Oral composition in bioadhesive gel form based on isoxazoline

Abstract

The present invention relates to a composition of a long-acting bioadhesive endoparasiticide gel based on an isoxazoline alone or in combination with other antiparasitic agents, having a high degree of adhesion to oral mucosa and high palatability greatly facilitating the dosing thereof, and to methods for preparing the same. Ectoparasitosis is a parasitic disease caused by fleas, ticks and mites that infest the surface layers of the skin in small animals. Control of this illness is of great importance and advantageously achievable through the use of appropriate antiparasitic agents such as isoxazolines, being a chemical compound widely administered by oral route in tablet form due to the organoleptic and physicochemical characteristics of the compositions known up to the present. The present invention demonstrates that it is possible to administer isoxazolines in the pharmaceutical form of an oral gel at concentrations of up to 20.0% weight / volume, overcoming the organoleptic and physicochemical restrictions of the compositions known up to the present. Factors never heretofore included in oral endoparasiticide compositions based on isoxazolines, presenting a wide differential advantage compared with the compositions known up to the present.

Description

[0001] ORAL COMPOSITION IN THE FORM OF A BIOADHESIVE GEL BASED ON ISOXAZOLINE

[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 antiparasitic formulations that have activity against external parasitosis by fleas, ticks and mites and that are easy to administer is a current need for the treatment and control of infestations in small animals.

[0006]

[0003] High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compounds are known in the state of the art, such as document CN 105566213 which teaches compositions capable of converting into parent drugs or drug metabolites after crossing the biological barrier and therefore capable of providing treatments. Furthermore, the compositions are capable of reaching areas that their parent drugs may not be able to access and generating sufficient concentration in the target areas and therefore providing novel treatments.Formulations suitable for oral administration may be capsules, cachets, pills, caplets, lozenges (using astringent base ingredients, typically sucrose, acacia or tragacanth), powders, granules, or a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or a lozenge (using an inert substrate, e.g., gel and glycerin, or sucrose and acacia) and / or mouthwashes and the like, each of which contains a predetermined amount of active ingredients such as isoxazoline derivative antibiotics among others. The compound may also be administered as a bolus, electrolyte, or paste.

[0007]

[0004] For its part, document ES2182485 teaches new substituted aminophenyl isoxazoline derivatives and pharmaceutical compositions containing them as active ingredients and methods for their use. The compounds of the invention are useful as antimicrobial agents to prevent and treat infectious diseases in humans or animals infected with pathogens and the preferred form of administration is oral.Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier and are dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable concentration. They are administered orally in solid and liquid dosage forms comprising gelatin, cellulosic materials, low melting waxes among others.

[0008]

[0005] Also known is document US2021 / 0220360 which teaches a hard and palatable chewable composition comprising at least one veterinarily acceptable isoxazoline, a stabilized macrocyclic lactone, an acceptable salt form of pyrantel, at least one natural palatability of animal origin and at least one veterinarily acceptable excipient.The invention also contemplates a method of use for treating and / or preventing a parasitic infection or infestation in an animal in need thereof by administering said composition to the animal, wherein the composition comprises binders to add cohesiveness to the separate granulations and to the final mixed composition, thereby providing the necessary bonding to form a cohesive mass and ensure a compacted tablet shape and veterinary acceptable binders include, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose (HPC), polyvinylpyrrolidone and copovidone, polyethylene glycol, acacia, corn syrup solids, tragacanth gum, gelatin, carnauba wax, alginate and mixtures thereof.

[0009]

[0006] WO2022 / 212399 provides methods for treating a clinical symptom and / or transmission risk associated with a pathogen in an individual, including related pharmaceutical formulations, the method comprising the steps of: administering to the individual having the clinical symptom or at risk of transmission of the pathogen, an active agent in a dose effective to inactivate Demodex mites in or on the individual; thereby resulting in an amelioration or cessation of the clinical symptoms and / or transmission risk associated with the pathogen, wherein the active ingredient may be applied together with pharmaceutically acceptable carriers such as lotions, creams, soaps, shampoos and gels.

[0010]

[0007] In this sense, there is still a need to provide an oral pharmaceutical composition or formulation in the form of a bioadhesive gel comprising as an active ingredient an isoxazoline that can be alone or in combination with other antiparasitics and that is easy to administer and that adheres to the mouth or to the internal walls thereof or to the palate of the animal in such a way as to ensure that the medication can be completely dosed to provide comprehensive protection against external parasites such as fleas, ticks and mites. The proposed composition contains an active ingredient from the isoxazoline family, which is highly effective against parasitosis and also allows the administration of multiple doses of the drug.

[0011]

[0008] The proposed composition is a broad spectrum parasiticide containing an isoxazoline alone or in combination with other antiparasitics, available in the form of a gel with bioadhesive characteristics that makes the pharmaceutical composition for veterinary use highly palatable, since the adhesiveness of the gel provides greater ease in the administration of the drug, allowing the product to remain adhered to the animal's mouth and ensuring that the correct dosage is supplied. The orally administered composition achieves good adhesion in the oral cavity and its use in the prevention and / or treatment of infestation of domestic animals by external parasites.

[0012] BRIEF DESCRIPTION OF THE INVENTION

[0013]

[0009] 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 an isoxazoline alone or in combination with other antiparasitics for the treatment of parasitic infestations in animals, wherein the composition is in the form of a bioadhesive oral gel.

[0014] DETAILED DESCRIPTION OF THE INVENTION

[0015]

[0010] The present invention relates to the composition of an endoparasiticidal bioadhesive gel based on isoxazoline, with a high level of adhesion to the oral mucosa of the treated animals and good palatability that greatly facilitates its dosage and procedures for its preparation.

[0016]

[0011] External parasitosis caused by fleas, ticks and mites is a very common condition in pets, for this reason the effective control of parasitosis is of great importance, which can be achieved with antiparasitics of proven effectiveness such as isoxazolines, but they must be easy to administer to achieve the objective.

[0017]

[0012] The present invention refers to a pharmaceutical composition or formulation for oral administration of an isoxazoline for the treatment of parasitic infestations in smaller animals, wherein the composition comprises as isoxazoline or a salt or solvate of isoxazoline having the structure of formula 1:

[0018] Formula 1

[0019]

[0013] 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 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. tetrahydrofuran, methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl; and where Z3 consists of O and S.

[0020]

[0014] An isoxazoline, salt or solvate according to the structure of formula 1 , wherein A1 , A2 and A3 is halogen and can be fluoro, bromo or chloro.

[0021]

[0015] An isoxazoline, salt or solvate according to the structure of formula 1 , wherein A1 and A2 is halomethyl and is trifluoromethyl.

[0016] An isoxazoline, salt or solvate according to the structure of formula , wherein R is monochloromethyl, thfluoromethyl, monochloro-difluoromethyl.

[0022]

[0017] An isoxazoline, salt or solvate according to the structure of formula 1, wherein X is hydrogen, bromine, iodine, chlorine, methyl, ethyl, thfluoromethyl.

[0023]

[0018] An isoxazoline, salt or solvate according to the structure of 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 wherein Z3 consists of oxygen or sulfur.

[0024]

[0019] The isoxazoline used in the present invention may have two or more conformational structures, but at least comprise a quinone carbon at position 5 of the isoxazoline ring. Other isoxazolines and their salts or solvates comprised in the present invention are selected from fluralaner, sarolaner, afoxolaner and lotinaler or combinations thereof and may be in combination with other antiparasitics.

[0025]

[0020] Surprisingly, isoxazolines have never been used in the pharmaceutical form of oral gel. This chemical compound is very frequently administered orally due to its organoleptic and physicochemical characteristics of the compositions known to date in tablet form.

[0021] The present invention favorably demonstrates, unlike the aforementioned patents, that it is possible to administer an isoxazoline in the pharmaceutical form of oral gel at concentrations of 0.01% to 30.00%, with long action, highly palatable and great adhesion to the oral cavity. Factors not included in oral antiparasitic compositions based on isoxazoline that present a wide differential advantage over the compositions known to date.

[0026]

[0022] For this reason, the present invention aims to provide:

[0027] • An isoxazoline-based oral parasiticidal gel composition for small animals.

[0028] • A parasiticidal oral gel composition based on isoxazoline in concentrations of up to 30% of the aforementioned active ingredient alone or in combination with other antiparasitics.

[0029] • A long-acting isoxazoline-based antiparasitic oral gel composition that demonstrates proven effectiveness for at least 60 days after administration.

[0030] • A highly palatable antiparasitic oral gel composition based on isoxazoline that encourages voluntary ingestion.

[0031] • An antiparasitic oral gel composition with a high degree of adhesion to the mucous membranes of the oral cavity that reduces the likelihood of voluntary or involuntary expulsion of the gel after administration.

[0032]

[0023] This bioadhesive antiparasitic oral gel composition comprises: a) From 0.10% to 30.00%; preferably from 0.50% to 25.00%; more preferably from 1.00% to 20.0% weight / volume of an isoxazoline. b) From 2.00% to 10.00% weight / volume of a viscosifying agent such as cellulose, ethylcellulose, methylcellulose, colloidal silicon dioxide, hydroxypropylmethylcellulose, povidone, similar components or mixtures thereof. c) From 1.00% to 80.00%; preferably from 5.00% to 70.00%; more preferably 10.00% to 60.00% weight / volume of a suitable diluent such as propylene glycol, polyethylene glycol 300, polyethylene glycol 400, glycerin, water, similar components or mixtures thereof.d) From 1.00% to 40.00%; preferably from 2.00% to 30.00%; more preferably from 2.50% to 20.00% weight / volume of a solvent such as N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, propylene glycol, water, benzyl alcohol, glycerin, glycerol formal, vegetable oil which may be soybean oil, coconut oil, sesame oil, corn oil, among others; polyethoxylated castor oil, salmon oil, macrogol 15 hydroxystearate similar components or mixtures thereof. e) From 1.00% to 50.00%; preferably from 2.00% to 40.00%; more preferably from 5.00% to 35.00% weight / volume of a natural or synthetic flavoring agent. f) From 0.01% to 4.00%; preferably from 0.05% to 3.00%; more preferably from 0.10% to 2.50% by weight and volume of a flavoring agent that is a natural or synthetic essence.g) From 0.01% to 5.00%; preferably from 0.05% to 3.00%; more preferably from 0.10% to 2.50% weight / volume of a sweetener selected from sucralose, saccharin, aspartame, cyclamate, similar components or mixtures thereof. h) From 0.01% to 1.00%; more preferably from 0.05% to 0.5% weight / volume of a preservative such as methylparaben, propylparaben, butylparaben, similar components or mixtures thereof. i) From 0.01% to 1.00%; more preferably from 0.02% to 0.5% weight / volume of an antioxidant agent are advantageously chosen from ethyl or propyl gallate, alpha tocopherol, ascorbic acid, ascorbyl palmitate, monothioglycerol, butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); as well as mixtures thereof.

[0024] The composition according to the present invention may further comprise another antiparasitic in combination, which may be, but is not limited to, for example, a pyrazinoisoquinoline such as praziquantel, pyrantel, febantel or combinations thereof.

[0033]

[0025] The composition according to the present invention may comprise an antiparasitic in combination with a macrocyclic lactone, selected from an avermectin of the group consisting of ivermectin, emamectin, eprinomectin, selamectin, doramectin, moxidectin, abamectin or combinations thereof.

[0034]

[0026] In a second aspect, the present invention relates to the method of producing a pharmaceutical composition comprising an isoxazoline, for the treatment of parasitic infestations in smaller animals, wherein the method comprises the following steps: a) Mixing the isoxazoline and the selected flavorings and sweeteners; b) Mixing the selected antioxidants and the flavoring agent with the selected solvent(s), stirring until completely dissolved until solution A is formed; c) Incorporating the selected preservatives into solution A, stirring until solution B is formed; d) Adding the diluent(s) to solution B, stirring until solution C is formed; e) Incorporating the selected viscosifying agent into solution C, until a homogeneous dispersion is formed, forming suspension D; and f) Mixing suspension D with solution A and the mixture from the first step. g) Bring to final volume with the selected diluent.

[0027] In a third aspect, the invention further comprises a method of treating an animal, wherein said method is for treating a parasitic infestation in an animal in need thereof, comprising administering to said animal a bioadhesive oral gel composition comprising as an active ingredient an isoxazoline which may be alone or in combination with other antiparasitics.

[0035]

[0028] In a fourth aspect, the invention further comprises the use of a bioadhesive oral gel composition comprising as an active ingredient an isoxazoline which may be alone or in combination with other antiparasitics for the treatment of an animal in need of such treatment.

[0036] Examples of formulation or compositions according to the invention

[0029] Examples of the declared composition are shown below in table No. 1.

[0037] Table No. 1. Examples of formulas with the declared composition

[0038] Palatability study of the composition of the present invention

[0039] Study design

[0040]

[0030] For the palatability test, 45 canines, older than 8 weeks of age, of both sexes, of different weights, of different breeds and clinically healthy, were worked with.

[0031] The dosing syringe was presented to them at the height of the snout, and a score for the product was determined according to the reaction based on the scale shown in Table No. 2.

[0041] Table No. 2 Palatability scale in canines.

[0042] Results

[0043]

[0032] Table 3 shows the average, as well as the percentage of voluntary acceptance and rejection for each sample evaluated.

[0033] The consistency of the gel is a determining factor in product acceptance. Samples with high adhesiveness to the oral cavity, such as samples D and E, have a higher percentage of acceptance. Table 3. Results of the palatability test

Claims

CLAIMS 1. A bioadhesive oral gel composition for the treatment of parasitic infestations in smaller animals is characterized in that it comprises as an active ingredient an isoxazoline that may be alone or in combination with other antiparasitics.

2. The composition according to claim 1, wherein the isoxazoline compound belongs to the chemical structure of formula 1: Formula No. 1 3. The compound according to claim 2, wherein A1, A2 and A3 are selected from the group consisting of hydrogen, halogen and halomethyl; and wherein R is a halomethyl; and wherein X is selected from the group consisting of hydrogen, halogen, methyl, halomethyl, ethyl and haloethyl; and wherein 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. , tetrahydrofuran, 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 halogen and may be fluoro, bromo or chloro.

5. The composition according to claim 2, wherein A1 and A2 is 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 and lotinaler or combinations thereof.

10. The composition according to claim 1, wherein the antiparasitic in combination may comprise a macrocyclic lactone selected from the group consisting of ivermectin, emamectin, eprinomectin, selamectin, doramectin, moxidectin, abamectin or combinations thereof.

11. The composition according to claim 1, wherein the antiparasitic in combination may comprise praziquantel, pyrantel, febantel or combinations thereof.

12. The composition according to claim 1, wherein the active ingredients may be present in a concentration between 0.1 and 30% based on the total weight of the composition; preferably from 0.50% to 25.00%; more preferably from 1.00% to 20.0% weight / volume of an isoxazoline.

13. The composition according to claim 1, wherein a solvent such as N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, propylene glycol, water, benzyl alcohol, glycerin, glycerol formal, vegetable oil which may be soybean oil, coconut oil, sesame oil, corn oil, among others; polyethoxylated castor oil, salmon oil, macrogol 15 hydroxystearate similar components or mixtures thereof may be present in a concentration of 1.00% to 40.00%; preferably 2.00% to 30.00%; more preferably 2.50% to 20.00% weight / volume.

14. The composition according to claim 1, wherein a viscosifying agent such as cellulose, ethylcellulose, methylcellulose, colloidal silicon dioxide, hydroxypropylmethylcellulose, povidone, similar components or mixtures thereof may be present in a concentration of 2.00% to 10.00% weight / volume.

15. The composition according to claim 1, wherein a suitable diluent such as propylene glycol, polyethylene glycol 300, polyethylene glycol 400, Glycerin, water, 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.

16. The composition according to claim 1, wherein a natural or synthetic flavoring agent may be present in a concentration of 1.00% to 50.00%; preferably 2.00% to 40.00%; more preferably 5.00% to 35.00% weight / volume.

17. The composition according to claim 1, wherein a flavoring agent that is a natural or synthetic essence may be present in a concentration of 0.01% to 4.00%; preferably 0.05% to 3.00%; more preferably 0.10% to 2.50% weight by volume.

18. The composition according to claim 1, wherein a sweetening agent selected from sucralose, saccharin, aspartame, cyclamate, similar components or mixtures thereof may be present in a concentration of 0.01% to 5.00%; preferably 0.05% to 3.00%; more preferably 0.10% to 2.50% weight by volume.

19. The composition according to claim 1, wherein a preservative such as methylparaben, propylparaben, butylparaben, similar components or mixtures thereof may be present in a concentration of 0.01% to 1.00%; more preferably 0.05% to 0.5% weight / volume.

20. The composition according to claim 1, wherein an antioxidant agent such as ethyl or propyl gallate, alpha tocopherol, ascorbic acid, ascorbyl palmitate, monothioglycerol, butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); as well as mixtures thereof may be present. present in a concentration of 0.01% to 1.00%; more preferably 0.02% to 0.5% weight / volume.

21. A method for preparing a composition according to claim 1, comprising the following steps: a) Mixing the isoxazoline and the selected flavorings and sweeteners; b) Mixing the selected antioxidants and the flavoring agent with the selected solvent(s), stirring until completely dissolved, forming solution A; c) Incorporating the selected preservatives into solution A, stirring until forming solution B; d) Adding the diluent(s) to solution B, stirring until forming solution C; e) Incorporating the selected viscosifying agent into solution C, until a homogeneous dispersion is formed, forming suspension D; and f) Mixing suspension D with solution A and the mixture from the first step.

22. A method for treating a parasitic infestation in an animal in need thereof, comprising administering to said animal a bioadhesive oral gel composition comprising as an active ingredient an isoxazoline which may be alone or in combination with other antiparasitics.

23. The use of a bioadhesive oral gel composition comprising as an active ingredient an isoxazoline which may be alone or in combination with other antiparasitics for the treatment of an animal in need of such treatment for a parasitic infestation.

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