring agent with a filler, a disintegrant, a coloring agent, and a glidant; 2) mixing the isoxazoline-pyrantel pamoate granules and moxidectin granules with the blend; and 3) preparing a final dry blend by mixing the blend with a lubricant and compressing the blend into a finished palatable chewable tablet. The present invention relates to a method for producing said palatable animal preparation, characterized in that:

[0021] In yet a further aspect, the present invention relates to the use of a palatable chewable dosage form according to the invention or obtainable by the process for producing a pharmaceutical composition according to the invention for the manufacture of a medicinal product for the treatment or prevention of parasitic infestations in animals.

[0022] An alternative embodiment is an isoxazoline compound of formula (I): [ka] [In the formula, R 1 are halogens, CF3, OCF3, CN, n is an integer from 0 to a maximum of 3, preferably 1, 2 or 3; R 2 is C1-C3-haloalkyl, preferably CF3 or CF2Cl, T is a 5-12 membered monocyclic or bicyclic ring system, which is optionally substituted by one or more groups Y; Y is methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent groups Y together form a chain, in particular a 3- to 4-membered chain; Q is X-NR3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more groups; X is CH2, CH(CH3), CH(CN), CO, or CS; R 3 is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanyl, alkylsulfinealkyl, alkylsulfonealkyl, cycloalkyl [ka] and; Z A is hydrogen, halogen, cyano, halomethyl, preferably CF3; R 4 is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; R 5is hydrogen, alkyl or haloalkyl; R 6 is hydrogen, alkyl or haloalkyl; Or R 3 and R 4 Together, [ka] or a salt or solvate thereof, pyrantel pamoate and a macrocyclic lactone compound, and a carrier comprising a stabilizing component comprising at least one flavoring and a poloxamer, more preferably poloxamer P188, preferably about 2 to about 15% by weight of said poloxamer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Definition With respect to the invention described and claimed herein, the following terms and phrases are defined as follows.

[0024] Within the context of the present invention, an "animal dosage form" refers to a composition comprising a drug used to treat and / or diagnose and / or cure and / or prevent a disease in a non-human animal. In this application, an "animal dosage form" may also be referred to as a "palatable chewable animal dosage form" or a "compressed tablet" or a "tablet" or a "chewable tablet", a "finished palatable chewable tablet" or a "tablet composition", or a "composition", or a "formulation" or a "pharmaceutical composition". Such a composition further comprises a veterinarily acceptable excipient, i.e. an excipient or a combination of excipients (non-active ingredients), in addition to the stabilizing components.

[0025] Further, a drug is a substance or combination of substances (composition) that is believed to have properties to treat or prevent disease in an animal; or a substance or combination of substances that can be used in or administered to an animal for the purpose of restoring, correcting or altering physiological function by exerting a pharmacological, immunological or metabolic effect, or for the purpose of performing a medical diagnosis.

[0026] According to the FDA glossary, in the context of this invention, a "pharmaceutical composition" or "animal dosage form" also refers to a "drug product," which is generally a finished dosage form that contains an active pharmaceutical ingredient, although not necessarily in association with other active or inactive ingredients.

[0027] According to the present invention, the term "veterinary" has the same definition as "pharmaceutical", but adapted for animals (meaning non-humans).

[0028] More precisely, "veterinary drug" (or drug product or composition) means a substance or mixture of substances that is manufactured, sold or represented as being used, or suitable for use, in the diagnosis, treatment, control, eradication, mitigation, or prevention of a disease or abnormal physical or mental condition or symptoms thereof in an animal; or in the restoration, correction, control, or alteration of a physical, mental or organ function in an animal.

[0029] As used herein, an approximation such as "about x" refers to a value of x having a margin of ±10% around that value, or ±9, 8, 7, 6, 5, 4, 3, 2, or 1% of that value.

[0030] According to the present application, the terms "% by weight" and "(w / w)%" can be used interchangeably and represent weight / weight. As used herein, these terms represent the weight percentage of the ingredient in the dosage unit formulation.

[0031] As used herein, "infection" or "infestation" refers to the state or condition of having parasites on the body (ectoparasites) or inside the body (endoparasites), unless otherwise specified.

[0032] "Macrocyclic lactone" as used herein refers to a veterinary compound in the avermectin family of compounds, including, for example, ivermectin, abamectin, doramectin, eprinomectin, selamectin, and the like, and also includes the milbemycin family of compounds, including, for example, moxidectin, milbemycin, milbemycin oxime, and the like. A preferred macrocyclic lactone of the compositions of the present invention is moxidectin. A preferred macrocyclic lactone is a stabilized macrocyclic lactone. A preferred stabilized macrocyclic lactone is moxidectin.

[0033] As used herein, unless otherwise specified, "palatable" refers to a pleasant, acceptable, or agreeable taste that will be voluntarily ingested by an animal when presented alone or at least when mixed into the animal's feed.

[0034] As used herein, a "parasite" is a harmful organism that adversely affects the health, welfare, or economic production level of a host animal. Parasites may be endoparasites or ectoparasites and may be temporarily or stationarily attached in or on the host animal.

[0035] "Parasites" as used herein refers to endoparasites and ectoparasites unless otherwise specified. Endoparasites are parasites that live inside the host's body, including helminths (trematodes, tapeworms, nematodes, etc.) and protozoa, more particularly nematodes such as gastrointestinal nematodes, lungworms, and heartworms. Ectoparasites are organisms of the Arthropoda phylum (such as arachnids and insects) that feed through or on the skin of the host. Preferred arachnids are Acari, such as ticks and mites. Preferred insects are midges, lice (blood-sucking and biting), fleas, mosquitoes, and biting flies (stable flies, horn flies, sand flies, blow flies, horseflies, etc.). Preferred compositions of the present invention can be used to treat ectoparasites and endoparasites, i.e., to treat parasitic infections or infestations including fleas, ticks, mites, lice, gastrointestinal nematodes, and heartworms. Parasites also include the various life stages of ectoparasites and endoparasites, such as eggs, pupae, and larvae that feed on or within the body.

[0036] As used herein, "treatment" and similar terms such as "treating" or "treat" refer to the administration of an effective amount of an active drug substance described for use in the present invention to an animal suffering from an infestation (of more or less severity) by one or more species of parasite.

[0037] What constitutes an "effective amount" for use in the present invention is the amount, dose or quantity of an isoxazoline as described herein that is required to completely eradicate the parasites infesting such animal, or at least to significantly reduce the parasitic infestation in the animal. Alternatively, it can refer to the amount, dose or quantity that can effectively control and / or reduce the presence of parasites in the animal's habitat or surroundings, such as a house, building, farm, field, etc.

[0038] "Prevention" or "prophylaxis" means preventing new parasite infestations of an animal by killing adult parasites and developmental or larval stages capable of infesting a host either before they infest the host or immediately after they infest the protected host, and / or preventing or reducing, completely or partially, the development of new generations of parasites.

[0039] As used herein, unless otherwise indicated, "stabilizing component" and "stabilizer" refer to an excipient or combination of excipients (non-active ingredients) that, when combined, are recognized to provide chemical and / or physical stability to one or more of the active agents, i.e., macrocyclic lactone, veterinarily acceptable isoxazoline of formula (I), and / or pyrantel, particularly pyrantel pamoate, which are more stable with the stabilizer than they would be without it. For example, the stabilizing component stabilizes the macrocyclic lactone, i.e., prevents degradation, particularly in the case of moxidectin, to provide a stabilized moxidectin.

[0040] "Stable" as used herein, unless otherwise specified, refers to the overall appearance, moisture content, analysis, antioxidant (BHT) content, degradation products, solubility, hardness, friability, light stability, and microbiological quality of the tablet, as measured under long-term and accelerated stability temperature and humidity conditions according to VICH guidelines GL4 and GL5. Of particular importance is the reduction in the appearance or increase of degradation products of the active ingredients, particularly macrocyclic lactones, especially moxidectin. Detailed Description.

[0041] The present invention provides a palatable animal chewable dosage form comprising an isoxazoline compound of formula (I), pyrantel pamoate, and a stabilized macrocyclic lactone compound selected from moxidectin and milbemycin oxime, and a carrier comprising at least one flavoring agent and a stabilizing component comprising an inorganic alkalizing agent, such as magnesium carbonate, porous silica, or mixtures thereof. In a preferred embodiment, such a dosage form comprises a poloxamer.

[0042] As will be apparent from the description and examples provided below, the inventors have devised a method of significantly improving the treatment of animals with a combination of active ingredients, namely, an isoxazoline compound of formula (I), pyrantel pamoate and a macrocyclic lactone, by administration via a palatable chewable dosage form in the form of a compressed tablet, due to the incorporation of a stabilizing component that provides protection from degradation to the macrocyclic lactone and other active ingredients.

[0043] Therefore, in a further aspect, the present invention relates to the use of a stabilizing component as described in the present application for protecting a macrocyclic lactone compound from degradation.

[0044] Furthermore, animal chewable dosage forms as compressed tablets have been found to be highly palatable and readily accepted by animals.

[0045] Surprisingly, the chewable animal dosage form is found to be so palatable that it is almost completely spontaneously consumed by dogs.This is unexpected, because the tablets examined contain only one flavoring.Most of the palatable compositions of the prior art require many flavorings or palatability enhancers to achieve the same or even lower palatability.

[0046] As used herein, an "isoxazoline" is a compound of formula (I) below, or a salt or solvate thereof: [ka] During the ceremony, R 1 are halogens, CF3, OCF3, CN, n is an integer from 0 to a maximum of 3, preferably 1, 2 or 3; R 2 is C1-C3-haloalkyl, preferably CF3 or CF2Cl, T is a 5-12 membered monocyclic or bicyclic ring system, which is optionally substituted by one or more groups Y; Y is methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent groups Y together form a chain, in particular a 3- to 4-membered chain; Q is X-NR 3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more groups; X is CH2, CH(CH3), CH(CN), CO, or CS; R 3 is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanyl, alkylsulfinealkyl, alkylsulfonealkyl, cycloalkyl [ka] and; Z A is hydrogen, halogen, cyano, halomethyl, preferably CF3; R 4is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; R 5 is hydrogen, alkyl or haloalkyl; R 6 is hydrogen, alkyl or haloalkyl; Or R 3 and R 4 Together, [ka] and forming a substituent selected from the group consisting of:

[0047] In a preferred embodiment of the invention and / or embodiments thereof, T is [ka] Selected from TIFF2024523472000012.tif184155, In T-1, T-3 and T-4, the group Y is preferably hydrogen, halogen, methyl, halomethyl, ethyl or haloethyl.

[0048] In a preferred embodiment of the present invention and / or embodiments thereof, Q in formula (I) is [ka] is selected from R 3 , R 4 , X and Z A is as defined above, Z B teeth [ka] and Z D teeth [ka] It is.

[0049] Preferred compounds of formula (I) are listed in Table 1.

[0050] Table 1: [Table 1]

[0051] TIFF2024523472000017.tif233170

[0052] More preferred compounds of formula (I) are listed in Table 2.

[0053] Table 2: [Table 2]

[0054] TIFF2024523472000019.tif78170

[0055] In particularly preferred embodiments and / or embodiments thereof of the present invention, the isoxazoline compound has the following formula (II): [ka] is represented by In the formula, R 1a , R 1b , R 1c are each independently hydrogen, Cl or CF3. Preferably, R 1a and R 1c is Cl or CF3, R 1b is hydrogen, T is [ka] where Y is methyl, bromine, Cl, F, CN or C(S)NH2, and Q is as defined above.

[0056] In another preferred embodiment of the present invention and / or embodiments thereof, R 3 is H and R 4 is -CH2-C(O)-NH-CH2-CF3, -CH2-C(O)-NH-CH2-CH3, -CH2-CH2-CF3 or -CH2-CF3.

[0057] In another preferred embodiment of the invention and / or embodiments thereof, the isoxazoline compound is selected from fluralaner, afoxolaner, esafoxolaner, sarolaner, lotilaner and tigolaner.

[0058] In one preferred embodiment of the invention and / or its embodiments, the isoxazoline is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CASRN864731-61-3), also known as fluralaner.

[0059] In one preferred embodiment of the invention and / or embodiments thereof, the isoxazoline is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalene-carboxamide (CASRN1093861-60-9). This compound is also known as 4-[5-(5-chloro-α,α,α-trifluoro-m-tolyl)-4,5-dihydro-5-(trifluoromethyl)-1,2-oxazol-3-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethylamino]ethyl]naphthalene-1- or afoxolaner. Afoxolaner is disclosed, for example, in WO 2007 / 079162. In one embodiment, the isoxazoline compound is esafoxolaner.

[0060] In one preferred embodiment of the invention and / or an embodiment thereof, the isoxazoline is 1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidin-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one, preferably 1-(5'-((5S)-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidin-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one (CAS RN: 1398609-39-6). This compound is also known as sarolaner.

[0061] In one preferred embodiment of the invention and / or in one embodiment thereof, the isoxazoline is 3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide, preferably methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[(5S)-5(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide (CAS RN: 1369852-71-0). This compound is also known as Lotilaner.

[0062] In one preferred embodiment of the present invention and / or its embodiments, the compound used as an alternative to the isoxazoline compound is 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2-methyl-5-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN1621436), also known as tigolaner.

[0063] In one preferred embodiment of the invention and / or an embodiment thereof, the isoxazoline is 4H-cyclopenta[c]thiophene-1-carboxamide, 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-(CAS 1414642-93-5), also known as mivorilaner.

[0064] In one preferred embodiment and / or embodiments thereof of the invention, the isoxazoline is ···, in another embodiment the compound of formula (I) is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN928789-76-8).

[0065] In one preferred embodiment of the invention and / or an embodiment thereof, the isoxazoline is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN1164267-94-0) as disclosed in WO2009 / 0080250.

[0066] In one preferred embodiment of the present invention and / or embodiments thereof, the isoxazoline is 5-[5-(3,5-d-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CASRN1231754-09-8) disclosed in WO2010 / 070068.

[0067] Particularly preferred is fluralaner (4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide) as a systemic insecticide and / or acaricide, represented by the following formula (III): [ka]

[0068] Isoxazoline compounds can exist in various isomeric forms. Reference to an isoxazoline compound always includes all possible isomers of such a compound. Unless otherwise stated, a compound structure that does not show a specific stereochemistry is intended to encompass all possible conformational isomeric compositions of the compound, as well as compositions of less than all possible stereoisomers. In some embodiments, the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.

[0069] The isoxazoline compounds of formula (I) can be prepared, for example, according to any one of the methods described in patent applications US2007 / 0066617, WO2007 / 079162, WO2009 / 002809, WO2009 / 080250, WO2010 / 070068, WO2010 / 079077, WO2011 / 075591 and WO2011 / 124998, or according to other methods within the capabilities of a person skilled in the art of chemical synthesis.

[0070] With respect to chemical preparation, it is deemed that the skilled artisan has at his disposal, inter alia, the entire contents of "Chemical Abstracts" and the documents cited therein.

[0071] In one preferred embodiment and / or embodiments thereof of the present invention, the amount of isoxazoline compound included in the palatable chewing animal dosage form can range from about 1 to about 30% by weight. In another embodiment, the amount of such compound can range from about 2 to about 20% by weight. A preferred range is from about 5 to about 18% by weight, particularly from about 10 to about 15% by weight.

[0072] Pyrantel pamoate is a known anthelmintic ingredient. Pyrantel pamoate is present in the dosage form for chewing animals in an amount of about 5% by weight to about 30% by weight, preferably about 10% by weight to about 25% by weight, and more preferably about 15% by weight to about 20% by weight.

[0073] Biologically active macrocyclic lactones (also referred to as macrolides or macrocyclic lactones-ML) are organic molecules that contain a ring structure, said molecules containing a lactone group. Such lactone groups can also be considered as intramolecular carboxylic acid ester groups. Macrocyclic lactones are often found in the metabolic products of bacteria and fungi. Additionally, in one embodiment, the palatable chewing animal dosage forms of the present invention may contain a combination of two or more macrocyclic lactone active agents.

[0074] For the avoidance of doubt, the term "macrocyclic lactones" as used herein includes both natural and synthetic or semi-synthetic macrocyclic lactones, particularly the parasiticidal avermectin and milbemycin compounds.

[0075] Macrocyclic lactones that may be used in the palatable chewing animal dosage forms of the present invention include, but are not limited to, naturally occurring avermectins (e.g., including components designated A1a, A1b, A2a, A1b, B1a, B1b, B2a, and B2b) and milbemycin compounds, semi-synthetic avermectins and milbemycins, avermectin monosaccharide compounds, and avermectin aglycone compounds. Examples of macrocyclic lactone compounds that may be used in the compositions include, but are not limited to, abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554, and milbemycins, such as, but not limited to, milbemectin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, and nemadectin. Also included are 5-oxo and 5-oxime derivatives of the avermectins and milbemycins.

[0076] Macrocyclic lactone compounds are known in the art and are readily available commercially or through synthetic techniques known in the art, see the widely available technical and commercial literature.

[0077] In one preferred embodiment of the present invention and / or embodiments thereof, the one or more biologically active macrocyclic lactones (f1) are selected from the group consisting of abamectin, zimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554 and milbemycins, such as, but not limited to, milbemectin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, nemadectin and mixtures thereof.

[0078] In one preferred embodiment of the present invention and / or embodiments thereof, the one or more biologically active macrocyclic lactones are selected from ivermectin, abamectin, milbemycin oxime, moxidectin, doramectin, selamectin, eprinomectin, emamectin and mixtures thereof. More preferred as biologically active macrocyclic lactones are milbemycin oxime or moxidectin, or ivermectin. Most preferred is moxidectin.

[0079] In one preferred embodiment of the present invention and / or embodiments thereof, the amount of macrocyclic lactone may range from about 0.001 to about 10% by weight of the composition, with effective concentrations varying between different macrocyclic lactone compounds.

[0080] In one preferred embodiment and / or embodiments thereof of the present invention, the palatable chewing animal dosage form includes one or more highly potent bioactive macrocyclic lactones, such as moxidectin, in an amount ranging from about 0.0075 to about 0.075% by weight. In another embodiment, the amount of moxidectin may range from about 0.01 to about 0.07% by weight. A preferred range is from about 0.0125 to about 0.065% by weight.

[0081] When the biologically active macrocyclic lactone is milbemycin oxime, the amount can range from 0.5 to 20% by weight of the aggregate, preferably about 1%, about 2%, about 3%, about 4%, or about 5% by weight.

[0082] In one preferred embodiment of the invention and / or embodiments thereof, the macrocyclic lactone is ivermectin contained in a palatable chewing animal dosage form and can be in the range of 0.0075-0.075% by weight, preferably about 0.015%, about 0.0225%, about 0.03%, about 0.0375% by weight.

[0083] Other medications known in the veterinary arts, such as vitamins, mineral supplements, and the like, are also contemplated for inclusion in palatable, chewable animal dosage forms according to the present invention.

[0084] The manufacture of the palatable chewing animal dosage form of the present invention in the form of a hard compressed tablet or as a soft chewing composition can involve the process of preparing several separate granules and combining them into a palatable chewing animal dosage form, for example, the manufacture of a granule containing a moxidectin active ingredient and a second granule containing an isoxazoline, e.g., fluralaner, and a pyrantel active ingredient, e.g., pyrantel pamoate.

[0085] These granules can be, for example, mixed with extragranular materials and compressed into a final palatable chewing animal dosage form in the form of a hard compressed tablet, or the granules (or granulations) are included in a soft chewing animal composition that is formed by molding, for example, rotomolding or extrusion.

[0086] In the palatable chewing animal dosage form of the present invention, the macrocyclic lactone compound, particularly moxidectin, is stabilized with a stabilizing component comprising an inorganic alkalizing agent, porous silica, or mixtures thereof. In a preferred embodiment, the stabilizing component includes a poloxamer.

[0087] The stabilizing component ingredients may be present in any of these components of the palatable chewable animal dosage form, in any of the granules (or granulations), or in the extragranular material.

[0088] Moxidectin is susceptible to hydrolytic and oxidative degradation. Stability issues can be observed due to interactions with flavors and other non-active ingredients used in tablet formulations. Stabilizing ingredients address these challenges and avoid the formation of moxidectin degradation products.

[0089] The amount of moxidectin, a highly potent macrocyclic lactone, in the palatable chewing animal dosage form of the present invention is very low compared to other active ingredients present. Therefore, degradation may easily lead to combination products with sub-therapeutic levels of moxidectin. Moxidectin degradants are known and include the acid-catalyzed degradants 23-Z-moxidectin, 23-keo nemadectin and 23-keto-alpha moxidectin, and the base-catalyzed degradants delta-2-moxidectin and 2-epimer moxidectin.

[0090] In addition to stability, the low amount of moxidectin in palatable chewable veterinary dosage forms can also cause issues with the uniformity of the pharmaceutical content. To overcome the degradation of moxidectin, improve the content uniformity, and ensure a stable, homogenous composition, moxidectin was stabilized with a stabilizing component to address these challenges.

[0091] In addition to stability, the stabilization approach also aids in the uniform distribution of moxidectin in the granules as well as in the final tablet composition to ensure content uniformity. Additional hydrophilic polymers, especially non-cellulosic polymers and antioxidants can be added to the moxidectin granules to enhance stability and ensure a longer shelf life of the final drug product.

[0092] Alternatively, the addition of hydrophilic polymers, particularly non-cellulosic polymers, and antioxidants to moxidectin granules improves stability compared to when either is used alone.

[0093] In one embodiment, the stabilizing component comprises at least one inorganic alkalizing agent, porous silica, or a mixture thereof.

[0094] Inorganic alkalizing agents can be used to help stabilize the active ingredient in some chewing animal dosage forms (composition granules and general blends) or tablets. In one embodiment, the inorganic alkalizing agent is incorporated into the moxidectin granules.

[0095] Preferably, the inorganic alkalizing agent is magnesium carbonate. The most common forms of magnesium carbonate are the anhydrous salt called magnesite (MgCO3) and the dihydrate, trihydrate, and pentahydrate known as barringtonite (MgCO3·2H2O), nesquehonite (MgCO3·3H2O), and lancefordite (MgCO3··5H2O), respectively. Several basic forms also exist as minerals, such as artinite (MgCO3·Mg(OH)2·3H2O), hydromagnesite (4MgCO3·Mg(OH)2·4H2O), and diepingite (4MgCO3·Mg(OH)2·5H2O). Preferably, the magnesium carbonate is light magnesium carbonate.

[0096] Light magnesium carbonate is an inorganic compound with the chemical formula MgCO3. The difference between light and heavy magnesium carbonate is that light magnesium carbonate is composed of four water molecules, while heavy magnesium carbonate contains five water molecules. References to "light" and "heavy" magnesium carbonate actually refer to hydromagnesium oxide and dipingite (respectively), which are magnesium hydroxycarbonates.

[0097] The magnesium carbonate can be included in any of the granular components or in extragranular materials, hi one embodiment, a portion of the magnesium carbonate is included in the moxidectin granules.

[0098] In certain embodiments, magnesium carbonate is included in the dry mix used to prepare the moxidectin granules.

[0099] In certain embodiments, some of the magnesium carbonate is included in the moxidectin solution and some is included in the dry mix that forms the moxidectin granules, hi another embodiment, magnesium carbonate is included in the moxidectin solution used to form the moxidectin granules.

[0100] In one preferred embodiment and / or embodiments thereof of the present invention, the inorganic alkalizing agent included in the chewing animal dosage form can range from about 0.5 to about 5% by weight, with a preferred range being from about 1.2 to about 1.8% by weight.

[0101] In one embodiment, the amount of magnesium carbonate in the moxidectin granules can range from about 1 to about 8% by weight, specifically 6%.

[0102] Porous silica can be used to help stabilize the active ingredient in some of the chewing animal dosage forms (composition granules and general blends) or in tablets. In one embodiment, porous silica is incorporated into the moxidectin granules.

[0103] In one embodiment, the porous silica is magnesium aluminum silicate. Magnesium aluminum silicate is an off-white powder used in pharmaceutical manufacturing processes as an absorbent, anti-caking agent, opacifier, slip modifier, and aqueous thickener. It can be used in tablet manufacture and pharmaceutical suspensions, and is also used in the cosmetics industry. Neutral and alkaline grades of magnesium aluminometasilicate are known.

[0104] Neusilin® is a synthetic amorphous form of magnesium aluminometasilicate. It is a multifunctional excipient that can be used in both direct compression and wet granulation of solid dosage forms. Particularly preferred is Neusilin® US2 (CAS number: 12511-31-8), available from, for example, Fuji Chemical Industry Co, Ltd.

[0105] In one preferred embodiment and / or embodiments thereof of the present invention, the amount of porous silica contained in the chewing animal dosage form can range from about 1 to about 15% by weight. In another embodiment, the amount of moxidectin can range from about 2 to about 10% by weight. A preferred range is from about 4 to about 8% by weight.

[0106] The stabilizing component preferably comprises a hydrophilic polymer. The hydrophilic polymer can be used to help stabilize the active ingredient in the part of the chewing animal dosage form (composition granules and general blend) or in the tablet, i.e., the final blended and compressed composition. In one embodiment, the hydrophilic polymer comprises a non-cellulosic polymer, preferably a poloxamer. Poloxamers are non-ionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).

[0107] Poloxamers are also known by the trade names Pluronic and Kolliphor (pharmaceutical grade).

[0108] Because the length of the polymer blocks can be customized, there are many different poloxamers with slightly different properties. For the general term poloxamer, these copolymers are usually named with the letter P (poloxamer) followed by three digits, where the first two digits are multiplied by 100 to give the approximate molecular weight of the polyoxypropylene core, and the last digit is multiplied by 10 to give the percent polyoxyethylene content (e.g., P407 = a poloxamer with a polyoxypropylene molecular weight of 4000 g / mol and a polyoxyethylene content of 70%).

[0109] Particularly preferred is Poloxamer 188.

[0110] Poloxamer 188 is a nonionic block copolymer of ethylene oxide and propylene oxide represented by the following structure, where the a and b blocks contain 80 and 27 units, respectively. [ka]

[0111] It has an average molecular weight of 7680-9510 g / mol. The surfactant properties of Poloxamer 188 make this copolymer useful in cosmetic, pharmaceutical and industrial applications. Its stabilizing role in the chewable dosage form of the present invention was surprising.

[0112] In one preferred embodiment and / or embodiments thereof of the present invention, the amount of poloxamer included in the chewing animal dosage form can range from about 1 to about 15% by weight. In another embodiment, the amount of moxidectin can range from about 2 to about 10% by weight. A preferred range is from about 4 to about 10% by weight.

[0113] The incorporation of poloxamer has been shown to have a significant positive effect on reducing the degradation of moxidectin during processing, on its stability during storage, especially under ambient conditions, and therefore on the shelf life of the chewing animal dosage form.

[0114] The poloxamer is preferably contained in a macrocyclic lactone, particularly a moxidectin granule, which is then combined with one or more additional granular and extragranular materials into a chewing animal dosage form.

[0115] A preferred embodiment is a moxidectin granule comprising a macrocyclic lactone, in particular stabilized moxidectin. In a preferred embodiment, such a moxidectin granule comprises at least one poloxamer, in particular poloxamer 188, in combination with at least one other stabilizing component, preferably selected from BHT, magnesium metasilicate, light magnesium carbonate and microcrystalline cellulose.

[0116] In one embodiment, such moxidectin granules are contained in a flavored compressed tablet.

[0117] In another embodiment, granules comprising macrocyclic lactones, particularly moxidectin stabilized according to the present invention, are used in a process of incorporating moxidectin in the form of moxidectin granules into soft chewing animal dosage forms.

[0118] In another embodiment, the hydrophilic polymer comprises a cellulose-based polymer, in particular HPMC. Hypromellose (INN), an abbreviation for hydroxypropyl methylcellulose (HPMC), is a semi-synthetic inert viscoelastic polymer used as an eye drop, and is also an excipient and controlled delivery component of oral drugs, and is included in a variety of commercial products. HPMC is used as an excipient in oral tablet and capsule formulations, and functions as a binder or sustained release agent depending on the grade.

[0119] In another embodiment, the hydrophilic polymer comprises a combination of a cellulosic polymer and a non-cellulosic polymer, particularly preferred is a combination of poloxamer and HPMC, preferably poloxamer 188 and HPMC.

[0120] Particularly useful is HPMC USP 2910 having 28-30% methoxy groups and 7-12% hydroxypropoxy groups.

[0121] It is commercially available from DuPont in the METHOCEL™ line of products. It is available in a variety of E grades ranging from low to high viscosity.

[0122] Particularly useful are HPMC of low viscosity grades E3, E5 or E6, corresponding to viscosities (2%) of 3, 5 or 6 mPas.

[0123] In one embodiment, the hydrophilic polymer is incorporated into the fluralanel-pyrantel granules and / or the moxidectin granules. An additional binder (HPMC5cps / HPMCE5) was evaluated to bind moxidectin to inert materials and reduce the loss of moxidectin during drying. Tests were performed using different concentrations of HPMC5 (1mg, 2mg, and 4mg).

[0124] In one preferred embodiment and / or embodiments thereof of the present invention, the amount of hydrophilic polymer in the chewing animal dosage form can range from about 1 to about 20% by weight. In another embodiment, the amount of hydrophilic polymer can range from about 2 to about 15% by weight. One preferred range is about 5 to about 10% by weight. One preferred range for HPMC is about 0.1 to 4% by weight.

[0125] The stabilizing component preferably consists of an antioxidant, which may also be used to help stabilize parts of the active ingredient (composition granules and general blends) or the entire tablet.

[0126] Antioxidants are substances used to inhibit oxidation. Antioxidants suitable for inclusion in the chewing animal dosage form include, but are not limited to, ascorbic acid, citric acid, glutathione, tocopherol and its esters, tert-butylhydroquinone (TBHQ), butylated hydroxyanisole (also known as BHA, 2-tert-butyl-4-hydroxyanisole, 3-tert-butyl-4-hydroxyanisole, or mixtures thereof), and butylated hydroxytoluene (BHT, also known as 2,6-ditert-butyl-4-methylphenol).

[0127] In one embodiment, the antioxidant is incorporated into the moxidectin granules. It is preferred that an antioxidant, particularly BHT, is present in the moxidectin granules. Butylated hydroxyl toluene protects moxidectin from oxidative degradation.

[0128] In one preferred embodiment and / or embodiments thereof of the present invention, the antioxidant contained in the palatable chewing animal dosage form may be in the range of 0.001-1.00% by weight.

[0129] The amount of antioxidant in the composition is about 0.01% to about 0.5% by weight of the total weight of the tablet. The preferred amount of antioxidant is about 0.05% to about 0.2% by weight of the total weight of the tablet.

[0130] A more preferred amount of antioxidant is about 0.1% by weight of the total weight of the tablet.

[0131] The palatable chewable dosage form according to the present invention further comprises at least one flavoring. According to the present application, the flavoring can be considered as the sensory impression of the palatable chewable dosage form. In particular, the flavoring can affect the sense of taste and smell. In this case, the flavoring is added to the palatable chewable dosage form in order to make the treated animal attracted to its administration. The flavoring can be selected depending on the treated animal.

[0132] In one preferred embodiment of the invention and / or embodiments thereof, the flavouring (e) is selected from chicken flavour, pork flavour, beef flavour, ham flavour, fish flavour, vegetarian flavour, Chardex hickory flavour, artificial flavour, sweet apple & molasses flavour and mixtures thereof, in particular pork liver flavour.

[0133] In one preferred embodiment of the present invention and / or its embodiments, the amount of flavorings contained in the palatable chewable dosage form may range from 2 to 35% by weight. In another embodiment, the amount of such compounds may range from 5 to 30% by weight. A preferred range is 10 to 25% by weight, in particular 5 to 10%. Alternatively, the amount of flavorings is less than 2% by weight.

[0134] Surprisingly, it has been discovered that just one flavoring agent present in the palatable chewable dosage form according to the present invention exhibits superior palatability when administered to dogs. In a preferred embodiment, the flavoring agent is pork liver flavor.

[0135] The palatable chewable dosage form further comprises a carrier comprising one or more veterinarily acceptable excipients, including those excipients understood as binders, fillers, disintegrants, surfactants, lubricants, glidants, and colorants.

[0136] Binders are used to add cohesion to the individual granules and the final blend composition, forming a clump and providing the necessary binding to ensure a suitable compressed tablet form. These binders are traditionally used in direct compression tablets and are described in Lieberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol.1, (1990).

[0137] Non-limiting examples of veterinarily acceptable binders include, but are not limited to, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (e.g., PVP, povidone (Kollidon 25, 30, and 90)), and copovidone (Kollidon VA64), polyethylene glycol, acacia, corn syrup solids, tragacanth gum, gelatin, carnauba wax, alginates, and mixtures thereof.

[0138] Preferred binders for palatable chewable dosage forms are carboxymethylcellulose, HPC, PVP, polyethylene glycol, corn syrup solids, gelatin, and mixtures thereof.

[0139] HPMC provides some binding properties to the moxidectin granules and thus could also be considered a binder, but for this palatable chewable dosage form, it is included among the ingredients as a stabilizing agent (stabilizer).

[0140] The amount of binder (excluding HPMC) in the composition is about 6-10% by weight of the total weight of the tablet. The preferred amount of binder in the composition is about 7-9% by weight of the total weight of the tablet.

[0141] The palatable chewable dosage form includes at least one veterinarily acceptable excipient that is a filler, non-limiting examples of which include starches (e.g., corn, potato, tapioca, etc.), sugars (e.g., lactose, fructose, mannitol), etc. (including hydrous and anhydrous forms), celluloses (e.g., methylcellulose, microcrystalline cellulose, ethylcellulose, etc.), etc.

[0142] The amount of filler is about 20-50% by weight of the total weight of the composition. A preferred amount of filler is about 40-48% by weight of the total weight of the composition. A more preferred amount of filler is about 42-46% by weight, or 20-30% by weight of the total weight of the composition.

[0143] The palatable chewable dosage form includes at least one veterinarily acceptable excipient that is a disintegrant.

[0144] Disintegrants are compounds that increase the ability of a tablet to break down into smaller pieces when contacted with a liquid, preferably water.

[0145] Non-limiting examples of veterinarily acceptable disintegrants include starch, including pregelatinized starch and modified starches, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, magnesium aluminum silicate, guar gum, alginic acid, sodium alginate, calcium alginate, chitosan, croscarmellose sodium (e.g., Ac-Di-Sol®), sodium starch glycolate, and the like, and mixtures thereof.

[0146] The amount of disintegrant in the composition is about 5 to about 15% by weight of the total weight of the composition. The preferred amount of disintegrant in the composition is about 8 to 12% by weight of the total weight of the composition.

[0147] Surfactants can be considered as substances that reduce the interfacial tension between two phases. Surfactants can also be added to promote solubilization of the active agent, prevent crystallization, and prevent phase separation.

[0148] Common surfactants are alkyl sulfates (eg, sodium lauryl sulfate), alkyl trimethyl ammonium salts, alcohol ethoxylates, and the like.

[0149] In one preferred embodiment and / or embodiments thereof of the present invention, the surfactant included in the palatable chewing animal dosage form is sodium lauryl sulfate, which may be in the range of 0.1-10.0% by weight, preferably about 2% by weight.

[0150] The palatable chewable dosage form contains at least one veterinarily acceptable excipient which is a glidant and a lubricant.

[0151] Glidants can be used to improve flowability. Traditionally, talc was used as a glidant but has now been almost completely replaced by colloidal silica.

[0152] The amount of glidant in the palatable chewable dosage form is about 0.1-0.75% by weight of the total tablet weight. In one preferred embodiment of the present invention and / or embodiments thereof, the amount of glidant included in the palatable chewable dosage form may range from 0.15-0.3% by weight.

[0153] A lubricant can generally be considered as a substance suitable for reducing friction, including static, sliding and rolling friction.

[0154] The lubricant is preferably a stearate or a fatty acid, more preferably an alkaline earth metal stearate, such as magnesium stearate. In one preferred embodiment of the present invention and / or embodiments thereof, the lubricant contained in the palatable chewable dosage form may be in the range of 0.1-10.0% by weight, preferably 0.2-1%.

[0155] The palatable chewable dosage form may include at least one veterinarily acceptable excipient which is a colorant. Colorants may be added to the composition to enhance its physical appearance.

[0156] The amount of colorant in the composition is about 0.1% by weight to about 2% by weight, preferably about 0.9% by weight to 1.5% by weight, of the total weight of the tablet.

[0157] The palatable chewable dosage form is prepared using at least one solvent.

[0158] Solvents are used in the dissolving, suspending and mixing operations to prepare the individual granulation ingredients, and the solvent evaporates from the granules as they are dried prior to further processing.

[0159] However, residual solvents may be present in the final composition blend and / or compressed tablets. Residual solvents may further evaporate over time. Solvents include water, ethanol, and mixtures thereof.

[0160] The palatable chewable dosage forms are prepared by conventional granulating, mixing, milling, sieving, and compressing procedures.

[0161] A wet granulation process was developed to granulate moxidectin, which is physically separated from the other active ingredients (fluralaner and pyrantel pamoate) during the granulation process, thereby forming a physical barrier around the moxidectin particles.

[0162] A palatable chewable dosage form is prepared as follows.

[0163] a.1) dry blending an isoxazoline compound and pyrantel pamoate with a disintegrant, a filler, a colorant and a surfactant; 2) preparing a solution of a solvent and a cellulosic polymer; 3) mixing the dry blend of fluralaner and pyrantel pamoate with the solution in a high shear mixer granulator to produce an isoxazoline-pyrantel granule; 4) drying and grinding the isoxazoline-pyrantel granule to produce an isoxazoline and pyrantel pamoate granule.

[0164] b.1) dry blending porous silica, fillers and an alkalizing agent, particularly magnesium carbonate; 2) dissolving moxidectin in a solvent along with a non-cellulosic polymer and an antioxidant; 4) mixing the dry blend with the moxidectin solution in a high shear mixer granulator to produce moxidectin granules; 4) drying and grinding the moxidectin granules to produce moxidectin granules.

[0165] c.1) preparing a blend by mixing flavor with filler, disintegrant, color, and glidant; 2) mixing the isoxazoline-pyrantel pamoate granules and moxidectin granules with the blend; 3) mixing the blend with a lubricant and compressing the blend into a finished palatable chewable tablet to produce a final dry blend.

[0166] The final composition blend is a generic blend that can be used to produce tablets of various sizes and shapes with consistent weight percent distribution of the active ingredient as a chewing animal dosage form. The compressed tablets are packaged.

[0167] In one embodiment, the palatable chewable dosage form contains about 12.5% ​​by weight of fluralaner. Tablet strengths and sizes contain different amounts of fluralaner. For example, each tablet can contain about 1 mg to about 800 mg of fluralaner. In one aspect, the tablets can contain about 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 and about 800 mg of fluralaner.

[0168] Preferred amounts of fluralaner in the palatable chewable dosage form are about 25 mg / tablet, 50 mg / tablet, 100 mg / tablet, 200 mg / tablet, 400 mg / tablet, and 600 mg / tablet. Different tablet strength dosages are used to accommodate animals of different weights, so that each animal can receive a fluralaner dose of about 1-35 mg / kg, preferably about 5-25 mg / kg. In one embodiment, the dose is 8-15 mg / kg, in particular 10 mg / kg.

[0169] The palatable chewable dosage form contains about 0.03% by weight (i.e., about 0.031% by weight) of moxidectin based on the total weight of the tablet. Tablet strengths and sizes contain different amounts of moxidectin. For example, the tablet can contain about 0.01 mg to about 3.6 mg of moxidectin. Preferably, the tablet can contain about 0.01 mg, 0.03 mg, 0.06 mg, 0.08 mg, 1.0 mg, or about 1.2 mg of moxidectin.

[0170] Preferred amounts of moxidectin are about 0.0625 mg / tablet, 0.125 mg / tablet, 0.25 mg / tablet, 0.5 mg / tablet, 1 mg / tablet, and 1.5 mg / tablet. Dosage amounts in different tablet strengths are used to accommodate animals of different weights, such that each animal can receive a dose of moxidectin of about 25 μg / kg, preferably about 0.025 to about 0.05 mg / kg.

[0171] The palatable chewable dosage form contains about 18% by weight of pyrantel pamoate (corresponding to 6.25% pyrantel) based on the total weight of the tablet. Those skilled in the art can calculate the amount of pyrantel pamoate required from the amount of pyrantel. Tablet strengths can contain different amounts of pyrantel pamoate. For example, each tablet can contain about 15 mg to about 1000 mg of pyrantel pamoate.

[0172] Preferred amounts of pyrantel are 12.5 mg / tablet, 25 mg / tablet, 50 mg / tablet, 100 mg / tablet, 200 mg / tablet, and 300 mg / tablet. Dosage amounts in different tablet strengths are used to accommodate animals of different weights, such that each animal can receive a dose of about 4.0 to about 10.0 mg / kg of pyrantel, preferably about 5 mg / kg of pyrantel.

[0173] Preferred tablet strengths of each active agent (fluralaner, moxidectin, and pyrantel) for the tableting composition include: 1) about 25 mg fluralaner, 0.0625 mg moxidectin, and 12.5 mg pyrantel base (36 mg pyrantel pamoate); 2) about 50 mg fluralaner, 0.125 mg moxidectin, and 25 mg pyrantel base (72 mg pyrantel pamoate); 3) about 100 mg fluralaner, 0.25 mg moxidectin, and pyrantel. 50 mg base (144 mg pyrantel pamoate); 4) approximately 200 mg fluralaner, 0.50 mg moxidectin, and 100 mg pyrantel (288 mg pyrantel pamoate); 5) approximately 400 mg fluralaner, 1 mg moxidectin, and 200 mg pyrantel base (576 mg pyrantel pamoate); and 6) approximately 600 mg fluralaner, 1.5 mg moxidectin, and 300 mg pyrantel base (864 mg pyrantel pamoate).

[0174] Tablet weights range from about 200 mg for 25 mg fluralaner tablets to about 4800 mg for 600 mg fluralaner tablets.

[0175] The palatable chewable dosage form and tablets of different sizes / strengths provide doses of about 10 mg / kg to 20 mg / kg fluralaner, about 25 μg / kg to about 50 μg / kg moxidectin, and about 5 mg / kg to about 10 mg / kg pyrantel.

[0176] The hardness of the palatable chewable dosage form can be measured by an actual laboratory or manufacturing tablet hardness tester device to determine the tablet's breaking point and structural integrity. Tablet hardness values ​​range from about 20N to about 500N. For example, the tablet hardness of 3mg, 6mg, 12mg, 24mg, 48mg, and 72mg tablets range from about 30-70N, 40-120N, 60-150N, 100-250N, 140-300N, and 200-400N, respectively.

[0177] The individual hard tablet weights are approximately 200 mg, 400 mg, 800 mg, 1600 mg, 3200 mg, and 4800 mg. The unit of hardness scale is N, Newton, which is a measure of the force required to break a tablet. 1 N is 1 kg*m / s 2 is equivalent to.

[0178] Hardness is based on a combination of factors including, but not limited to, tablet shape, surface area, thickness, active agents, excipients, and compression force. Depending on the size of the tablet, tablet hardness ranges from approximately 20N to 500N. The unit of force can also be defined as kilopond (kp), where 1kp=9.80665N.

[0179] In another embodiment, granules comprising a macrocyclic lactone, in particular moxidectin stabilized according to the present invention, are used in a process for incorporating moxidectin in the form of moxidectin granules into a soft chewing animal dosage form.

[0180] Thus, in an alternative embodiment, the present invention relates to a palatable soft chew composition comprising the moxidectin granules described herein, stabilized as described herein. Such a palatable soft chew composition has a hardness lower than that of the compressed tablets described herein. Such soft chew compositions are known in the art, and processes for producing such dosage forms by molding or extrusion are described in the prior art.

[0181] The palatable chewable dosage forms of the present invention are particularly suitable for combating parasites in mammalian subjects, such as humans, including primates (e.g., monkeys), equines (e.g., horses), canines (e.g., dogs), and felines (e.g., domestic cats).

[0182] In some embodiments of the present invention, the palatable chewable dosage form is administered to treat (or to manufacture a medicament for) a parasitic disease in an animal. The term "parasitic disease" includes pathological conditions and diseases directly related to or caused by one or more ectoparasites, such as anemia and flea allergy dermatitis. It also includes pathological conditions or diseases related to or caused by one or more vector-borne pathogens, such as Lyme disease, ehrlichiosis (especially canine ehrlichiosis), and tick-borne Rocky Mountain spotted fever.

[0183] The present invention also relates to a method of treatment in which at least a concomitant goal of controlling ectoparasites in and / or on an animal is to control ectoparasitic infestations in an environment occupied (regularly or continuously) by the animal. In some such embodiments, for example, the animal is a companion animal (e.g., a cat or a dog). The environment can be, for example, a house or other residence, a room, an enclosure, a shed or containment, bedding, etc. EXAMPLES

[0184] The present invention is further described by the following compositional examples, which are intended to further illustrate the invention and are not intended, nor should they be construed, to limit the scope of the invention.

[0185] A palatable hard-chew composition containing fluralaner, moxidectin, and pyrantel pamoate was prepared and evaluated for palatability, stability, and pharmacokinetics.

[0186] Example 1 illustrates an example of a stable, palatable composition.

[0187] Example 1. Composition [Table 3]

[0188] A single tablet blend is used to prepare chewable tablets.

[0189] The manufacture of the tablets involves the preparation of a granule containing the moxidectin active ingredient and a second granule containing the isoxazoline, eg, fluralaner and pyrantel, active ingredients.

[0190] These two granules are then mixed with extra-granular material and compressed.

[0191] Part A: Fluralaner and pyrantel granules Fluralaner, pyrantel pamoate, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium and brown pigment blend were sieved and blended in a high shear mixer granulator to form a dry mixture.

[0192] Binder solution was prepared by dissolving hypromellose in purified water with stirring. The dry mixture was granulated with binder solution. The wet mass was dried in a fluid bed apparatus. The dry granules were milled and sieved.

[0193] Part B - Moxidectin Granules: A moxidectin solution was prepared by slowly adding poloxamer 188 to ethanol. Purified water was added to it in an ethanol to water ratio (80:20) (40 wt%) to obtain a clear solution. An aliquot of butylated hydroxytoluene was added to the clear solution. After the BHT was dissolved, an aliquot of moxidectin was added to the solution and stirred until a clear solution was formed.

[0194] Microcrystalline cellulose (Ceolus UF711), Neusilin US2, light magnesium carbonate, and hypromellose were sieved and blended in a mixer granulator. The dry blend material was granulated with moxidectin solution. The wet blend was dried in a fluid bed apparatus, and the moxidectin granules were milled and sieved.

[0195] Part C: Extra-granular materials: Step 1: Part A and Part B granules were dispensed as per batch size.

[0196] The brown pigment blend, microcrystalline cellulose, croscarmellose sodium, pork liver flavor, and colloidal silicon dioxide were blended and sieved.

[0197] Mixing Part A Granules with Part B Granules: The fluralaner granules, pyrantel pamoate granules and moxidectin granules were weighed and mixed with the extra-granular materials and magnesium stearate to prepare the final mixture for compression. The blend was compressed into the finished smooth chewable tablets.

[0198] [Table 4]

[0199] TIFF2024523472000026.tif255157

[0200] TIFF2024523472000027.tif255159

[0201] TIFF2024523472000028.tif251168

[0202] TIFF2024523472000029.tif255152

[0203] TIFF2024523472000030.tif255160

[0204] Example 2: Evaluation of mouthfeel Objective: To determine the oral acceptability of chewable tablets with different flavors in Beagle-type dogs.

[0205] Test items: Three different placebo chewable tablets (A, F, G). Tablet A contained 8% pork liver flavor. Tablet F contained 12% pork liver flavor and contained no brewer's yeast or NaCl. Tablet G contained 8% pork liver flavor and contained no brewer's yeast or NaCl. Tablets F and G contained 1% of the alkalizing agent magnesium carbonate (equivalent to 4% magnesium carbonate in moxidectin granules).

[0206] Placebo chewable tablets were prepared in a similar manner to that described in this application.

[0207] Table 1: Composition Test Formulations [Table 5]

[0208] Thirty dogs participated in the study (10 dogs per group). The study was conducted over 6 days, during which the dogs were given three different flavors of chewable tablets (Formulations A, F, and G) on two consecutive days each. Tolerability was determined based on whether the chewable tablets were consumed completely, partially, or not at all.

[0209] result: Percent acceptability was 100% for all chewable tablet formulations. The study demonstrated that the alkalizing agent, magnesium carbonate, did not affect palatability and that lower levels of flavoring were equally effective.

[0210] Conclusions: All flavored chewable tablets tested demonstrated palatability of 80% or greater. The addition of the alkalizing agent magnesium carbonate did not affect palatability, and a single flavoring agent was sufficient to reach very high palatability in dogs.

[0211] Example 3 Pharmacokinetic profile of a chewable formulation of a combination of isoxazoline, moxidectin and pyrantel following oral administration The objective of this study was to compare the plasma pharmacokinetic profile of compressed tablets containing fluralaner, moxidectin, and pyrantel according to the present invention as described in Table 3 with the commercially available combination chewable tablet Simparica Trio (Zoetis) and a fluralaner-only chewable formulation after a single oral administration to dogs.

[0212] Study Design: Test compounds were administered orally to 15 dogs in total, 5 beagles per dose group.

[0213] Table 2: Composition of the test formulation according to the invention [Table 6]

[0214] Table 3: Study Plan [Table 7]

[0215] Each animal was administered a chewable tablet or chew by placing it on the tongue in the back of the mouth and allowing swallowing to be initiated.

[0216] Plasma was obtained from the collected blood samples and analyzed for concentrations of the test compounds (R-fluralaner, S-fluralaner, moxidectin, and pyrantel). Individual blood samples (approximately 3 mL per sample) were collected from all dogs by jugular or cephalic vein puncture into EDTA tubes for analysis. Blood samples were collected at the following time points: pretreatment (within 2 hours before dosing) and approximately 2, 4, 8 (± 15 minutes), 24, 48 (± 30 minutes), 72, 168, 336, and 720 (± 60 minutes) hours after dosing.

[0217] result: Fluralane AUC tlast , T max and half-life were comparable in all treatment groups.

[0218] Moxidectin C max was slightly higher for the competitive tablet compared to the test formulation. AUC tlast was slightly higher for the test formulation compared to the competitor. T max was comparable across all treatment groups. The half-life was greater for the test formulation compared to the comparator. Pyrantel C max was slightly higher for the test formulation compared to the competitive tablet. AUC tlast was slightly higher for the test formulation compared to the competitive tablet. T max and half-life were comparable in all treatment groups.

[0219] Table 4 Fluralaner Comparison [Table 8]

[0220] Table 5. Comparison of moxidectin and pyrantel [Table 9]

[0221] Given that moxidectin is known to be relatively unstable in the presence of agents that accelerate acid hydrolysis, generating the two most commonly observed degradation products, 23-ketonemadectin and 23-Z moxidectin, efforts were made to optimize the formulation in a manner that minimized this effect.

[0222] Because moxidectin is susceptible to degradation, various combinations of polymers, pH modifiers, complexing agents, and adsorbents were evaluated to further protect moxidectin and mitigate stability issues. Polymers included poloxamer 188 (P188) and hydroxypropyl methylcellulose (HPMC); complexing agents included HP-β-cyclodextrin; adsorbents included magnesium aluminometasilicate and porous microcrystalline cellulose; pH modifiers included sodium citrate, magnesium carbonate, meglumine, arginine, and tromethamine.

[0223] Various combinations of polymers, adsorbents, and alkalizing agents were screened for moxidectin granulation. Polymers included HP-β-cyclodextrin, poloxamer 188 (P188), and hydroxypropyl methylcellulose (HPMC); absorbents included magnesium aluminometasilicate (Neusilin US2) and microcrystalline cellulose (Ceolus UF711); alkalizing agents included sodium citrate, magnesium carbonate, meglumine, arginine, and tromethamine.

[0224] The moxidectin granules were mixed with fluralaner-pyrantel granules, added with at least one veterinarily acceptable excipient, compressed and placed under accelerated (40° C. / 75% RH) stability conditions.

[0225] From these studies, it was observed that moxidectin significantly degrades without the use of a stabilizing component comprising a veterinarily acceptable excipient selected from the group consisting of inorganic alkalizing agents, porous silica, and mixtures thereof. Thus, one aspect of the present invention is the use of a stabilizing component comprising a veterinarily acceptable excipient selected from the group consisting of hydrophilic polymers, inorganic alkalizing agents, porous silica, and mixtures thereof in a moxidectin granulation process to provide stability to moxidectin.

[0226] A combination of poloxamer 188 (P188), magnesium aluminometasilicate (Neusilin US2), and magnesium carbonate was found to be the most effective in stabilizing moxidectin.

[0227] The combination of poloxamer 188 (9.375%) + Neusilin US2 (6.250%) + magnesium carbonate (0.5-1% in tablet) was found to be the most effective in stabilizing moxidectin at 2 months compared to HP-β-cyclodextrin (1.00%) + Neusilin US2 (8.47%) and HPMC (2.00%) + sodium citrate (0.75%).

[0228] Next, a high poloxamer:moxidectin (288:1) solution with magnesium carbonate added to the premix as a dry form (4% in moxidectin granules) and a low poloxamer:moxidectin (200:1) solution adsorbed onto Neusilin-Ceolus and alkalized with magnesium carbonate (2% in moxidectin granules) were evaluated to determine their effect on the stability of moxidectin in compressed tablets. Under accelerated stability conditions for 3 months, these combinations were found to be effective in stabilizing moxidectin with low levels of degradants in the tablets (0.6 for ketomoxidectin and 0.7 for Z-moxidectin).

[0229] Although low levels of degradants were achieved, the optimum level of magnesium carbonate was further evaluated. Best stability was achieved with a high poloxamer:moxidectin (288:1) solution (18.75% poloxamer in the moxidectin granules) and an optimum level of magnesium carbonate added as a dry form in the premix. The amount of magnesium carbonate in the moxidectin granules is about 2-6% by weight; the preferred amount is about 4-6% by weight; the most preferred amount is about 6% by weight.

[0230] Six-month stability studies on compressed tablets manufactured with poloxamer, Neusilin, and magnesium carbonate revealed a total moxidectin degradation rate of approximately 2-4% under accelerated stability conditions.

[0231] In the final composition, the amount of magnesium carbonate is about 0.5-1.5% by weight of the total tablet weight; more preferably about 1.0-1.5% by weight of the total tablet weight; even more preferably about 1.2-1.5% by weight of the total tablet weight.

[0232] To further reduce moxidectin degradation, an antioxidant, BHT, was added to the moxidectin granules. The amount of BHT in the moxidectin granules is about 0.1-1.0 wt.%, preferably about 0.2-0.8 wt.%, more preferably about 0.3-0.6 wt.%, and most preferably about 0.3-0.5 wt.%, which accounts for about 0.1 wt.% of the total tablet weight.

[0233] In one stability study, moxidectin stability at 25° C. / 60% RH and 40° C. / 75% RH in the final compressed tablets is shown in Table 1 below.

[0234] In a separate stability study, moxidectin stability at 30° C. / 65% RH and 40° C. / 75% RH in the final compressed tablets is shown in Table 2. Stability results represent initial / 6 month results.

[0235] The 25mg-F tablet contains 25mg of fluralaner, 0.0625mg of moxidectin, and 12.5mg of pyrantel. The 50mg-F tablet contains 50mg of fluralaner, 0.125mg of moxidectin, and 25mg of pyrantel. The 100mg-F tablet contains 100mg of fluralaner, 0.25mg of moxidectin, and 50mg of pyrantel. The 200mg-F tablet contains 200mg of fluralaner, 0.50mg of moxidectin, and 100mg of pyrantel. The 400mg-F tablet contains 400mg of fluralaner, 1mg of moxidectin, and 200mg of pyrantel. The 600mg-F tablet contains 600mg of fluralaner, 1.5mg of moxidectin, and 300mg of pyrantel.

[0236] [Table 10]

[0237] [Table 11]

[0238] Stability results of Poloxamer 188 level test at 40℃ / 75%RH A study was conducted to evaluate the effect of different concentrations of Poloxamer 188 on the stability of moxidectin. Concentrations of 0 wt% (no poloxamer), 4.688 wt%, and 11.25 wt% were evaluated in the formulation. Details of the study are provided in Table 8. [Table 12]

[0239] The formulation without poloxamer showed a significant reduction in the moxidectin assay (86.1% LC) and high related substance levels (2.5% 23-ketonemadectin; 0.8% 23Z-moxidectin) at early time points, followed by a rapid loss of moxidectin upon storage. The results provide evidence that poloxamer 188 is useful in inhibiting moxidectin degradation.

Claims

1. A carrier containing a full laranel or a salt or solvate thereof, pyrantel pamoate and moxidectin, and a stabilizing component containing at least one flavoring agent and a mixture of magnesium carbonate and porous silica, An oral chewable dosage form for animals in the form of a compressed tablet.

2. The oral chewable dosage form for animals with a good taste according to claim 1, wherein the magnesium carbonate is light magnesium carbonate.

3. The oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, wherein the compressed tablet contains about 1 to about 4% by weight of the magnesium carbonate.

4. The oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, wherein the porous silica is magnesium aluminometasilicate.

5. The oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, wherein the compressed tablet contains about 2 to about 10% by weight of the porous silica.

6. The oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, wherein the stabilizing component further contains at least one poloxamer.

7. The oral chewable dosage form for animals with a good taste according to claim 6, wherein the poloxamer is poloxamer P188.

8. The oral chewable dosage form for animals with a good taste according to claim 6, wherein the compressed tablet contains about 2 to about 15% by weight of the poloxamer.

9. The oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, wherein the stabilizing component further contains an antioxidant, preferably butylated hydroxytoluene (BHT).

10. The oral chewable dosage form for animals with a good taste according to claim 9, wherein the compressed tablet contains about 0.05 to about 2% by weight of the antioxidant.

11. The oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, wherein the composition contains a natural flavoring agent.

12. The oral chewable dosage form for animals with a good taste according to claim 11, wherein the composition contains a pork liver flavor.

13. A method for manufacturing the oral chewable dosage form for animals with a good taste according to any one of claims 1 to 2, a. The febantel and pyrantel pamoate granules are prepared by: 1) dry mixing the febantel and pyrantel pamoate with a disintegrant, a filler, a colorant, and a surfactant; 2) preparing a solution of a solvent and a cellulose polymer; 3) mixing the febantel and pyrantel pamoate and dry mixing the solution therewith in a high-shear mixer granulator to prepare febantel-pyrantel granules; 4) drying and pulverizing the febantel-pyrantel granules. b. The moxidectin granules are prepared by: 1) dry mixing porous silica, a filler, and magnesium carbonate; 2) dissolving moxidectin in a solvent together with a non-cellulose polymer and an antioxidant; 3) mixing the dry blend with the moxidectin solution in a high-shear mixer granulator to prepare moxidectin granules; 4) drying and pulverizing the moxidectin granules. c. The final dry blend is prepared by: 1) mixing a flavoring agent with a filler, a disintegrant, a colorant, and a glidant to prepare a mixture; 2) mixing the febantel-pyrantel pamoate granules and the moxidectin granules with the mixture; 3) mixing the mixture with a lubricant and compressing the blend to form a finished chewable tablet with a good mouthfeel. A manufacturing method characterized by the above.

14. The chewable dosage form for animals with a good mouthfeel according to any one of claims 1 to 2, for use in the treatment or prevention of parasite invasion in non-human animals.