Composition for domestic animals, production process and use of composition

Abstract

The invention features oral solid compositions comprising active ingredients with low water solubility in high concentrations with high bioavailability in a reduced solid composition size. In the present invention such compositions are obtained by a sustainable production process, which does away with the use of solvents and heating. The invention also discusses the use of such compositions for the production of veterinary medicines in the form of insecticides and / or acaricides.

Description

[0001] “COMPOSITION FOR DOMESTIC ANIMALS, PRODUCTION PROCESS AND USE OF COMPOSITION”

[0002] Field of Invention

[0003]

[0001] The present invention is in the field of veterinary medicine, more specifically, in the field of anhydrous veterinary compositions for domestic animals. The invention overcomes the challenge of providing solid oral compositions comprising active ingredients with low water solubility in high concentrations. Surprisingly, the present composition also provides high bioavailability in a reduced solid composition size. Such compositions are obtained by a sustainable production process in the present invention, which dispenses the use of solvents and heating. The invention also discusses the use of such compositions for the production of veterinary drugs such as insecticides and / or acaricides.

[0004] Fundamentals of the Invention

[0005]

[0002] Animals require special care when it comes to parasites that can infect them. Domestic animals, in particular, which live in close contact with humans, require means to prevent and treat parasites and their associated diseases to prevent the animals from suffering health problems and to prevent humans from becoming infected.

[0006]

[0003] However, the development of oral compositions containing high concentrations of active ingredients presents pharmacotechnical challenges that must be overcome. Some of these challenges include developing a composition with a suitable size for easy ingestion by animals, especially when the composition contains a high concentration of active ingredient. Other challenges relate to the bioavailability of the oral composition, which must be adequate for the active ingredient to be released and maintained in the body long enough for its action to be perceived. Another challenge concerns the production process for such compositions, as it should ideally be efficient, sustainable, and capable of maintaining the physicochemical properties of the molecules until they reach their destination.

[0004] Specifically in the present invention, we were able to observe that some processes for producing oral compositions with moisture can lead to the hydrolysis of active molecules with low water solubility in a wide pH range. Therefore, certain processes and parameters must be adopted in order to obtain a suitable active product.

[0007]

[0005] Furthermore, there is a need for such production processes to be sustainable, helping the environment and nature.

[0008]

[0006] Thus, the present invention comprises solid oral compositions containing compounds with low water solubility, more specifically, isoxazoline actives, in high concentrations. Such compositions demonstrate high bioavailability of the compound in the organism of domestic animals and are in reduced sizes, when considering the high concentrations of compounds in said compositions.

[0009]

[0007] Additionally, a production process is presented that dispenses with the use of organic solvents, which can be carcinogenic or intoxicating, also avoiding their dispersion in nature.

[0010]

[0008] We have verified some state-of-the-art documents that may be potentially related to the present invention and these are exemplified below.

[0011]

[0009] Document BR 1 1 2014 024832 0 comprises a soft chewable tablet with specific organic solvents (such as 2-pyrrolidone and DMAC) with low amounts of isoxazolines. Document BR 1 1 2021 004218 0 describes a chewable tablet with a combination of low amounts of isoxazolines and macrocyclic lactones, in addition to additional active ingredients, such as the anthelmintic pyrantel palmoate, with a hardness of at least 30 N. Finally, document BR 1 1 2020 008853 6 comprises isoxazolines with a certain particle size distribution (D50 of 25 to 250 microns) in an injectable formulation.

[0012]

[0010] Thus, none of the prior art documents was able to anticipate the aspects of the present invention, individually or together, among which we highlight: - compositions with a high concentration of active ingredients with low water solubility (low flowability and / or compressibility), making the process of producing a composition in solid form difficult; - compositions with an adequate relationship between the high concentration of active ingredient and the size of the composition, in addition to high bioavailability; - sustainable production process, free of organic solvents and heating; - use of said composition as an insecticide or acaricide. Thus, the present invention provides a unique and inventive composition, as well as its production process and its possible uses.

[0013] Summary of the Invention

[0014]

[0011] The present invention comprises solid veterinary compositions with high bioavailability comprising a high concentration of active ingredients with low water solubility.

[0015]

[0012] More specifically, the present invention comprises a composition for domestic animals comprising: i) from 30 to 70% of at least one low water-soluble active ingredient; ii) from 30 to 70% of at least one excipient.

[0016]

[0013] In a preferred embodiment, said solid composition in oral form has a diameter of less than 10 mm for compositions of up to 200 mg, less than 15 mm for compositions of 200 to 800 mg and less than 30 mm for compositions of 800 mg to 1200 mg.

[0017]

[0014] Additionally, the size and hardness ratio of the composition is 0.5-1.5.

[0018]

[0015] In a preferred embodiment, the composition of the present invention is an anhydrous solid veterinary composition.

[0019]

[0016] In a preferred embodiment, the composition comprises an active concentration of approximately 50% in the composition.

[0020]

[0017] In a preferred embodiment, the excipients comprise at least one of the following elements: binder, glidant, disintegrant, surfactant, palatability enhancer, lubricant and / or diluent.

[0021]

[0018] In a preferred embodiment, the excipient of said composition comprises at least one of the following elements: - from 1 to 10% w / w of binder; - from 0.1 to 5% w / w of surfactant, glidant, lubricant or disintegrant; - from 1 to 20% w / w of palatability; - from 5% to 50% w / w of diluent.

[0022]

[0019] The present invention additionally comprises a sustainable production process for obtaining solid veterinary compositions comprising active ingredients with low water solubility.

[0023]

[0020] The production process of the present invention dispenses with the use of solvents and heating means.

[0021] In a preferred embodiment, the production process comprises the steps of: a) mixing part of the diluent with the active; b) mixing part of the diluent with part of the glidant; c) mixing a) with part of the diluent and homogenizing; d) mixing b), surfactant, disintegrant, binder, c) and homogenizing; e) compacting the mixture of d); f) obtaining granules and transferring the compacted mixture of e to the mixer); g) adding and mixing the remainder of the disintegrant, glidant, lubricant, total palatability and diluent.

[0024]

[0022] In a preferred embodiment, the granules are obtained using the dry granulation technique.

[0025]

[0023] Said production process presents a high productive performance allowing a rapid and highly efficient production of solid oral compositions.

[0024] The present invention further comprises the use of said composition for the treatment of veterinary diseases.

[0026] Description of the Invention and Examples

[0027]

[0025] The above examples should not be seen as limiting but rather as proof of concept of the said invention.

[0028]

[0026] Oral solid compositions

[0029]

[0027] The solid oral compositions of the present invention comprise a high concentration of actives that have low water solubility. The actives with low water solubility selected to represent the invention comprise actives with water solubility of less than 1 mg / ml at 25 sC. More specifically, it comprises the isoxazoline compounds. Even more preferably, it comprises the compounds fluralaner, sarolaner, afoxolaner, and lotilaner.

[0030]

[0028] In another modality, the high concentration of active ingredients comprises values ​​between 30 and 70% of active ingredients in the composition, more specifically 40 to 60%, preferably 45 to 55%, even more preferably 50%.

[0031]

[0029] Determining the high bioavailability of said composition comprises measurements of areas under the curve (AUC) and Cmax and comparison between compositions comprising the elements of the present invention and compositions without at least one of these elements, in order to demonstrate that the composition of the present invention can assist in the bioavailability of the active ingredient in domestic animals.

[0032]

[0030] The solid oral compositions of the present invention have a reduced size in mm in relation to their concentration of actives. For example, a formulation with a weight of 90 mg comprising 50% by weight of low water-soluble active (45 mg) has a size smaller than 10 mm, preferably 6 mm (round). In general, the solid composition in oral form of the present invention comprises a diameter smaller than 10 mm for compositions of up to 200 mg, smaller than 15 mm for compositions of 200 to 800 mg and smaller than 30 mm for compositions of 800 mg to 1200 mg.

[0033]

[0031] The size of the composition is associated with the appropriate dosage of low water-solubility active ingredient according to the weight and / or size of the animal, with presentations of 10 to 2000 mg being considered, even more specifically of 50 to 1500 mg, even more preferably of 90, 200, 400, 800 and 1120 mg. Each composition has a weight proportional to its size, according to the aforementioned relationships. In a preferred embodiment, the average weight of the composition ranges from 5 to 3000 mg, even more preferably of 25-2250 mg, even more preferably of 80-90 mg, of 180-220 mg, of 370-430 mg, of 750-850 mg and of 1000-1200 mg.

[0034]

[0032] Preferably, the present invention comprises an ideal relationship between the concentration of the active in the composition (weight in mg) and the size of the tablet (diameter in mm) is 5-15 mm for tablets containing up to 150 mg of active, 10-30 mm for tablets containing from 50 mg to 250 mg of active and 25-50 mm for tablets containing more than 200 mg of active.

[0035]

[0033] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, preferably tablets with hardness of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Kgf, and useful ranges can be selected from any of these values. The hardness of the solid oral composition of the present invention can also be verified in the relationship between the average hardness of the tablet (Kgf) and the size of the tablet (mm), where a surprising relationship of 0.5 - 1.5 was verified, which pharmacotechnically characterizes the solid oral composition of the present invention.

[0036]

[0034] In such solid dosage forms, the active compound is mixed with: a) from 5 to 50% or in amounts sufficient to complete the expected weight of the composition (qsp) of at least one inert pharmaceutically acceptable excipient or carrier or diluent, such as sodium citrate or dicalcium phosphate, starches, lactose, sucrose, glucose, mannitol, silicic acid, talc and silicified microcrystalline cellulose; b) from 1 to 10%, even more preferably 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, of binders such as, for example, cellulose derivatives, such as carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; c) from 0.1 to 5%, even more preferably 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%, of lubricants such as stearic acid or its salt, such as calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, glyceryl palmitostearate and mixtures thereof;d) from 0.1 to 5%, even more preferably 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%, of glidant, such as microcrystalline wax, yellow beeswax, white beeswax and silicon dioxide; e) from 0.1 to 5%, even more preferably 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%, of disintegrant, such as sodium starch glycolate, croscarmellose sodium, corn starch, crospovidone; f) from 0.1 to 5%, even more preferably 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%, of surfactant, such as fatty acids and sodium lauryl sulfate;g) from 1 to 20%, even more preferably 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% of palatability selected from among those known in the state of the art, such as natural or artificial palatability enhancers, capable of stimulating one or more senses of domestic animals, such as smell, synesthesia, taste or texture, including, but not limited to, palatability enhancers capable of simulating the taste of chicken, meat or vegetables and others, applicable to solid oral compositions, especially veterinary ones.;

[0037]

[0035] In one embodiment, the composition provides high bioavailability of active ingredients with low solubility. In another embodiment, it provides compositions with a large amount of active ingredient, above 30%, 40% or even 50% in the composition. In another aspect, the composition of the present invention provides reduced-sized tablets, from 5 to 50 mm, depending on the dosage of active ingredient used. In a different embodiment, said composition has a unique ratio between the hardness of its solid composition and the amount of active ingredient between 0.5-1.5. In another embodiment, the composition is anhydrous.

[0038]

[0036] Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also comprise a composition that releases the active ingredient(s) only or releases the active only in a particular portion of the animal intestinal tract, optionally in a delayed manner.

[0039]

[0037] Treatment and prevention of diseases

[0040]

[0038] The present invention comprises active ingredients with low solubility in water and excipients, and can be obtained from a sustainable production process, being used in the treatment and / or prevention of parasites, insects and mites, preferably fleas and ticks, even more preferably, ticks of the species Rhipicephalus sanguineus sensu lato and fleas of the species Ctenocephalides fells felis and diseases potentially related to these animals, caused directly by them or through their infection by other pathogens.

[0041]

[0039] Said composition can be used to prevent such diseases, depending on the dosage, the composition used and the condition of the animal. Thus, the composition of the present invention, when administered at the recommended dose, is effective in combating fleas for at least 77 days and ticks for at least 63 days after treatment in domestic animals. Thus, said composition can be used for monthly or bimonthly treatments of domestic animals.

[0042]

[0040] Production process

[0043]

[0041] The present invention comprises a sustainable production process for obtaining solid veterinary compositions comprising actives with low solubility.

[0042] Said process comprises steps that do not require solvents (including water) and that do not require heating, comprising the steps of: a) mixing part of the diluent with the active; b) mixing part of the diluent with part of the glidant; c) mixing a) with part of the diluent and homogenizing; d) mixing b), surfactant, disintegrant, binder, c) and homogenizing; e) compacting the mixture of d); f) obtaining granules and transferring the compacted mixture of e) to the mixer; g) adding and mixing the remainder of the disintegrant, glidant, lubricant, total palatability and diluent.

[0044]

[0043] In one embodiment, the purpose of the process is to obtain a composition as described in the present invention.

[0045]

[0044] Examples

[0046]

[0045] Example

[0047]

[0046] As previously stated, the production process of the invention comprises a sustainable process, which dispenses the use of solvents and heating, providing a product with unique pharmacotechnical characteristics and bioavailability for actives with low water solubility. Preferably, the production process comprises the steps of: a) mixing part of the diluent with the active; b) mixing part of the diluent with part of the glidant; c) mixing a) with part of the diluent and homogenizing; d) mixing b), surfactant, disintegrant, binder, c) and homogenizing; e) compacting the mixture of d); f) obtaining granules and transferring the compacted mixture of e) to the mixer; g) adding and mixing the total amount of palatability enhancer and diluent to the remainder of the disintegrant, glidant, lubricant.

[0048]

[0047] Specifically, the production process of the present invention comprises the steps of: a) mixing 30 to 50% of the diluent with the active; b) mixing 1 to 20% of the diluent with 40 to 60% of the glidant; c) mixing a) with 40 to 60% of the diluent and homogenizing; d) mixing b), surfactant, 40 to 60% of the disintegrant, binder, c) and homogenizing; e) compacting the mixture of d); f) obtaining granules and transferring the compacted mixture of e) to the mixer; g) adding and mixing the remaining amount of the disintegrant, the glidant, the lubricant, the total amount of the palatability enhancer and the diluent.

[0049]

[0048] In a preferred embodiment, the dry granulation process is carried out. In one aspect, the diluent(s), active(s), glidant(s), surfactant(s), disintegrant(s), binder(s) may be sieved alone or together, in whole or in part. In one embodiment, the diluent is sieved together with the active in step a). Preferably, the diluent is sieved together with the glidant in step b). Preferably, the diluent from step c) is previously sieved alone. In one embodiment, 35 to 45% diluent is used in step a). In another embodiment, 5 to 15% diluent is used in step b). In another embodiment, 1 to 10% diluent is used in step g). In one embodiment, 50% glidant is used in step b). In one embodiment, 50% glidant is used in step g). Preferably, 45 to 55% of the diluent is used in step c). Preferably, 50% of the disintegrant is used in step d).Preferably, 50% of the disintegrant is used in step g). In a preferred embodiment, after step d), 20 to 50% of the lubricant is added and homogenization is carried out, before proceeding to step e). In a preferred embodiment, the remaining amount of lubricant is 80 to 50%. The active ingredient, surfactant, palatability enhancer and binder are used in their entirety (100%) in the steps in which they are required.

[0050]

[0049] The production process, in one embodiment, resulting in a product comprising the desired characteristics of bioavailability, hardness, size, average weight, and friability, as exemplified below:

[0051]

[0050] Wherein said composition, in another embodiment, may be obtained by means other than the aforementioned process.

[0051] Said solid oral composition of the present invention comprising the following elements and their respective concentrations:

[0052]

[0052] Some examples of compositions comprising said elements can be seen below:

[0053] [0531 Palatability

[0054]

[0054] All study protocols were submitted to the Animal Use Ethics Committee (CEUA) of the respective CRO. Each study was only initiated after approval. The trials took place at the CRO sites, whose facilities and management meet the determinations of the chapter “Domestic dogs and cats kept in facilities of educational or scientific research institutions” of the Brazilian Guide for the Production, Maintenance or Use of Animals in Educational or Scientific Research Activities of CONCEA (gov.br / mcti / pt- br / composicao / conselhos / concea / arquivos / arquivo / publicacoes-do concea / guia_concea_1 ed_animais-_ensino_ou_pesquisa_2023.pdf).

[0055]

[0055] The studies also included investigation of adverse events (any response that is harmful, unintentional, and may manifest as disease, abnormality, or injury, observed in animals participating in a clinical study after administration of PVI, which may or may not be related to the use of PVI. No adverse events occurred during any of the studies. All animals included in the studies were evaluated for their general health, and were found to be healthy, with no abnormalities. During the studies, all dogs were monitored daily for health, and no abnormalities were observed. Only dogs weighing over 2.0 kg of live weight, with an ideal body condition score, healthy, in good health and nutritional status, were selected for participation in the trial. Females must not be pregnant and / or lactating.

[0056]

[0056] In this study, 29 animals were used per group. The palatability of each product was tested on a panel of adult male and female dogs of small, medium, and large breeds. Each animal was offered a tablet according to its weight, in a single-day monadic test. Two criteria were evaluated: grasp (instantaneous, in the hand, or did not grasp) and consumption (partial, total, or did not consume). Acceptability was calculated based on the percentage of dogs that fully consumed the product. Regarding the behavior of the dogs in all groups, the assistant commented that all were very attracted to the respective products and consumed them quickly. The grasp of the product of the present invention was 93.1% and the acceptability of the product was 93.1%.

[0057]

[0057] Effectiveness

[0058]

[0058] The study consisted of groups of six dogs each, following a randomized block design: the animals were listed in descending order of tick counts, forming blocks, within which they were randomly assigned to one of the groups, ensuring the formation of homogeneous groups. The experimental treatments were randomly assigned to these groups. The study was controlled (one of the groups was unmedicated, maintained as a negative control), randomized in randomized blocks, and blinded. Therefore, the researcher responsible for randomizing the dogs into groups and treating the animals did not participate in the collection of post-treatment variables related to determining efficacy and investigating adverse events. Those responsible for all these post-treatment collections were blinded to the experimental groups and their respective treatments.The animals underwent a 21-day acclimation period to the study conditions between pre-selection and the start of treatment administration. They were identified and assessed for health, being observed at least once a day. All animals were clinically assessed during pre-selection to determine their general health status and weighed on the same day, and again two days before treatment to confirm the dose each individual should receive. Each animal's body condition score was assessed at each weighing. Before weighing, the scale was checked with a known weight. The tablets were administered orally to the pre-selected animals in their respective groups, ensuring proper administration and swallowing after administration, in a single dose.All animals received the appropriate dose for their weight range, specifically, oral tablets containing 100, 200, and 400 mg of the active substance (Fluralaner) were administered in the efficacy and bioavailability trials. Flea and tick infestations of dogs occurred on days -7 and -2, pre-treatment, and after days 5, 12, 19, 26, 33, 40, 47, 54, 61, 68, 75, and 82 of treatment. On day -5, a count and parasite removal were performed to rank the animals and confirm their ability to retain fleas and ticks. After treatment, inspections / counts / removals were performed after 1 (at this time the parasites were not removed), 2, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 and 84 days of treatment. The calculation of efficacy was based on the number of live fleas and attached live ticks, counted in the negative control and in each treated group, on each count date.Initially, count data were assessed for normality using the Shapiro-Wilk test. When the distribution was normal (parametric data - P > 0.05), the data were evaluated by comparing tick and flea counts between groups at all time points using Analysis of Variance (ANOVA). Nonparametric data (P < 0.05) were assessed using the Kruskal-Wallis test. The significance level considered in all tests was 95% (P < 0.05). For animals in the group medicated with the product of the present invention, no live fleas were found until day 49 post-treatment, thus demonstrating 100% efficacy against fleas up to that point in the study. On days 56, 63, 70 and 77 post-treatment, the efficacies presented were respectively 99.2%, 98.7%, 96.1% and 90.2% over the days.Therefore, the product of the present invention demonstrated 100% efficacy against fleas up to 49 days after treatment and maintained efficacy above 90% up to 77 days after treatment. No live ticks were found on the animals up to 28 days after treatment, demonstrating 100% efficacy against ticks during this period. On the remaining days after treatment, the efficacy of this formulation continued until D+63, when the demonstrated efficacy was 95.4%. Therefore, regarding acaricidal efficacy, the same product demonstrated 100% efficacy up to 28 days after treatment and maintained efficacy above 90% up to 63 days after treatment. Therefore, it can be concluded that the product, when administered at the recommended dose, is effective against fleas for at least 77 days and against ticks for at least 63 days after treatment.

[0059] [0591 Biodisposability

[0060]

[0060] A larger number of dogs were pre-selected to ensure the selection of animals suitable for participation in the study, using a randomized block design, composing two groups containing 12 dogs each, homogeneous in terms of breed, category, sex, age and weight, ensuring non-interference of these factors in the results. The animals underwent a seven-day acclimatization period between pre-selection and treatments. To form the groups, the selected animals were initially divided into two blocks according to sex and listed in decreasing order of weight within each block. Animals of the same sex and weight were listed in increasing order of age. From this list, replicates were formed within each block, and the animals within each replicate were assigned to one of the groups by drawing lots. By drawing lots, it was determined which group was medicated with the product of the present invention.These animals underwent daily general health observations and clinical and laboratory examinations. Clinical examinations were performed at two pre-treatment time points: 48 and 96 hours after treatment, and on days 7, 14, 28, 42, and 56. All animals were weighed at the same time points on a scale calibrated for a known standard weight. The animals were evaluated for possible signs of systemic intoxication both before treatment and on days 2, 4, 7, 14, 28, 42, and 56 post-treatment. The weight obtained the day before treatment was used to calculate each animal's dose, for treatment administration according to the proposed dosage. Treatments were administered with feeding, as administration to fed dogs increases the plasma bioavailability of the active ingredient. On day 0, the animals received wet food (pate) approximately 15 minutes before treatment, and the remaining half of the pate immediately after administration.To prevent the use of wet food from impacting the study, the animals were acclimated to this type of diet. Blood samples were collected and used for the analytical stage, quantifying the active ingredient in plasma, calculating pharmacokinetic parameters, and assessing plasma bioavailability. Samples were collected for quantification of the active ingredient at the following post-treatment time points: 0 (pre-administration - control sample); 2 hours; 4 hours; 8 hours; 1 day; 2 days; 3 days; 4 days; 7 days; 14 days; 21 days; 28 days; 35 days; 42 days; 49 days; 56 days; 63 days; 70 days; 77 days; 84 days; 91 days; 98 days; 105 days; and 12 days. At least 4 ml of blood were collected from each animal, using disposable syringes and needles and, immediately after collection, the blood was placed in tubes with anticoagulant (sodium citrate).The samples were centrifuged immediately after collection and properly packaged for sending to the analysis laboratory contracted to quantify the active ingredient.

[0061]

[0061] The pharmacokinetic variables calculated after receiving the active ingredient concentrations in plasma, quantified by a duly validated method, were: ASC0-24h (area under the plasma concentration versus time curve, from time zero to 24 hours); ASCO-inf (area under the plasma concentration versus time curve, from time zero to infinity); ASCIast (area under the plasma concentration versus time curve, from time zero to the last sample collected); Cmax (maximum concentration reached); Clast (last plasma concentration reached); Tmax (time at which the maximum concentration was reached); T1 / 2 (elimination half-life); Vd (volume of distribution); Kel (elimination constant); CL (“clearance”). These were calculated by the PKSolver add-on package, developed in Visual Basic for Applications (VBA) and available for Microsoft Excel® software.

[0062]

[0062] An example of the results obtained can be seen in the Table below: data obtained from the literature

[0063]

[0063] As can be seen in the Table above, when comparing the bioavailability results of a formulation made in accordance with the teachings of this patent application with a second composition that does not have the same characteristics as the first composition, we found that the Cmax and AUC parameters of the composition of 10 to 25 mg / kg (average in this study of 14.4 mg / kg) of active ingredient present higher results than the Cmax and AUC of the composition of 25 mg / kg of active ingredient, indicating a greater bioavailability of the first composition, and this result may be caused by the different pharmaceutical form of the first composition, claimed herein.

[0064]

[0064] A person skilled in the art will understand that the examples revealed here serve to corroborate the invention, and are not necessarily limited to them.

Claims

CLAIMS 1. COMPOSITION for domestic animals characterized by comprising: i) from 30 to 70% of at least one active ingredient with low water solubility; ii) from 30 to 70% of at least one excipient.

2. COMPOSITION, according to claim 1, characterized in that the excipients comprise at least one of the following elements: binder, glidant, disintegrant, surfactant, palatability agent, lubricant and / or diluent.

3. COMPOSITION, according to claim 1, characterized by comprising from 45 to 55% of at least one active ingredient with low water solubility.

4. COMPOSITION, according to claim 2, characterized by comprising the excipients comprising at least one of the following elements: from 1 to 10% binder, from 0.1 to 5% glidant, from 0.1 to 5% disintegrant, from 0.1 to 5% surfactant, from 1 to 20% palatability enhancer, from 0.1 to 5% lubricant and / or diluent qsp.

5. COMPOSITION, according to claim 1 or 3, characterized by comprising a high concentration of active ingredients that have low solubility in water selected from active ingredients with solubility in water of less than 1 mg / ml at 25 s C isoxazoline compounds, such as fluralaner, sarolaner, afoxolaner or lotilaner.

6. COMPOSITION, according to claim 1, 2 or 4, characterized by comprising at least one element selected from the groups comprising: at least one inert pharmaceutically acceptable excipient or carrier or diluent, such as sodium citrate or dicalcium phosphate; starches, lactose, sucrose, glucose, mannitol, silicic acid, talc and silicified microcrystalline cellulose; binders such as cellulose derivatives, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; lubricants such as stearic acid or its salt, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, glyceryl palmitostearate and mixtures thereof; glidant, such as wax microcrystalline, yellow beeswax, white beeswax and silicon dioxide; disintegrant, such as sodium starch glycolate, croscarmellose sodium, corn starch, crospovidone; surfactant, such as fatty acids and sodium lauryl sulfate.

7. COMPOSITION, according to claim 1, characterized by providing a composition with high bioavailability of active ingredients with low solubility.

8. COMPOSITION, according to claim 1, characterized by providing reduced-size tablets, from 5 to 50 mm, depending on the dosage of active ingredient used.

9. COMPOSITION, according to claim 1, characterized by having a diameter smaller than 10 mm for compositions of up to 200 mg, smaller than 15 mm for compositions of 200 to 800 mg and smaller than 30 mm for compositions of 800 mg to 1200 mg.

10. COMPOSITION, according to claim 1, characterized by presenting a ratio between the hardness of its composition and the amount of active ingredient between 0.5-1.

5. 1 1. COMPOSITION, according to claim 1, characterized by being an anhydrous solid composition.

12. PROCESS FOR PRODUCTION of composition according to claim 1, characterized by comprising the steps of: a) mixing part of the diluent with active; b) mixing part of the diluent with part of the glidant; c) mixing a) with part of the diluent and homogenizing; d) mixing b), surfactant, disintegrant, binder, c) and homogenizing; e) compacting the mixture of d); f) obtaining granules and transferring the compacted mixture of e to the mixer); g) adding and mixing the remainder of the disintegrant, the glidant, the lubricant, the total of the palatability agent and the diluent.

13. PROCESS, according to claim 12, characterized by being a dry granulation.

14. PROCESS, according to claim 12, characterized by being a sustainable process, dispensing with the use of heating and solvents.

15. PROCESS, according to claim 12, characterized by comprising the steps of: a) mixing 30 to 50% of the diluent with active; b) mixing 1 to 20% of the diluent with 40 to 60% of the glidant; c) mixing a) with 40 to 60% of diluent and homogenizing; d) mixing b), surfactant, 40 to 60% of disintegrant, binder, c) and homogenizing; e) compacting the mixture of d); f) obtaining granules and transferring the compacted mixture of e to the mixer); g) adding and mixing the remainder of the disintegrant, the glidant, the lubricant, the total of the palatability agent and the diluent.

16. USE of composition according to claim 1, characterized in that it is for the preparation of a medicine for the treatment and prevention of infestations of parasites, insects and / or mites, as well as diseases potentially related to these animals, caused directly by them or through their infection by other pathogens.

17. USE, according to claim 16, characterized in that it is for the treatment or prevention of flea and / or tick infestation.

18. USE, according to claim 16, characterized by being for the treatment or prevention of infestation caused by ticks of the species Rhipicephalus sanguineus and fleas of the species Ctenocephalides felis.

19. USE, according to claim 17, characterized by being efficient for the treatment or prevention of infestation for at least 77 days and against ticks for at least 63 days.

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