Topical pharmaceutical composition comprising an association of an isoxazoline with a macrocyclic lactone and a pyrazino-isoquinoline derivative for treating parasitic infestations in small animals

Abstract

The present invention relates to a pharmaceutical composition or formulation and to a method for manufacturing or producing same, wherein the pharmaceutical composition comprises a synergic association of an isoxazoline with a macrocylcic lactone and a synthetic pyrazino-isoquinoline derivative, wherein the composition is in the form of a topical solution for localised topical application, called spot-on, which has the feature of high skin permeability when applied to the skin of the animal. The invention also relates to the uses thereof to prevent and / or treat infestation of small animals by external and internal parasites.

Description

TOPICAL PHARMACEUTICAL COMPOSITION COMPRISING AN ASSOCIATION OF AN ISOXAZOLINE WITH A LACTONE MACROCYCLIC AND A PYRAZINO-ISOQUINOLINE DERIVATIVE FOR THE TREATMENT OF PARASITIC INFESTATIONS IN SMALL ANIMALS TECHNICAL FIELD

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

[0002] The development of pharmaceutical compositions or formulations comprising a combination of antiparasitics that exhibit synergistic activity against internal parasitosis caused by flatworms and other species of bandworms, as well as against external parasitosis caused by fleas, ticks, and mites, is a current need for the treatment and control of infestations in small animals.

[0003] In the field of patent literature, there is document US11,464,763 which refers to topical compositions for combating ectoparasites and endoparasites in animals, comprising at least one isoxazoline active agent and a pharmaceutically acceptable carrier, optionally in combination with one or more additional active agents. This invention also provides methods for eradicating, controlling and preventing parasitic infections and infestations in an animal comprising administering the compositions of the invention to the animal in need thereof.

[0004] For its part, document US9,682,949 refers to processes for the preparation of new insecticidally active thietane derivatives. The invention also relates to thietane derivatives and intermediates used in the preparation of thietane derivatives, as well as to methods for using thietane derivatives to combat and control insect pests, mites, nematodes, and mollusks.

[0005] US Patent 8,466,115 provides spirocyclic isoxazoline derivative compounds and their stereoisomers, which act as parasiticides, in particular, ectoparasiticides; therefore, they can be used to prevent, treat, repel and control infections and infestations by mites and insects in animals. Furthermore, the invention contemplates the control and prevention of tick-borne diseases, for example, Lyme disease, canine and bovine anaplasmosis, canine ehrlichiosis, canine hckettsiosis, canine and bovine babesiosis, epizootic bovine abortion and theileriosis. The compounds can be administered topically through a support matrix individually or with veterinarily acceptable excipients, diluents or carriers, optionally with additional veterinary agents or salts thereof.

[0006] Patent EP2619189 teaches isoxazoline oxime derivatives having parasiticidal activity. The compounds of interest are isoxazoline oxymadione derivatives. The invention also relates to compositions and methods of using them for treating or preventing a parasitic infection or infestation in an animal, which includes the step of administering to said animal in need of such treatment a therapeutically effective amount of an isoxazoline derivative compound, geometrical isomer, stereoisomer thereof, or pharmaceutically or veterinarily acceptable salt thereof for oral, topical, and subcutaneous administration.

[0007] Document MX2013001437 teaches isoxazoline-substituted azetidine derivative, stereoisomers thereof and veterinarily acceptable salts thereof and their use as a parasiticide in mammals and birds.

[0008] US9,376,434 teaches dihydroazole compounds of formula (I) which are biologically active against endoparasites and ectoparasites that harm animals and against pests that harm crops and also teaches parasiticidal and pesticidal compositions comprising the dihydroazole compounds in combination with a pharmaceutically acceptable carrier or an agriculturally acceptable carrier and a method comprising administering an effective amount of a compound of the invention to the animal or to the plants, or to the soil in which the infected plant grows.

[0009] In this regard, there is still a need to provide a pharmaceutical composition or formulation for topical administration that includes a combination 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, a macrocyclic lactone, and a synthetic pyrazino-isoquinoline derivative.

[0010] The proposed composition is a broad-spectrum parasiticide containing a combination of an isoxazoline with at least one macrocyclic lactone and at least one pyrazino-isoquinoline derivative available for topical application. The composition, for topical administration, achieves high cutaneous permeability when applied to the animal's skin, and its uses are in the prevention and / or treatment of infestation of domestic animals by external and internal parasites. DESCRIPTION OF THE FIGURE

[0011] Figure 1 shows the area counts that were performed at six locations on each animal: neck, dorsal midline, base of tail, left side, right side, and inguinal area. BRIEF DESCRIPTION OF THE INVENTION

[0012] 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 at least one isoxazoline, at least one macrocyclic lactone or derivative thereof and at least one pyrazino isoquinoline for the treatment of parasitic infestations in animals, wherein the composition is in the form of a topical solution. DETAILED DESCRIPTION OF THE INVENTION

[0013] In a first aspect, the present invention refers to a pharmaceutical composition or formulation of an isoxazoline associated with a macrocyclic lactone or derivative thereof and a synthetic derivative of pyrazino-isoquinoline for the treatment of parasitic infestations in smaller animals, wherein the composition comprises the active ingredients together with pharmaceutically and veterinarily acceptable excipients for topical administration.

[0014] The present invention relates to a pharmaceutical composition or formulation for topical application of an isoxazoline associated with a macrocyclic lactone or derivative thereof, and a synthetic derivative of pyrazino-isoquinoline for the treatment of parasitic infestations in smaller animals, wherein the composition comprises as isoxazoline or a salt or solvate of isoxazoline having the following formula as structure: Formula 1

[0015] An isoxazoline, salt or solvate according to the structure of formula 1 wherein A1, A2 and A3 are selected from the group consisting of hydrogen, halogen and haloalkyl of 1 to 6 carbon atoms, for example, halomethyl, haloethyl, halopropyl; and where R is a haloalkyl of 1 to 6 carbon atoms, for example, halomethyl; and where X is selected from the group consisting of hydrogen, halogen, alkyl of 1 to 6 carbon atoms, for example, methyl, ethyl; haloalkyl of 1 to 6 carbon atoms, for example, halomethyl and haloethyl; and wherein Z1 and Z2 are substituents selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, for example, but not limited to methyl, ethyl, propyl, butyl, tert-butyl, haloalkyl of 1 to 6 carbon atoms, for example, but not limited to haloemethyl, haloethyl, halopropyl, halobutyl; alkyl of 1 to 6 carbon atoms-O- alkyl of 1 to 6 carbon atoms, for example, methoxymethyl, ethoxyethyl;halo-C1-C6alkyl-O-C1-C6alkyl, for example, but not limited to halomethoxymethyl; ethoxymethyl, haloethoxymethyl, propoxymethyl, C1-C6alkyl-aminocarbonyl-C1-C6alkyl, for example, but not limited to ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl; N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuran, methylaminocarbonylmethyl, (N,N- dimethylamino-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl; and where Z3 consists of O and S and halogen is fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).;

[0016] The present invention then comprises an isoxazoline, salt or solvate according to formula 1, wherein A1, A2 and A3 is halogen and can be fluoro, bromo or chloro.

[0017] The present invention then comprises an isoxazoline, salt or solvate according to formula 1, wherein A1 and A2 is halomethyl and is thiofluoromethyl.

[0018] The present invention then comprises an isoxazoline, salt or solvate according to formula 1, wherein R is monochloromethyl, thiofluoromethyl, monochloro-difluoromethyl.

[0019] The present invention then comprises an isoxazoline, salt or solvate according to formula 1, where X is hydrogen, bromine, iodine, chlorine, methyl, ethyl, thiofluoromethyl.

[0020] The present invention then comprises an isoxazoline, salt or solvate according to formula 1, wherein Z1 and Z2 are selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrophenyl, methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl; and where Z3 consists of oxygen (O) or sulfur (S).

[0021] The isoxazolines used in the present invention may have two or more conformational structures, but at least comprise a quinone carbon at the 5-position of the isoxazoline ring. Other isoxazolines and their salts or Solvates comprised in the present invention are selected from fluralaner, sarolaner, afoxolaner and lotinaler, the like and / or combinations thereof.

[0022] The present invention relates to a pharmaceutical composition or formulation for topical application of an isoxazoline associated with a macrocyclic lactone or derivative thereof, and a pyrazino-isoquinoline derivative for the treatment of parasitic infestations in smaller animals, wherein the composition comprises a macrocyclic lactone selected from the group consisting of ivermectin, emamectin, ephnomectin, selamectin, doramectin, moxidectin, abamectin, the like and / or combinations thereof.

[0023] The present invention relates to a pharmaceutical composition or formulation for topical application of an isoxazoline associated with a macrocyclic lactone and a pyrazino-isoquinoline derivative for the treatment of parasitic infestations in smaller animals, wherein the composition comprises as a pyrazino-isoquinoline derivative praziquantel, or other antiparasitics such as pyrantel, febantel or combinations thereof. In the present invention, at least one systemically active parasiticide can be used as an active agent against internal parasites, selected from the group consisting of one or more macrocyclic lactones, one or more benzimidazoles, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, one or more aminoacetonitrile active agents and one or more arylazol-2-yl cyanoethylamino active agents or combinations thereof.

[0024] In this regard, the active ingredients may be present in a concentration between 0.1 and 50% based on the total weight of the composition. In one embodiment of the invention, the isoxazoline may be present in a concentration between 2.5% and 40%. The pyrazino-isoquinoline-derived active ingredient, which may be, for example, praziquantel, may be present in the composition in a concentration between 0.1% and 20%. The macrocyclic lactone is found in a concentration of 0.10% to 5%.

[0025] With regard to the pharmaceutically acceptable excipients or components that may be present in the pharmaceutical composition or formulation of the present invention, said excipients are selected from the group consisting of solvents, antioxidants, carriers, flavorings, and mixtures thereof, among others. The term "pharmaceutically acceptable" is used to indicate that the component is suitable for use in a pharmaceutical product, is compatible with the other components, and is not harmful to the animal to which the product is administered.

[0026] The present invention also relates to a method for the prevention and / or treatment of infestation by external parasites, such as fleas, ticks and mites, in domestic animals, particularly dogs and cats, comprising the administration, preferably topical administration, more preferably administration by spot application, of an effective therapeutic amount of the liquid pharmaceutical composition as previously described.

[0027] According to this use, the preferred administration is the “spot-on” application, such that said medication is intended to be applied by direct deposit on the animal's skin, at the level of the shoulder blades or along a dorsal line that starts from the base of the tail and goes back up to the neck.

[0028] Thus, the present invention relates to a veterinary topical liquid in spot-on presentation whose pharmaceutical composition is comprised of a suitable organic solvent chosen from ethanol, isopropyl alcohol, butanol, isobutanol, isopropyl alcohol, propylene glycol, similar components, as well as mixtures thereof, which may be present in a concentration of 0.50% to 30.00%; preferably 1.00% to 20.00%; more preferably 2.00% to 10.00% weight / volume.

[0029] The use of the term "comprising" should be interpreted inclusively and not exclusively.

[0030] The composition of the present invention is also comprised of an organic carrier selected from propylene glycol monomethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethylene glycol ether and N-methyl 2-pyrrolidone, similar components, as well as mixtures thereof which may be present in a concentration of 1.00% to 80.00%; preferably 5.00% to 70.00%; more preferably 10.00% to 60.00% weight / volume.

[0031] The antioxidants are advantageously selected from ethyl or propyl gallate, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, monothioglycerol, butylhydroxytoluene (BHT), and butylhydroxyanisole (BHA), and similar components, as well as mixtures thereof, and may be present at a concentration of 0.01% to 1.00%; more preferably, 0.02% to 0.5% weight / volume.

[0032] The composition may optionally contain an essence or scent, to provide fragrance and increase the comfort of the end user when applying the product to their pet. These may be present in a concentration of 0.01% to 15.00%; preferably 0.05% to 10.00%; more preferably 0.10% to 5.00% weight / volume.

[0033] In a second aspect, the present invention relates to the method of producing a pharmaceutical composition comprising an isoxazoline, a macrocyclic lactone and a pyrazino-isoquinoline derivative. for the treatment of parasitic infestations in smaller animals, where the method comprises the following steps: a) Mix the antioxidants with the selected vehicle(s), shake until solution A is formed; b) Add the active ingredient Praziquantel to solution A, shake until solution B is formed; c) Add the selected isoxazoline to solution B, shake until solution C is formed; d) Add the selected macrocyclic lactone to solution C, shake until solution D is formed; e) Mix solution D with the selected aroma and the organic solvent, shake until solution E is formed; f) Make up to volume with the selected solvent; and g) Check the appearance, the solution obtained must be clear and free of particles.

[0034] A method for the prevention or treatment of external and internal parasitic infestations in small animals where the method comprises administering or applying a pharmaceutical composition or formulation of an isoxazoline associated with a macrocyclic lactone and a pyrazino-isoquinoline derivative for the treatment of parasitic infestations in small animals SDFDSD

[0035] In a fourth aspect, the invention further comprises the use of a topical composition of an isoxazoline associated with a macrocyclic lactone or derivative thereof and a synthetic pyrazino-isoquinoline derivative for the treatment of an animal in need of such treatment. Examples of formulation or compositions according to the invention

[0036] 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 No. 1. Examples of formulas with declared composition Efficacy studies of the composition of the present invention Study design

[0037] Each animal received a pipette containing the combination proposed by the present invention. The pipettes were applied to the skin at the base of the the entire nape of the neck. The treatment day was established as the experimental day “H”

[0038] A flea count was performed between experimental days “-7” and “0”, based on which the animals were divided into two strata according to their parasitic load, considering the median obtained as the division point.

[0039] Following treatment, animals were clinically evaluated within 15, 30, 60, and 120 minutes post-treatment to determine the possible presence of adverse effects.

[0040] The area count technique was used to determine flea burden. Area counts were performed in six locations on each animal: neck, dorsal midline, tail base, left flank, right flank, and inguinal area, as shown in Figure 1.

[0041] The effectiveness evaluation was carried out at 2 hours, 1, 2, 7, 14, 28, 42, 56, 70 and 84 days post-treatment, based on the total number of fleas on each animal. Results

[0042] The summary of the flea counts, as well as the effectiveness found for each group, can be seen in Table 2. The use of the composition of the present invention represents an effective alternative for the treatment and control of fleas in smaller animals for a minimum period of 12 weeks. Table No. 2. Results of the effectiveness test

Claims

CLAIMS 1. A pharmaceutical composition, characterized in that it comprises as active ingredients an association of an isoxazoline with a macrocyclic lactone and a synthetic derivative of pyrazino-isoquinoline.

2. The pharmaceutical composition according to claim 1 wherein the isoxazoline compound is a compound of formula 1: Formula 1 3. The composition according to claim 2, wherein A1, A2 and A3 are selected from the group consisting of hydrogen, halogen and halomethyl; and where R is a halomethyl; and where X is selected from the group consisting of hydrogen, halogen, methyl, halomethyl, ethyl and haloethyl; and where Z1 and Z2 are substituents selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, 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; and where Z3 consists of O and S.

4. The composition according to claim 2, wherein A1, A2 and A3 is a halogen and may be fluoro, bromo or chloro.

5. The composition according to claim 2, wherein A1 and A2 is a halomethyl and is thiofluoromethyl.

6. The composition according to claim 2, wherein R is monochloromethyl, thiofluoromethyl, monochloro-difluoromethyl.

7. The composition according to claim 2, wherein X is hydrogen, bromine, iodine, chlorine, methyl, ethyl, thiofluoromethyl.

8. The composition according to claim 2, wherein Z1 and Z2 are selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrophenyl, methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl; and wherein Z3 consists of oxygen or sulfur.

9. The composition according to claim 1, wherein the isoxazoline compound, its salts or solvates are selected from fluralaner, sarolaner, afoxolaner, lotinaler, similar components or combinations thereof.

10. The composition according to claim 1, wherein the macrocyclic lactone compound is selected from ivermectin, emamectin, eprinomectin, selamectin, doramectin, moxidectin, abamectin, similar components or combinations thereof.

11. The composition according to claim 1, wherein the pyrazino-isoquinoline compound is praziquantel or another antiparasitic such as pyrantel, febantel or combinations thereof.

12. The composition according to claim 1, wherein the active ingredients may be present in a concentration between 1.00 and 50.00% based on the total weight of the composition; preferably from 2.5% to 40.00%.

13. The composition according to claim 1 wherein it further comprises a carrier selected from propylene glycol monomethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethylene glycol ether and N-methyl 2-pyrrolidone, similar components or mixtures thereof may be present in a concentration of 1.00% to 80.00%; preferably 5.00% to 70.00%; more preferably 10.00% to 60.00% weight / volume.

14. The composition according to claim 1 comprising a suitable organic solvent selected from ethanol, isopropyl alcohol, butanol, isobutanol, isopropyl alcohol, propylene glycol, as well as mixtures thereof, may be present in a concentration of 0.50% to 30.00%; preferably 1.00% to 20.00%; more preferably 2.00% to 10.00% weight / volume.

15. The composition according to claim 1 which is comprised of antioxidants which may be selected from ethyl or propyl gallate, alpha tocopherol, ascorbic acid, ascorbyl palmitate, monothioglycerol, butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA), as well as mixtures thereof, may be present in a concentration of 0.01% to 1.00%; more preferably, 0.02% to 0.5% weight / volume.

16. The composition according to claim 1, comprising an essence or aroma to provide fragrance and enhance the comfort of the end user when applying the product to their pet, and may be present in a concentration of 0.01% to 15.00%; preferably 0.05% to 10.00%; more preferably 0.10% to 5.00% weight / volume.

17. A method for preparing a composition according to claim 1, comprising the following steps: a) Mixing the antioxidants with the selected vehicle(s), stirring until solution A is formed; b) Adding the active ingredient Praziquantel to solution A, stirring until solution B is formed; c) Adding the selected isoxazoline to solution B, stirring until solution C is formed; d) Adding the selected macrocyclic lactone to solution C, stirring until solution D is formed; e) Mixing solution D with the selected aroma and the organic solvent, stirring until solution E is formed; and f) Making up to volume with the selected solvent.

18. A method for the prevention or treatment of external and internal parasitic infestations in small animals where the method comprises administering or applying a pharmaceutical composition or formulation of an isoxazoline associated with a macrocyclic lactone and a pyrazino derivative. isoquinoline for the treatment of parasitic infestations in small animals.

19. The method according to claim 21, wherein the administration is topical and may preferably be spot-on.

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