Pharmaceutical composition comprising fluralaner, moxidectin and praziquantel for treating parasitic infestations in small animals

Abstract

The present invention discloses a pharmaceutical formulation or composition and a method for manufacturing or producing same, wherein the pharmaceutical composition comprises fluralaner, moxidectin and praziquantel for treating parasitic infestations in animals. The composition may be in tablet form, more particularly as a chewable tablet, and more preferably as a soft chewable tablet that masks the bitter flavour of the active ingredient praziquantel based on a series of bitter taste receptor blockers.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING FLURALANER, MOXIDECTIN AND PRAZIQUANTEL FOR THE TREATMENT OF PARASITIC INFESTATIONS IN SMALL ANIMALS

[0002] TECHNICAL FIELD

[0003]

[0001] The present invention is framed within the technical field of the pharmaceutical industry, mainly with the veterinary pharmaceutical products industry.

[0004] STATE OF THE ART

[0005]

[0002] The development of pharmaceutical compositions or formulations comprising fluralaner, moxidectin and praziquantel is a current need for the treatment and control of infestations in smaller animals, for the treatment of parasitosis caused by flatworms and other species of ribbon worms.

[0006]

[0003] WO2022 / 051478 is known which reports oral dosage formulations comprising an effective amount of an isoxazoline parasiticidal agent, an avermectin and a pyrazinoisoquinoline, and optionally one or more additional active ingredients, such as a tetrahydropyrimidine. The formulation may comprise fluralaner, praziquantel and moxidectin together with microcrystalline cellulose (25% to 30%), lactose monohydrate (5% to 6%), butyl hydroxytoluene (0.05-0.06%), croscarmellose sodium (3 to 5%), sodium lauryl sulfate (0.4 to 0.5%), flavoring (5 to 20%), magnesium stearate (0.5 to 1.5%) and colloidal silicon dioxide) in palatable dosage forms for veterinary use wherein the composition has a first coated granulate comprising praziquantel and moxidectin together with a diluent, an antioxidant and a disintegrant in a physiologically acceptable polymeric matrix and a second granulate comprising an isoxazoline, mainly lotilaner together with a diluent, a wetting agent, a disintegrant and a binder.

[0007]

[0004] Also known is WO2021 / 046305 which discloses a palatable granular veterinary composition comprising at least one active agent, at least one wetting agent and at least one flavouring for controlling or treating a condition in an animal, wherein the composition may comprise praziquantel and moxidectin in a concentration from 0.001% to 75% based on the total weight of the palatable granulated composition and may contain glycerin, fatty acids, polyethylene glycol, croscarmellose sodium and microcrystalline cellulose as a disintegrant, sodium lauryl sulphate and magnesium stearate as lubricants, hydroxypropyl methylcellulose as a binder, butyl hydroxy anisole and butyl hydroxy toluene as antioxidants and parabens as buffering agents.

[0008]

[0005] Also known is WO2021 / 046296 which provides a palatable soft chew veterinary composition comprising at least one active agent, at least one wetting agent and at least one flavouring, wherein the composition may comprise praziquantel and moxidectin and may further contain glycerin, fatty acids, polyethylene glycol, croscarmellose sodium and microcrystalline cellulose as disintegrants, sodium lauryl sulphate and magnesium stearate as lubricants, hydroxypropyl methylcellulose as a binding agent (binder), butyl hydroxy anisole and butyl hydroxy toluene as antioxidants and parabens as buffering agents.

[0009]

[0006] Patent W02020 / 051106 reports a palatable hard chewable composition comprising at least one veterinarily acceptable isoxazoline, a macrocyclic lactone, an acceptable salt form of pyrantel, at least one natural animal flavoring and at least one veterinarily acceptable excipient. The composition is compressed into a hard tablet. The isoxazoline may be sarolaner, afoxalaner, fluralaner or lotilaner, stabilized moxidectin (macrocyclic lactone stabilized with an antioxidant) and an antiparasitic such as praziquantel. The composition may have as excipients croscarmellose sodium (disintegrant), polyethylene glycol, sodium lauryl sulfate, hydroxypropyl methylcellulose as a stabilizer, butyl hydroxyanisole and butyl hydroxy toluene as antioxidants, magnesium stearate as a lubricant.

[0010]

[0007] Patent EP2662075 relates to improvements in oral formulations of the anthelmintic praziquantel used for the control and treatment of endoparasite infestations in warm-blooded animals, particularly in companion animals such as cats, dogs and horses, wherein the composition comprises praziquantel particles with moxidectin with an integral coating of a lipid or a mixture of lipids that are insoluble in water and that serve to mask the bitter taste of praziquantel. The composition may comprise starch and purified water.

[0011]

[0008] In this sense, there is still a need to provide a pharmaceutical composition or formulation comprising an association of active ingredients that can provide comprehensive protection against external parasites such as fleas, ticks and mites, as well as against internal parasites such as Dirofilariasis, gastrointestinal nematodes and tapeworms, among others. The proposed composition contains an active ingredient from the isoxazoline family, an avermectin and a synthetic derivative of isoquinoline-pyrazine.

[0012]

[0009] The proposed composition is a broad-spectrum parasiticide containing a combination of fluralaner, moxidectin and praziquantel available for oral administration. The composition for oral administration wherein the masking of the bitter taste of one of the active ingredients is achieved, in the form of a tablet, more specifically a soft chewable tablet having a high palatability. BRIEF DESCRIPTION OF THE INVENTION

[0013]

[0010] The present invention is directed to a pharmaceutical formulation or composition and a method of manufacturing or producing the same, wherein the pharmaceutical composition comprises fluralaner, moxidectin and praziquantel for the treatment of parasitic infestations in animals, wherein the composition may be in tablet form, more particularly the latter as a chewable tablet and more preferably as a soft chewable tablet that manages to mask the bitter taste of the active ingredient praziquantel based on an association of bitter taste receptor blockers.

[0014] DETAILED DESCRIPTION OF THE INVENTION

[0015]

[0011] In a first aspect, the present invention refers to a pharmaceutical composition or formulation of fluralaner associated with moxidectin and praziquantel for the treatment of parasitic infestations in smaller animals, wherein the composition comprises fluralaner, praziquantel, moxidectin, together with pharmaceutically acceptable excipients for oral administration.

[0016]

[0012] The present invention relates to a palatable oral pharmaceutical composition or formulation of fluralaner associated with moxidectin and praziquantel for the treatment of parasitic infestations in smaller animals, wherein the composition comprises fluralaner, praziquantel, moxidectin, together with pharmaceutically acceptable excipients such as flavor enhancers, diluents, disintegrants, humectants, plasticizers, solvents, surfactants, taste maskers, sweeteners, binders, lubricants, preservatives, antioxidants and mixtures thereof.

[0013] In this sense, the active ingredients may be present in a concentration between 0.1% and 40% based on the total weight of the composition.In one embodiment of the invention, the active ingredient fluralaner may be present at a concentration between 5% and 30% relative to the total weight of the final pharmaceutical composition, for oral administration it may preferably be between 10% and 15% relative to the total weight of the final pharmaceutical composition. The active ingredient praziquantel may be present in the composition at a concentration between 0.1% and 10% relative to the total weight of the final pharmaceutical composition, for oral administration it may preferably be between 1% and 5% relative to the total weight of the final pharmaceutical composition. The active ingredient moxidectin is present at a concentration of 0.10% to 5% relative to the total weight of the final pharmaceutical composition, for oral administration it may preferably be at a concentration of 0.10 to 1% relative to the total weight of the final pharmaceutical composition.

[0017]

[0014] In relation to the pharmaceutically acceptable excipients or components that may be in the pharmaceutical composition or formulation of the present invention, said excipients are selected from the group consisting of flavor enhancers, diluents, disintegrants, humectants, plasticizers, solvents, surfactants, flavor maskers, sweeteners, binders, lubricants, preservatives, antioxidants and mixtures thereof.

[0018]

[0015] As for the flavor enhancer, it may be a flavoring or a mixture thereof which include flavorings of natural origin of animal origin which may be pork, chicken or beef and / or added to flavorings of synthetic origin that provide improvement in the smell, these may also be of meat flavor. The flavor enhancer(s) may be present in the pharmaceutical composition or formulation of the present invention in a proportion between 5% and 30% in relation to the total weight of the final pharmaceutical composition.

[0016] In addition to the diluent or disintegrant, the pharmaceutical composition according to the present invention may further comprise a solvent, a preservative, antioxidants and a cosolvent or diluent.

[0019]

[0017] The diluent or disintegrant that may be in the pharmaceutical composition according to the present invention may be sodium starch glycolate, sodium alginate, calcium alginate, microcrystalline cellulose, pregelatinized corn starch, corn starch, which may be in a range between 5% and 40% in relation to the total weight of the final composition. In a preferred embodiment of the invention, the disintegrant may comprise, in addition to starch, croscarmellose sodium in a proportion between 0.5% and 5% in relation to the total weight of the final pharmaceutical composition.

[0020]

[0018] The composition according to the present invention may further comprise humectants, such as oils of vegetable origin such as soybean oil, sunflower oil, canola oil and mixtures thereof. The oils as humectants may be in a proportion between 5% and 25% in relation to the total weight of the final composition. In one embodiment of the invention, the composition may additionally contain glycerin as a humectant in a proportion between 5% and 20% in relation to the total weight of the final composition.

[0021]

[0019] The pharmaceutical composition according to the present invention comprises a forming agent or plasticizer to provide the final texture of the tablet polyethylene of a suitable molecular weight, which should preferably be equal to or greater than soft, such as polyvinylpyrrolidone, hydroxypropylmethylcellulose and polyethylene glycol, preferably 1000 g / mol in the present pharmaceutical composition the plasticizer may be in a concentration between 5% and 15% based on the weight of the final pharmaceutical composition.

[0020] The pharmaceutical composition according to the present invention may further contain other solvents and diluents. In a preferred embodiment of the invention, the additional diluent may be microcrystalline cellulose in a concentration between 2% and 10% in relation to the total weight of the final composition and more preferably 2.5% by weight based on the total weight of the final pharmaceutical composition.The additional solvent may be propylene glycol in a concentration between 1% and 10% in relation to the total weight of the final composition, more preferably 2.5% by weight based on the total weight of the final pharmaceutical composition.

[0022]

[0021] The pharmaceutical composition according to the present invention may further comprise a surfactant, preferably an anionic surfactant which may be dodecylbenzene sulfonate, sodium dioctylsulfosuccinate or sodium lauryl sulfate in a concentration between 0.5% and 3.0% relative to the total weight of the final composition, more preferably 2.0% based on the total weight of the final pharmaceutical composition. In a preferred embodiment of the present invention, the surfactant is sodium lauryl sulfate.

[0023]

[0022] The pharmaceutical composition according to the present invention may further comprise one or more bitter taste blockers. The bitter taste blockers may be adenosine 5'-monophosphate (AMP), thymidine 5'-monophosphate (TMP), adenosine 5'-triphosphate (ATP), monosodium glutamate and mixtures thereof, in a concentration between 0.10% and 1.0%, more preferably 0.50%, based on the total weight of the final pharmaceutical composition.

[0024]

[0023] The pharmaceutical composition according to the present invention may further comprise one or more sweeteners, such as saccharin, sorbitol, aspartame and sucralose in a concentration between 0.1% and 2% based on the total weight of the final pharmaceutical composition.

[0024] The pharmaceutical composition according to the present invention may further comprise one or more binders such as copovidone, crospovidone, povidone, carboxymethylcellulose, hydroxypropylmethylcellulose in a concentration between 0.1% and 1% based on the total weight of the final pharmaceutical composition.

[0025]

[0025] The pharmaceutical composition according to the present invention may further contain one or more lubricants, such as magnesium stearate, in a concentration between 0.1% and 1.0%, more preferably 0.50% based on the total weight of the final pharmaceutical composition.

[0026]

[0026] The pharmaceutical composition according to the present invention may further contain one or more preservatives such as sodium sulfite, sodium metabisulfite, ethyl paraben, methyl paraben and propyl paraben, in a concentration between 0.01% and 0.10% relative to the total weight of the final composition. In a preferred embodiment of the invention, the preservatives are methyl paraben in a concentration of 0.05% and propyl paraben in a concentration of 0.02% based on the total weight of the final pharmaceutical composition.

[0027]

[0027] The pharmaceutical composition according to the present invention may further contain antioxidants, which may be one or more synthetically produced antioxidants, such as propylgallate (PG), tert-butylhydroxyquinone (TBHQ), butylhydroxyanisole (BHA) and butylhydroxytoluene (BHT) and may be in the pharmaceutical composition or formulation in a proportion between 0.005 and 0.05% by weight of the final formulation and more preferably in 0.04% in relation to the total weight of the final composition.

[0028]

[0028] The pharmaceutical composition according to the present invention may further contain purified water as a solvent during the process of obtaining the formulation in a concentration between 1.0% and 10% more preferably a concentration of 7.0% based on the weight of the composition before its obtaining, where the water evaporates during the process. Also, the composition may comprise as an additional solvent ethyl alcohol (ethanol) in a concentration of 1.50% based on the weight of the composition before its obtaining which evaporates during the process.

[0029]

[0029] The pharmaceutical composition according to the present invention is for veterinary use and may be in a pharmaceutically acceptable form for oral administration such as a tablet, more preferably as a chewable tablet and most preferably as a highly palatable soft chewable tablet wherein the unpleasant taste of the active ingredient praziquantel is masked by the presence of bitter taste receptor blockers, said blockers being adenosine 5'-monophosphate and monosodium glutamate.

[0030]

[0030] In a second aspect, the present invention relates to the method of producing a pharmaceutical composition comprising fluralaner, moxidectin and praziquantel for the treatment of parasitic infestations in animals, wherein the method comprises the following steps: a) Dissolving the binder(s) with ethyl alcohol; b) Dissolving the sweetener in purified water; c) Mixing the result of step b) with the result of step a); d) Mixing praziquantel with the diluent (microcrystalline cellulose) and the bitter taste blockers; e) Performing wet granulation with the result of steps c) and d) and drying at 45 degrees Celsius; f) Dissolving the Moxidectin in propylene glycol as a solvent; g) Adding the preservatives to step f) and continuing with the dissolution; h) Disperse the flavor enhancer(s) in glycerin for a period of 2 minutes to 15 minutes i) Dissolve the antioxidants in the humectant (soybean oil);j) Mix the result of step e) with fluralaner, flavor enhancers, diluent / disintegrant (starch), disintegrant (croscarmellose sodium), surfactant, flavor blockers, sweetener and lubricant; k) Add the result of step h) to the result of step i) and knead; l) Add the result of step g) and glycerin to the result of step j); m) Add polyethylene glycol to the result of step k); knead; and n) Tablet.

[0031]

[0031] In step c) the mixture is mixed until completely homogenized for a period of 60 minutes, preferably 30 minutes.

[0032]

[0032] In step d) and mixed with the other components for a period of 30 minutes, more preferably 15 minutes.

[0033]

[0033] In step e) the drying time is carried out for a period between 6 hours and 10 hours, more preferably 8 hours.

[0034]

[0034] In step f) the dissolution is carried out in a suitable container until complete dissolution for a period of 1 minute to 30 minutes, more preferably 5 minutes.

[0035]

[0035] In step g) the preservatives are added and stirring is continued until completely dissolved, for a period of 20 minutes to 60 minutes, more preferably 25 minutes.

[0036]

[0036] In step h) the dispersion of the flavor enhancer(s) is carried out over a period of 2 to 15 minutes, more preferably 10 minutes.

[0037] In step i) the mixing of the antioxidants in the humectant is carried out in a suitable container and for a period of 30 minutes to 120 minutes, more preferably 60 minutes.

[0037]

[0038] In step j), the mixture is mixed for 5 minutes and then placed in a kneading bowl. Mixing is then continued for a period of 20 to 120 minutes, preferably 40 minutes.

[0038]

[0039] In step k) the mixture is kneaded for a period of 30 to 60 minutes, preferably 45 minutes until the solid part is completely moistened.

[0039]

[0040] In step I) stirring is continued for a further period of 30 minutes to 60 minutes, more preferably 45 minutes until complete wetting / formation of a mouldable mass.

[0040]

[0041] In step m), the excipient (propylene glycol) is heated in a suitable container until it is completely melted with constant stirring at a temperature between 60°C and 70°C and kneaded until a moldable mass is formed over a period of 30 minutes to 60 minutes, more preferably 45 minutes.

[0041] Examples of formulation or compositions according to the invention

[0042]

[0042] Examples of the declared composition are shown below in Table 1. The water and alcohol solvents used in granulation evaporate during the process and are therefore not included in the weight of the final composition. Table 1. Examples of formulas with the declared composition

[0043] * Evaporates during the manufacturing process

[0044] Study design

[0043] The palatability of the different formulas under evaluation was determined by working with 113 canines of both sexes, older than 8 weeks of age, of different weights, of different breeds and clinically healthy. The tablets were presented to the animals and a score was determined for each composition according to the reaction based on the scale shown in Table No. 2. Table No. 2. Acceptance scale in canines

[0045] Results

[0046]

[0044] Table 3 shows the averages for each formula under evaluation, as well as the number of canines on which they were tested. With the exception of formula D, all formulas had an average greater than 2.6, considering them highly palatable. Formula C had an average of 3, which places it as the most palatable formula of those evaluated. In general, most of the tablets were well accepted. However, D had an average acceptance (74.19%), unlike the others, which had an acceptance greater than 80%. C had an acceptance of 100%. When performing a Kruskal Wallis test to determine if there is a statistical difference between the groups, it was determined that there are only statistically significant differences between C and D.

[0047] Table No. 3. Acceptance results of the evaluated formulas

[0045] According to the evaluation, it is evident that the combination of adenosine 5'-monophosphate with monosodium glutamate at a concentration of 2.0% is effective in blocking the bitter taste of the active ingredient praziquantel.

Claims

MODIFIED CLAIMS received by the International Bureau on February 21, 2024 (21.02.2024) CLAIMS 1. A pharmaceutical composition for the treatment of parasitic infestations in small animals, characterized in that it comprises as active ingredients fluralaner, moxidectin and praziquantel, bitter taste receptor blockers and pharmaceutically acceptable excipients.

2. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to claim 1, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of flavor enhancers, diluents, disintegrants, humectants, plasticizers, solvents, surfactants, flavor maskers, sweeteners, binders, lubricants, preservatives, antioxidants and mixtures thereof.

3. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to claim 1, characterized in that the active ingredients are in a concentration between 0.1% and 40% based on the total weight of the composition.

4. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to claim 1, characterized in that the bitter taste receptor blockers are selected from the group consisting of adenosine 5'-monophosphate (AMP), thymidine 5'-monophosphate (TMP), adenosine 5'-triphosphate (ATP), monosodium glutamate and mixtures thereof in a concentration between 0.10% and 1.0%.

5. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to claim 1, characterized in that it also contains purified water as a solvent in a concentration between 1.0% and 10% based on the weight of the composition before obtaining it.

6. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to claim 1, characterized in that it comprises as an additional solvent ethyl alcohol (ethanol) in a concentration of 1.50% based on the weight of the composition before its production.

7. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to any of the preceding claims, characterized in that it is in the form of a tablet.

8. The pharmaceutical composition for the treatment of parasitic infestations in smaller animals according to claim 7, characterized in that the tablet is a soft chewable tablet.

9. A method for producing a pharmaceutical composition comprising fluralaner, moxidectin and praziquantel for the treatment of parasitic infestations in animals, characterized in that the method comprises the following steps: a) Dissolving the binder(s) with ethyl alcohol; b) Dissolving the sweetener in purified water; c) Mixing the result of step b) with the result of step a); d) Mixing praziquantel with the diluent (microcrystalline cellulose) and the bitter taste blockers; e) Performing wet granulation with the result of steps c) and d) and drying at 45 degrees Celsius; f) Dissolving the Moxidectin in propylene glycol as a solvent; g) Add the preservatives to step f) and continue dissolving; h) Disperse the flavor enhancer(s) in glycerin for a period of 2 to 15 minutes; i) Dissolve the antioxidants in the humectant (soybean oil); j) Mix the result of step e) with fluralaner, the flavor enhancers, the diluent / disintegrant (starch), the disintegrant (croscarmellose sodium), the surfactant, the flavor blockers, the sweetener, and the lubricant; k) Add the result of step h) to the result of step i) and knead; l) Add the result of step g) and glycerin to the result of step j; m) Add polyethylene glycol to the result of step k); knead; and n) Tablet.

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