A pharmaceutical composition comprising fluralaner, moxidectin, and praziquantel for the treatment of parasitic infections in small animals.

Abstract

The present invention discloses pharmaceutical formulations or pharmaceutical compositions and methods for manufacturing or producing them, the pharmaceutical compositions comprising fluralaner, moxidectin and praziquantel for the treatment of parasitic infections in animals. The compositions may be in the form of tablets, more specifically as chewable tablets and more preferably as soft chewable tablets, which mask the bitterness of the active ingredient praziquantel based on a series of bitterness receptor blockers.

Description

Technical Field

[0001] The present invention mainly belongs to the technical field of the pharmaceutical industry by the pharmaceutical industry for veterinary use.

Background Art

[0002] The development of pharmaceutical compositions or pharmaceutical preparations containing fluralaner, moxidectin, and praziquantel is currently needed for the treatment and control of parasitic infections in small animals and for the treatment of parasitic infections caused by platyhelminths and other nematode species.

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

[0004] Patent document WO2021 / 046305 is also known to disclose a palatable granular veterinary composition comprising at least one active substance, at least one wetting agent, and at least one flavoring agent for controlling or treating pathological conditions in animals, the composition may contain praziquantel and moxidectin at concentrations of 0.001% to 75% based on the total weight of the palatable granular composition, and may also contain glycerin, fatty acids, polyethylene glycol, croscarmellose sodium, and microcrystalline cellulose as disintegrants, sodium lauryl sulfate and magnesium stearate as lubricants, hydroxypropyl methylcellulose as a binder, butylated hydroxyanisole and butylated hydroxytoluene as antioxidants, and parabens as buffers.

[0005] Patent document WO2021 / 046296 is also known to disclose a palatable soft chewing composition for veterinary use comprising at least one active substance, at least one wetting agent and at least one flavoring agent, the composition may comprise praziquantel and moxidectin, and may further comprise glycerin, fatty acids, polyethylene glycol, croscarmellose sodium and microcrystalline cellulose as disintegrants, sodium lauryl sulfate and magnesium stearate as lubricants, hydroxypropyl methylcellulose as a binding agent or binder, butylhydroxyanisole and butylhydroxytoluene as antioxidants, and parabens as buffers.

[0006] Patent document WO2020 / 051106 reports a palatable hard chewable composition comprising at least one veterinarily acceptable isoxazoline, a macrocyclic lactone, pyrantel in an acceptable salt form, at least one natural flavoring of animal origin, and at least one veterinarily acceptable excipient. The composition is compressed into hard tablets. The isoxazoline may be sarolaner, afoxolaner, fluralaner, or lotilaner, stabilized moxidectin (a macrocyclic lactone stabilized by an antioxidant), and an antiparasitic agent (such as praziquantel). The composition may also contain croscarmellose sodium (disintegrant), polyethylene glycol, sodium lauryl sulfate as excipients, hydroxypropyl methylcellulose as a stabilizer, butylhydroxyanisole and butylhydroxytoluene as antioxidants, and magnesium stearate as a lubricant.

[0007] Patent document EP2662075 relates to an improvement of an oral formulation of the anthelmintic praziquantel used for the control and treatment of endoparasitic infestations in warm-blooded animals, particularly pet animals such as cats, dogs, and horses, wherein the composition comprises moxidectin-containing praziquantel particles with an integral coating of a lipid or mixture of lipids that is insoluble in water and has the effect of masking the bitter taste of praziquantel. The composition may also contain starch and purified water.

[0008] In this context, there remains a need for compositions or pharmaceutical formulations containing combinations of active ingredients that can provide comprehensive protection against external parasites, particularly fleas, ticks, and mites, as well as internal parasites, such as dyrofilariasis, gastrointestinal nematodes, and tapeworms. The composition presented contains active ingredients of the isoxazoline family, avermectin, and synthetic derivatives of isoquinoline-pyrazine.

[0009] The presented composition is a broad-spectrum antiparasitic agent comprising a combination of fluralaner, moxidectin, and praziquantel, available for oral administration. The composition for oral administration is in the form of a tablet, more specifically a soft chewable tablet with a very good taste, in which masking of one of the bitter tastes of the active ingredients is achieved. [Overview of the Initiative]

[0010] The present invention relates to pharmaceutical formulations or pharmaceutical compositions and methods for manufacturing or producing the same, wherein the pharmaceutical composition comprises fluralaner, moxidectin and praziquantel for the treatment of parasitic infections in animals, the composition may be in tablet form, more specifically the tablet may be in the form of a chewable tablet, and more preferably a soft chewable tablet, which may mask the bitterness of the active ingredient praziquantel based on the binding of bitterness receptor blockers. [Modes for carrying out the invention]

[0011] In the first aspect, the present invention relates to a pharmaceutical composition or formulation of fluralaner in combination with moxidectin and praziquantel for the treatment of parasitic infections in small animals, the composition comprising fluralaner, praziquantel, and moxidectin, together with a pharmaceutically acceptable excipient for oral administration.

[0012] The present invention relates to a palatable oral pharmaceutical composition or formulation of fluralaner in combination with moxidectin and praziquantel for the treatment of parasitic infections in small animals, the composition comprising fluralaner, praziquantel, and moxidectin, together with pharmaceutically acceptable excipients such as flavor enhancers, diluents, disintegrants, wetting agents, plasticizers, solvents, surfactants, flavor masking agents, sweeteners, binders, lubricants, preservatives, antioxidants, and mixtures thereof.

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

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

[0015] With respect to flavor enhancers, they may be flavorings or mixtures thereof, including natural animal-derived flavorings that may be pork, chicken, or beef, and / or which may be added to synthetic flavorings that improve odor, and these may also be meat flavorings. Flavor enhancers may be present in the pharmaceutical composition or formulation of the present invention in a proportion of 5% to 30% of the total weight of the final pharmaceutical composition.

[0016] In addition to diluents or disintegrants, the pharmaceutical compositions according to this specification may further comprise solvents, preservatives, antioxidants, and co-solvents or diluents.

[0017] Diluents or disintegrants that may be present in the pharmaceutical compositions according to this specification may be sodium starch glycolate, sodium alginate, calcium alginate, microcrystalline cellulose, pregelatinized corn starch, or corn starch, and may be present in an amount of 5% to 40% of the total weight of the final composition. In a preferred embodiment of the present invention, the disintegrant may, in addition to starch, contain croscarmellose sodium in an amount of 0.5% to 5% of the total weight of the final pharmaceutical composition.

[0018] The compositions according to this specification may further contain humectants such as vegetable oils (soybean oil, sunflower oil, canola oil, and mixtures thereof). The amount of oils as humectants may be 5% to 25% of the total weight of the final composition. In one embodiment of the present invention, the composition may further contain glycerin as a humectant at an amount of 5% to 20% of the total weight of the final composition.

[0019] The pharmaceutical compositions according to this specification include a shaping agent or plasticizer (polyethylene glycol of a suitable molecular weight) to impart the texture of the final tablet, which is preferably equivalent to or even softer than polyvinylpyrrolidone, hydroxypropyl methylcellulose, and polyethylene glycol, preferably in the pharmaceutical composition at 1000 g / mol, and the plasticizer may be concentrated at a concentration of 5% to 15% based on the weight of the final pharmaceutical composition.

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

[0021] The pharmaceutical compositions according to this specification may further contain a surfactant, preferably an anionic surfactant, which may be dodecylbenzenesulfonate, sodium dioctyl sulfosuccinate, or sodium lauryl sulfate in a concentration of 0.5% to 3.0% of the total weight of the final composition, and more preferably 2.0% based on the total weight of the final pharmaceutical composition. In one preferred embodiment of the present invention, the surfactant is sodium lauryl sulfate.

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

[0023] The pharmaceutical compositions according to this specification may further contain one or more sweeteners (such as saccharin, sorbitol, aspartame, and sucralose) in a concentration of 0.1% to 2% based on the total weight of the final pharmaceutical composition.

[0024] The pharmaceutical compositions according to this specification may further contain one or more binders (such as copovidone, crospovidone, povidone, carboxymethylcellulose, or hydroxypropylmethylcellulose) in a concentration of 0.1% to 1% based on the total weight of the final pharmaceutical composition.

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

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

[0027] The pharmaceutical composition according to the present specification may further contain antioxidants, which may be one or more synthetically prepared antioxidants (such as propyl gallate (PG), tert-butylhydroquinone (TBHQ), hydroxybutyl anisole (BHA), and butylated hydroxytoluene (BHT), etc.), and may be present in the pharmaceutical composition or formulation at a ratio of 0.005% to 0.05%, more preferably 0.04% based on the weight of the final formulation.

[0028] The pharmaceutical composition according to the present specification may further contain purified water as a solvent during the process of obtaining the formulation at a concentration of 1.0% to 10% and above, preferably 7.0% based on the weight of the composition before obtaining it, and this water evaporates during the process. Further, the composition may contain ethyl alcohol (ethanol) as an additional solvent at a concentration of 1.50% based on the weight of the composition before obtaining it, and it evaporates during the process.

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

[0030] In a second aspect, the present invention relates to a method for producing a pharmaceutical composition comprising fluralaner, moxidectin, and praziquantel for the treatment of parasitic infections in animals, the method comprising the following steps: (a) A step of dissolving the binder with ethyl alcohol; (b) A step of dissolving the sweetener in purified water; (c) A step of mixing the product of step 1 with the product of step 2; (d) Mixing praziquantel with a diluent (microcrystalline cellulose) and a bitterness blocker; (e) A wet granulation process is carried out using the products from steps (c) and (d), followed by drying at 45°C; (f) A step of dissolving moxidectin in propylene glycol as a solvent; (g) A step in which a preservative is added to step (f) and the dissolution process is continued; (h) A step of dispersing the flavor enhancer in glycerin for 2 to 15 minutes; (i) A step of dissolving an antioxidant in a humectant (soybean oil); (j) A step of mixing the product of step (e) with fluralaner, flavor enhancer, diluent / disintegrant (starch), disintegrant (croscarmellose sodium), surfactant, flavor blocker, sweetener, and lubricant; (k) A step in which the product of step (i) is added to the product of step (h) and mixed; (l) Add the product of step (g) and glycerin to the product of step (j); (m) A step of adding polyethylene glycol to the product of step (k) and mixing, (n) The process of forming tablets.

[0031] In step (c), mixing is carried out for 60 minutes, preferably 30 minutes, until the mixture is homogenized.

[0032] In step (d), mixing is carried out with the other components for 30 minutes, more preferably 15 minutes.

[0033] In step (e), the drying time is 6 to 10 hours, preferably 8 hours.

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

[0035] In step (g), a preservative is added, and stirring is continued for 20 to 60 minutes, preferably longer than 25 minutes, until complete dissolution occurs.

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

[0037] In step (i), the mixing of the antioxidant in the wetting agent is carried out in a suitable container for 30 to 120 minutes, more preferably 60 minutes.

[0038] In step (j), it is mixed for 5 minutes and placed in a mixer. Mixing is then continued for 20 to 120 minutes, more preferably for 40 minutes.

[0039] In step (k), the mixture is mixed for 30 to 60 minutes, more preferably 45 minutes, until the solid portion is completely wetted.

[0040] In step (l), stirring is continued for 30 to 60 minutes, more preferably 45 minutes, until the moldable mass is completely wetted / formed.

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

[0042] Examples of formulations or compositions according to this specification Examples of the compositions of this disclosure are shown in Table 1 below. The water and alcohol solvents used for granulation evaporate during the process and are therefore not considered in the weight of the final composition.

[0043] [Table 1]

[0044] Test design The taste of different formulations under evaluation was determined using 113 clinically healthy dogs of different body weights, strains, and ages of 8 weeks or older, of both sexes. The tablets were administered to the animals, and scores were determined for each composition according to the response scale shown in Table 2.

[0045] [Table 2]

[0046] result Table 3 shows the mean values ​​for each formulation evaluated, as well as the number of dogs tested. All formulations, except for formulation D, had a mean value of over 2.6, indicating very palatability. Formulation C had a mean value of 3, making it the most palatable formulation evaluated. Generally, most tablets were well-received. However, formulation D had moderate acceptance (74.19%), unlike the other formulations which had acceptance of over 80%. Formulation C had 100% acceptance. When the Kruskal-Wallis test was performed to determine if there were statistical differences between the groups, it was determined that only a significant statistical difference existed between C and D.

[0047] [Table 3]

[0048] Evaluation clearly shows that a combination of adenosine 5'-monophosphate and monosodium glutamate at a concentration of 2.0% is effective in blocking the bitter taste of the active ingredient praziquantel.

Claims

1. A pharmaceutical composition for the treatment of parasitic infections in small animals, characterized by comprising fluralaner, moxidectin and praziquantel as active ingredients, a bitter taste receptor blocker and a pharmaceutically acceptable excipient.

2. A pharmaceutical composition for the treatment of parasitic infections in small animals according to claim 1, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of flavor enhancers, diluents, disintegrants, wetting agents, plasticizers, solvents, surfactants, flavor masking agents, sweeteners, binders, lubricants, preservatives, antioxidants, and mixtures thereof.

3. A pharmaceutical composition for treating parasitic infections in small animals according to claim 1, characterized in that the active ingredient is concentrated at a concentration of 0.1% to 40% based on the total weight of the composition.

4. The pharmaceutical composition for treating parasitic infections in small animals according to claim 1, characterized in that the bitter taste receptor blocker is 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 of 0.10% to 1.0%.

5. A pharmaceutical composition for the treatment of parasitic infections in small animals according to claim 1, characterized in that it further contains purified water as a solvent at a concentration of 1.0% to 10% based on the weight of the composition before acquisition.

6. A pharmaceutical composition for the treatment of parasitic infections in small animals according to claim 1, characterized by containing ethyl alcohol (ethanol) as a further solvent at a concentration of 1.50% based on the weight of the composition before acquisition.

7. A pharmaceutical composition for the treatment of parasitic infections in small animals according to any of the claims, characterized in the form of a tablet.

8. A pharmaceutical composition for treating parasitic infections in small 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 infections in animals, The following steps: (a) A step of dissolving the binder with ethyl alcohol; (b) A step of dissolving the sweetener in purified water; (c) A step of mixing the product of step 1 with the product of step 2; (d) A step of mixing the diluent (microcrystalline cellulose) and bitterness blocker with praziquantel; (e) A wet granulation process is carried out using the products of steps (c) and (d), and the products are dried at 45°C; (f) A step of dissolving moxidectin in propylene glycol as a solvent; (g) A step of adding a preservative to step (f) and continuing the dissolution process; (h) A step of dispersing the flavor enhancer in glycerin for 2 to 15 minutes; (i) A step of dissolving an antioxidant in a wetting agent (soybean oil); (j) A step of mixing the product of step (e) with fluralaner, flavor enhancer, diluent / disintegrant (starch), disintegrant (croscarmellose sodium), surfactant, flavor blocker, sweetener and lubricant; (k) Adding and mixing the product of step (i) with the product of step (h); (l) Adding the product of step (g) and glycerin to the product of step (j); (m) The step of adding polyethylene glycol to the product of step (k) and mixing it, (n) The process of forming tablets, A method characterized by including

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