WO2014033230A1

WO2014033230A1 - Compositions for oral administration to animals, production methods thereof and uses of same

Info

Publication number: WO2014033230A1
Application number: PCT/EP2013/067934
Authority: WO
Inventors: Guy Derrieu; Giancarlo Mazzola
Original assignee: Friulchem Spa
Priority date: 2012-08-31
Filing date: 2013-08-29
Publication date: 2014-03-06
Also published as: CA2883139C; CA2883139A1

Abstract

The invention relates to a method for the production of a time-stable, solid appetising composition and to the use thereof, said composition comprising at least one active substance which is introduced in the final production step, by adding same to the already formed mixture of other components at ambient temperature, without the use of water or heat. The composition is intended for use as a drug, a nutraceutical or a food supplement for oral administration to mammals, except humans, in particular for pets such as dogs, cats or horses. The stable solid composition is obtained by compressing the mixture using a press for compressing formulations having a high fat content.

Description

COMPOSITIONS FOR ORAL ADMINISTRATION TO ANIMALS, METHODS OF OBTAINING THEM AND USES THEREOF

The present invention relates to the field of the preparation of appetizing compositions for therapeutic purposes more particularly to improve the oral intake and ensure treatment, formulated in solid form, by animals (domestic, farmed or wild).

Animal care is evolving, and the oral route is becoming a preferred route for drug administration by the health professional or by the owner, and this is particularly true for nutraceutical products. . In fact, the usual parenteral administration routes (intramuscular, subcutaneous, intradermal or intravenous), in particular medicinal products, have certain disadvantages. The intramuscular or subcutaneous routes may, for example, be the cause of hematomas or abscesses. The intravenous route often requires the intervention of a specialist (veterinarian). As for the intradermal route, it requires the use of solvents to pass the skin barrier to active molecules. These parenteral routes of administration also require the restraint of the animals. On the other hand, some active substances are difficult to formulate in parenteral dosage forms. Finally, certain active substances will exert their therapeutic action in animals only if they arrive directly in the digestive system. In order to have the composition taken by the animal it is necessary that it be attracted and that it absorbs the latter one will note then the satisfaction of the animal which will be manifested by a solicitation of the animal in order to obtain another composition. It is this satisfaction that will please the owner of the animal and that he seeks. It is known that the natural acceptance and consumption by an animal of a composition rests on its galenic form mainly on two characteristics, the palatability and the texture of said composition, and with less importance the shape and the size of this composition. last.

To these parameters we must add two others:

- A perfect control of the amount of one or more active substances as well if the composition is a drug or a nutraceutical or food supplement, and - the cost of the composition particularly if it is a nutraceutical or a dietary supplement.

Galenic formulations adapted to the administration of oral or oral compositions are generally in liquid form (such as syrups, solutions or oral suspensions, drops, etc.) in semi-solid form (such as pasta for oral administration) or in solid form. The solid forms commonly used per os in the animal kingdom, come in various formulations of nature different and are obtained by different methods. For example, tablets, cachets, capsules, capsules, chewing gums, pills, lozenges, tablets are distinguished. Mainly for the observance of oral treatments (that is to say, the respect of instructions and directives of the health professional concerning the taking of the drugs), one notes that the treatment is not always properly followed, in because of the difficulty in administering all the treatments to the animals. Indeed, the administration to animals of drugs in solid oral dosage form is often difficult because of the bad taste of certain active substances or excipients constituting the drug and the highly developed sense of smell and taste of animals . It has been observed in animals that the main reason why oral medication compliance is very difficult or impossible is lack of appetite for the drug. It is the same with nutraceuticals or food supplements. Indeed, an owner is particularly sensitive to the reactions of his animal when it comes to taking a composition. A composition given to an animal must be a pleasure shared by the owner with his animal.

Appetence is defined as the psychological state corresponding to a desire to absorb a food or a drink in response to the perception of the organoleptic characters of this product. The ability to arouse palatability is called appetite. The combination of these characters determines the attractiveness of a product to be taken orally on normally fed animals. More particularly, the appetite of a drug is largely involved in the refusal or acceptance by the animal of the spontaneous treatment and the repetition of the catch over sometimes long periods. In the context of certain treatments, the treatment may be taken daily or even for life.

Appetence of a drug, nutraceutical or dietary supplement administered orally leads to acceptance and voluntary ingestion by the animals. This palatability can be measured in a general palatability test taking into account different parameters of the composition formulated in a solid form, such as spontaneous taking by hand or on the ground, or its consumption, even if it is given several times. or taken at regular intervals by the animal.

The texture is defined as a physical state corresponding to a formulation arranged in a certain way by a obtaining technology. The hardness, the friability, the softness, the elasticity, the color of the composition depend on the texture. As for the parameters, shape or size, they will facilitate the gripping of the composition or its absorption in one go.

In the prior art, many solutions combining or not these two major parameters or the others have been proposed to facilitate the absorption mainly of drugs by an animal. Concerning palatability, several ways have been proposed:

A first option consists in masking the unpleasant taste and / or odor of the constituent (s), mainly one or more active substances, by encapsulation or by coating them.

The following patent applications: EP 0 997 143, EP 1 490 037, WO 01/15547, AU 2001279664, FR 2 350 105, US 5,380,535, US 3,037,91 1, describe how to encapsulate or coat one or more constituents as well as the techniques to get there. These solutions require many encapsulation or coating steps or they involve a production step such as extrusion which is likely to degrade fragile active substances or denature constituents such as flavorings or edible materials.

According to another option to facilitate oral administration is to encompass the composition, primarily the drug, into palatable matter.

The following patent applications: FR 2 896 958, FR 2 715 803, US 5,853,757, US 6,143,316, US 5,792,470, US 5,674,515, EP 0 574 301, US 4,857,333, DE 198 53 729, WO 03/030863, WO 2004/043427. WO 2007/090987 disclose lures made from palatable materials.

The disadvantage of these decoys is that their use requires manipulation namely the introduction of the drug beforehand in the lure, which can put off some users and also become annoying when a large number of animals must be treated. In addition, their large volume (necessarily larger than the drug) requires a large amount of material and their manufacture must be adapted to their complex shape; thus these lures are often expensive.

Yet another option, the active substances are isolated in the middle of a matrix obtained by compression of dry constituents, comprising a substance appétible to hide their taste and facilitate their intake and consumption.

The patent application EP 0 320 320 describes a pet tablet characterized in that it consists of at least one core containing one or more active substances completely encompassed in a matrix that is palatable to the animal. In such compositions it is the texture which constitutes the major disadvantage. Indeed the tablet or tablet form gives hard forms unappreciated animals. In addition, it takes great rigor in the manufacture of this type of stone tablets to be sure to fully encompass the central part.

The following patent applications EP 0 725 570, EP 0 725 627, propose compositions consisting of two parts, one central containing the constituents taste and / or unpleasant odor, the other external encompassing the central portion. Those are baits and their objective is to attract the animal so that it bites it so that it is vaccinated. Several disadvantages appear: When making the matrix, it is necessary to increase the temperature to obtain the melting of certain constituents in order to melt the polymer so that it is intimately mixed, which can constitute a strong constraint for the stability of the active substance,

"The realization of such matrices is complex and expensive,

• preservation in special conditions to ensure the integrity of the dosage form.

The patent application FR 2 709 420 describes a shape and a size for a tablet so that it is more sensitive to animals, especially cats.

The following patent applications: IE 2004 0393, and GB 2 432 506, describe appetizable chewing objects, obtained by extrusion or extrusion molding. The main disadvantage of these objects is that they are consumed for several minutes or even abandoned and resumed to be re-chewed before being consumed. It is therefore not possible to follow a therapeutic scheme with certainty.

US patent application 201 1/0183036 describes palatable rewards, obtained by extrusion-molding. The main disadvantage of these rewards is that they are obtained hot, temperature above 82 ° C, from an extruded-molded dough therefore a lack of regularity of weight. In addition, this paste contains water, part of which, between 3 and 15%, remains in the reward after its conformation. The demand speaks of a reward and not of a medicinal object.

U.S. Patent No. 6,455,083 discloses edible chewings obtained by extrusion molding. The main disadvantage is that they are thermoplastics that is, in the extruder, there is a polymerization mainly of proteins with water (10 to 20%). Given their texture these objects will not be absorbed in one fell swoop but chew at risk of being abandoned. The patent describes many nutritional chews and no drug objects.

The following patent applications: FR 2,154,424 and US 5,894,029 refer to the production of pet food. The production processes used are not adapted to the production of particular drug. They can greatly affect the stability of the active substances by the use of water in formulas or processes, by the use of heat with or without pressure.

The patent application US Pat. No. 5,637,313 describes particular compositions but especially a particular process for obtaining coated tablets, namely the matrix after mixing is rolled into a bead of a certain diameter and cut to a certain length to obtain the desired weight. This production does not ensure a perfect control of the weight and therefore the amount of active substance per unit which is antinomic with a drug. Regarding the texture, knowing that it is strongly linked to the composition and also to the palatability, three methods of obtaining were mainly proposed:

The first, the oldest, dry compression giving tablets, tablets or pills. The patent applications already cited: EP 0 997 143, EP 1 490 037, EP 0 574 301, EP 0 320 320, US 5,380,535, US 3,037,91 1, FR 2 709 420 describe hard forms hard not appreciated by animals and many refusals by the animals are reported.

The second, more recent, is the production of chewing tablets obtained by extrusion Thus the following patent applications: US 2004/0043925, US 2004/0037869, US 2001/036464, WO 2008/030469, WO 2005/013714, WO 89 / 12442, describe extremely appetizing forms having a relatively soft texture highly appreciated by animals, particularly domestic animals such as dogs and cats. Given the mode of production namely the use of an extruder, there is an online output so continuous matrix that is then cut to the desired length to have the required weight so the constant amount of substance (s) ) active (s) to be in particular a drug. This requires perfect control of the extrusion parameters. Unfortunately we know that with this technique we are not immune to a variation in density of the extrudate which inevitably leads to constant length to a change in weight. To overcome this it is necessary to weigh one by one the chewing tablets and to discard the out-of-order that can not be recycled on pain of seeing the provision of the modified active substance by a new extrusion. This technique is not economical. In conclusion, it would not be retained by those skilled in the art to make a medicament or a nutraceutical or dietary supplement where the amount of active substance (s) must be perfectly controlled.

US patent application 2004/151759 describes chewable tablets obtained by conventional techniques, compression of dry granulated powder or extrusion with drying at 50 ° C. Both manufacturing processes involve water for granulation, water removed before compression to obtain conventional tablets or after extrusion to obtain chewable tablets. The disadvantages of the two techniques that have already been mentioned are present.

The third, last proposed, is the production of soft tablets by molding with equipment to squeeze hamburgers, steaks, nuggets, cookies (before cooking) (patty pressing machine in English). Thus, the following patent applications: US 2005/0226908 and the patent applications of the same family WO 2009/064859 and US 7,955,632, US 8,293,265, WO 2012/049156, US 8.1 14.455, and US 2012/0141574 describe tablets. chewable obtained by molding a paste with little or no pressure (explicit in the applications WO 2009/064859, US 7,955,632, US 8,293,265, US 8,1 14,455, US 2012/0141574) prepared with water (application WO 2012/049156) or presence of water (US application 2005/0226908), use of heat (US applications 2005/0226908, WO 2012/049156) all the claims advocating the same equipment of Formax Corporation: Formax F6 ™. Given the mode of production namely the use of a machine-fed hamburger machine fed by a paste although that can be homogeneous has a random density that induces a random quantity in the mold so a random quantity of or active substances to be in particular a medicine. This requires perfect control of the physical characteristics of the dough. Unfortunately we know that we are not immune to a variation in density with a paste that is not very fluid because it is cold-molded. To this disadvantage is added the feeding system of the molds which aerates the dough, which inevitably leads to a variation of the weight of the tablets. To overcome this it is necessary to weigh the chewing tablets one by one and to discard the non-standard that can not be recycled, otherwise the modified active substance will be made available by a new formatting. This technique is not economical. In conclusion, it will not be retained by those skilled in the art to make a medicament or a nutraceutical or dietary supplement where the amount of active substance (s) must be perfectly controlled.

The Applicant's aim is to overcome the disadvantages of the prior art and by developing compositions and by finding a method for imparting to the compositions a homogeneity, and stability over time, of the active substance (s). administration in solid form having a preferred texture and better appetence for animals. In particular, it has worked on the development of a veterinary composition with simple oral administration adapted and appreciated by each animal species, which is economical, the manufacture of which is easily industrializable and the quantity of each component is perfectly controlled more particularly for the one or more active substances in the case of a medicament or a nutraceutical or dietary supplement.

In the work that led to the development of the appetizing composition according to the invention, the Applicant has found that obtaining this appetizing composition containing the maximum of appetizing materials by the compression technique formulas high content of materials fat led to veterinary oral compositions in solid form containing one or more active substances perfectly consumed by all animal species. This technique makes it possible to choose a perfectly adapted composition that is therefore appreciated by each of the target animal species by choosing the components of the formula well, while seeking for them, in their majority, to be appetizing materials, the texture as well as their shape and size. to the target animal species. This technique also makes it possible to choose the components of the composition so that they are not the cause of instability, in particular degradation of the active substance (s). Furthermore, it has surprisingly been found that the introduction into the mixture last of the active substance (s) has made it possible to better preserve their integrity and their stability throughout the solid form preservation period. This technique makes it possible to produce very homogeneous compositions and to guarantee with a great deal of precision the quantity of active substance (s) that it contains during manufacture and over time. This technique is also very economical and easily industrializable. The invention relates to a method of manufacturing a solid composition, stable over time, perfectly dosed in active substance, to this composition and its use, especially as appetizing compositions for oral administration for animals where the active substances are introduced at the last stage of the preparation by adding to a granulate previously obtained with all the other components (advantageously these other components do not comprise active substance). At the introduction of the active substance (s), advantageously of all the active substances, the granulate is advantageously cold, ie it is at ambient temperature, which can vary from 15 ° C. to 30 ° C., advantageously 15 ° C to 25 ° C, and that it does not contain water.

By "stable in time" is meant that after at least one year of storage of the composition at 25 ° C (+/- 5 ° C), under conditions of relative humidity ranging from 30% to 70%, the mixture remains homogeneous because the active substance dosage values are all in the dose range. The dose range corresponds to the target dose +/- 5%, the percentages being expressed by weight.

The compositions have a texture, shape and size appreciated by the animal species. The present composition is advantageously in the form of a perfectly dosed and stable cube over time, appetizing very well accepted by all animals, whatever the species, absorbed quickly, whether given occasionally or repeatedly .

The description of the invention will be made hereinafter in particular by reference to examples given by way of simple illustration and with reference to the last appended in which:

FIG. 1 is a diagrammatic representation of a press to compress the high-fat formulas, and FIG. 2 schematically illustrates a demagneter-calibrator advantageously mounted on the feed tank of the press to compress the high-grade formulas. in fat. More particularly, the subject of the invention is a process for the preparation of a solid appetizing composition that is stable over time, characterized in that the composition comprises:

at. 3 to 30%, preferably 5 to 15% by weight of at least one fat selected from fat or wax, or liquid oil, or thickened liquid oil, or a mixture thereof, liquid oil, from the liquid oil or thickened oil, can not represent more than 8% by weight of the composition, β. 0.001 to 57% by weight of at least one active substance,

χ. 40 to 96.999% by weight of at least one appetizing material,

when the active substance is also an appetizing material, the content of active substance may be up to 97% by weight, advantageously up to 85% by weight, and the composition may comprise as appetizing material this only active substance or a mixing the active substance with at least one other appetizing material,

δ. optionally one or more additives, advantageously chosen from fillers, binders, solvents, absorbing / gelling substances, flavorings, surfactants, flavor enhancers, sweeteners, antioxidants, chelating agents, preserving agents, dyes, and pH regulators,

a) the liquid or thickened oil is chosen from olive oil, peanut oil, rapeseed oil, sunflower oil, triglycerides of capric and caprylic acids, propylene glycol of acids dicaprique / dicaprylic, and mixtures thereof;

b) the fat is selected from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, possibly hydrogenated palm oil, palmitate cetyl, hydrogenated coconut oil, triglycerides of capric, caprylic, myristic and stearic acids, and mixtures thereof;

c) the wax is selected from beeswax, carnauba wax, candelilla wax, and mixtures thereof;

d) the appetizing material is selected from meat, meat flours, fishmeal, cheese powders, milk derivatives, liver powder, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apple, carrot, mangels, sugar beet, thyme, alfalfa, sugar cane, and cereals such as oats, wheat rice and corn, soybeans, their derivatives such as flours, and mixtures thereof; sugar (sucrose) in all its forms, crystallized, powdered, ice-cream, glucose, invert sugar, molasses, honey or its derivatives, and mixtures thereof, salt (sodium chloride), and mixtures thereof; e) the solid appetizing composition has a unit weight of plus or minus 3% of the theoretical value of the required weight, and preferably of plus or minus 2% of the theoretical value of the required weight;

f) the solid appetizing composition is stable for more than one year when stored at room temperature;

and in that the method comprises the following successive steps:

i. preparation of homogeneous aggregates comprising, or advantageously consisting of, the appetizing substance (s), the fat and optionally one or more additives,

ii. addition, with stirring, at room temperature without addition of water or heat, to the cold aggregates obtained following step i) of the active substance (s), advantageously of all the active substances,

iii. calibration of the mixture of aggregates obtained after step ii), dry and fluid, to retain aggregates having a granulation of between 50 and 1000 μηη, preferably between 200 and 800 μηη, even more preferably between 200 and

600 μηι,

iv. compressing the dry granules and calibrated fluids, obtained following step iii), with a press to compress the formulas with high fat content, v. recovery, following step iv) of the appetizing solid composition.

The fat is preferably in solid or waxy or pasty form.

Step i) advantageously comprises the following successive steps:

11. mixing the appetizing material (s) and optionally one or more additives, the appetizing materials and any additives being in pulverulent form;

12. Adding the fat to the mixture obtained following step i);

13. mixing or triturating without adding water or heat until homogeneous aggregates are obtained.

It is preferable that in step II) the appetizing materials and the optional additives have a particle size of less than 200 μηη, advantageously less than 100 μηη. The mixing can be carried out in a mixer-granulator.

According to a preferred embodiment, the fat is in solid or waxy or pasty or thickened liquid form.

To ensure the stability of the compositions obtained, the active substance (s) are introduced once the other components, advantageously all the other components, are mixed and granulated. When adding the active ingredient (s), the granulate of step iii) is cold and does not contain water. By "cold" is meant that it is at ambient temperature, that is to say between 15 ° C. and 30 ° C., advantageously between 15 ° C. and 25 ° C. By "does not contain water" is meant that the water content is less than 5% by weight, based on the total weight of the aggregate. Said active substances may be in the form:

of powders, or

solubilized in a suitable nonaqueous solvent to be vaporized or poured onto the granulate of step i), or

solubilized in a suitable non-aqueous solvent and then converted into a gel or powder by the addition of an absorbent substance, or

in the form of a granule, after a coating operation for example.

The active substance (s) may be simply distributed in powder form in the cube to be eaten, or may be previously sprayed on all or a part of the granulate after having been solubilized in a suitable non-aqueous solvent, or transformed into solid after gelation of a solution, or granulated or coated by the techniques known to those skilled in the art so as not to modify their bioavailability, or to increase the masking of their smell and taste to the olfactory perception or taste of the animal.

When in the form of a powder, the active substance advantageously has a particle size less than 200 μηη, more preferably less than 100 μηη.

When it is in the form of a granulate, the active substance advantageously has a particle size at most equivalent to that of the granulate of step iii), granulation of between 50 and 1000 μηη, preferably between 200 and 800 μηη, and even more preferably between 200 and 600 μπι.

Step ii) is advantageously carried out without adding heat or water.

Then, a calibration of the homogeneous mixture is carried out in order to obtain a particle size of between 50 and 1000 μηι, preferably between 200 and 800 μηι, and even more preferably between 200 and 600 μηη. Then, a compression of the mixture, fluid and calibrated, with a standard equipment like compression presses the formulas with high fat content of Fette, Bonals, IMA or Corazza (figure 1: diagram of the principle of operation of the press), giving compact and homogeneous masses. Said equipment being advantageously modified:

• by adding a demagneter-calibrator on the feed tank of the press to compress the formulas with high fat content which makes it possible to improve the filling of the cell by a constant volume, that is to say ie to make the volume of granulate so the weight introduced into the cell is as constant as possible in order to guarantee a very small variation in the weight of the cube to eat / chewing resulting from the theoretical weight fixed, as a result of which the amount of active substance present in the cube will be perfectly constant (Figure 2: demo-calibrator), and • to improve the extraction of the cube to eat / chew, but also to avoid any heating that could be detrimental to the cubic stability / active substance, the compression stage is refrigerated.

Thus, the press to compress the high-fat formulas is advantageously equipped with a demagneter-calibrator and / or a refrigerated compression stage.

During step iv), the compression force is advantageously between 5 and 80 kN, more advantageously between 20 and 60 kN, more advantageously between 35 and 45 kN. The compression step is advantageously carried out at ambient temperature, that is to say between 15 ° C. and 30 ° C., advantageously between 15 ° C. and 25 ° C.

The appetizing composition obtained is advantageously in the form of a compact mass with at least the upper and lower plane surfaces. Advantageously, the composition has the shape of a cube or a parallelepiped whose side advantageously varies from 10 mm to 40 mm, more advantageously from 12.5 mm to 35 mm (depending in particular on the mammal to which the composition is intended ). The process according to the invention makes it possible to obtain compositions having a very homogeneous unit weight which does not deviate by more or less than 3% from the theoretical value of the required weight and preferably from plus or minus 2% of the theoretical value. the weight required.

Compositions according to the present invention are typically in the form of eating / chewing cubes used to facilitate oral intake by animals, preferably mammals. Even if the appetizing composition for oral administration in solid form for animals is designated as "cube to eat / chew", other forms can be envisaged, while respecting the constraints of the equipment that at least both upper and lower faces of the cube to eat / chew are flat.

The hardness of the eating / chewing cubes can be controlled by adjusting the pressure exerted by the press to compress the high fat formulas and by the formula of the composition.

The compositions or "cubes to eat / chew" according to the present invention are obtained by compression using a press to compress the formulas with high fat content, banishing all equipment working continuously as extrusion or involving a continuous manufacturing step such as extrusion-molding, or working from a heterogeneous dough or mixture such as burgers pressing equipment, with or without the presence of heat or moisture. The compression technique using a press to compress the high fat formulas is widely used in the human food field as evidenced by the following patent applications: US 6,126,979, WO 2004/1 12513, WO 2006 / 063694, WO 2007/085609, WO 2009/068378, OA 12967 describing compositions and the use of compression for forming cubic broth also called broth tablets. Their use is not direct, it must first dissolve in water or an aqueous vehicle and preferentially hot or at least warm. In addition these bouillon cubes are very friable because they must be crumbled easily on the dishes to cook. As a result, those skilled in the art would not turn to these formulations and their method of production to obtain an appetizing solid composition having the desired texture.

The method for compressing formulas with a high fat content is known from the prior art, and is in particular used in the field of human nutrition. These products are typically cubic broth. However, the compositions obtained by this method of compressing formulas with a high fat content have hitherto never been used in the veterinary field, that is to say given directly to animals, more particularly to mammals by direct oral intake with the exception of the man who consumes them indirectly is dissolved in warm or warm water or crumbled on his dishes before cooking.

Furthermore, it was not taught that the stability of the compositions could be improved by adding the active substance (s) to the other components, advantageously to all the other components, premixed and granulated.

Compared with other techniques for the manufacture of oral products for the animal described in the prior art, in particular dry powder compression, extrusion, and molding, the compression of high-fat formulas allows to obtain products richer in fat and appetizing material which leads to a perfect appetence that is to say a total catch even if it is repetitive by the animal. All compositions contain an active substance, this compression method allows to perfectly control the weight of the cube to eat / chew and therefore the amount of active substance present in each unit of the final product and thus ensure the therapeutic treatment.

In the methods of the prior art:

The compression of dry powder does not make it possible to manufacture products sufficiently rich in appetizing matter, having a texture appreciated by animals, • the extrusion and extrusion-molding processes do not make it possible to produce products rich enough in non-exuding fat, while perfectly dosing the product,

• The burgers molding process does not allow to produce products rich enough in non-exuding fat, while perfectly dosing the product.

Thus, the products manufactured in particular by extrusion or molding generally have large weight variations. These variations are due to various factors such as feeding the equipment in mixture, but also to the mixture itself in the form of a paste forming in the extruder screws or directly for molding, which has a high degree of heterogeneity . These variations can be offset by a sorting of the products at the output of the production lines, but such sorting is associated with a significant loss of product resulting in a significant additional cost. Calibration of the products is particularly critical for compositions incorporating an active substance. To allow the administration of a constant quantity of active substance, the final product must be perfectly calibrated as to its weight. This calibration is advantageously obtained by manufacturing the compositions according to the present invention by compression of the formulas with a high fat content. Comprising one or more active substances, the appetizing solid compositions obtained are advantageously used to be administered to the animals for a therapeutic treatment either medicinal or nutraceutical or food supplement, the animals being more particularly mammals. "Active substance" means a drug substance, nutraceutical or dietary supplement, having a therapeutic effect or having a biological activity. The content of active substance is adapted in the composition according to the active ingredient chosen and the animal to be treated.

The amount of an active substance per solid composition depends on its effectiveness. Thus it can be very low, a few tens of micrograms to several grams.

The minimum content of active substance (s), expressed by weight relative to the total weight of the composition, may be at least 0.001% or at least 0.01% or at least 0.1%, or minus 1%.

A solid composition may contain a single active substance or a combination of active substances. The total content of active substance (s) varies from 0.001% to 57% by weight, preferably from 0.001 to 50% by weight, more preferably from 0.001 to 40% by weight or 0.001 to 30% by weight. However, these ranges may be different when one of the active substances is at the same time an appetizing substance. Indeed, the active substance can also be an appetizing material which allows to have a content of up to 97% by weight, preferably up to 85% by weight.

Preferably, the active drug substance is selected from anti-infectives such as antibiotics and sulfonamides, cardiotonics; internal and external parasiticides; insecticides; insect growth inhibitors; anti-arthritics; anti-inflammatory steroids or not; antihistamines; hormones such as prostaglandins; digestive therapy substances such as gastrointestinal dressings and sedatives, antiulcer and replacement flora; antidiarrheals; hepatoprotectors; antispasmodics; laxatives; intestinal antiseptics; respiratory therapy substances such as respiratory analgesics, antitussives, bronchodilators, bronchial and mucolytic fluidifiers, and respiratory antiseptics; substances acting on the nervous system such as analgesics, sedatives and tranquilizers; antiepileptics; anesthetics; orexigenes; anorectics, immune therapy substances such as interleukins and in particular interferon; anticancer therapeutic substances such as antimitotics and cytostatics; macro-, micro- and trace elements; vitamins; extracts of plants or organs of animals; and their mixtures.

In an advantageous embodiment, the active substance is chosen from antibiotics such as arnoxicillin, clavulanic acid, cephalexin, rifaximin; antiparasitics such as ivermectin, moxidectin, milbemycin, pyrantel, and its derivatives such as pamoate, praziquantel, benzimidazoles, their salts or their derivatives; insecticides such as fampronil; cardiotonics such as levosimendan; anti-arthritics such as diacein.

Preferably, the nutraceutical active substance or dietary supplement is selected from animal plant or animal extracts for their anti-infectious, antibacterial, antifungal, anti-diarrheal, hepatoprotective, anti-spasmodic, laxative, anti-infectious action. -septic intestinal; respiratory problems such as cough, as bronchodilators, bronchial and mucolytic thinners, respiratory antiseptic, analgesic, sedative, tranquilizer, anti-osteoarthritis, insecticide, antiparasitic, antiulcer, anti-stress; and substitution floras; macro-, micro- and trace elements; vitamins; and their mixtures.

In an advantageous embodiment, the nutraceutical active substance or food supplement is chosen from extracts of plants or animal organs for their anti-osteoarthritic action such as chondroitin sulfate, chitosan and its derivatives; for their anti-ulcer and / or anti-stress action such as fermented soy extract; for their insecticidal or insect repellent action such as pyrethrum; vitamins such as vitamin C, vitamin D3; surrogate floras such as Enterococcus faecium; microelements such as selenium provided by a strain of Saccharomyces cerevisiae.

It will be understood that an active substance can have several functions so that the fermented soy extract can be both an active substance and an appetizing material.

The compositions according to the present invention comprise at least one appetizing material in large quantity contributing to the organoleptic characteristics of the composition according to the invention and its palatability for animals.

The appetizing material content is advantageously at least 40% by weight, more preferably at least 50% by weight, or even more preferably at least 60% by weight, relative to the total weight of the composition. The composition may comprise up to 96.999% by weight, preferably up to 90% by weight of appetizing material.

When the appetizing material is also the active substance, the appetizing content may be 97% by weight.

The appetizing materials for the target animal are, for example, substances of animal or vegetable origin, directly powdered after treatments such as drying or dehydration, grinding, sizing but also after processing with the addition of other components for promote conservation for example. Appetizing components are selected from among the substances of choice that have a high palatability for target species, particularly domestic carnivores such as dogs and cats or herbivores such as horses.

In the uses and compositions according to the invention, the appetizing material is chosen either in the animal kingdom or in the plant kingdom according to the target animal species, preferably from meat, meat flours, fishmeal, powders of cheese, milk derivatives, liver powder, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apple, carrot, mangels, sugar beet, thyme, alfalfa, sugar cane, and cereals such as oats, wheat rice and corn, soybeans, their derivatives such as flours, and mixtures thereof; sugar (sucrose) in all its forms - crystallized, powdered, ice, glucose, invert sugar, molasses, honey or its derivatives; and their mixtures; either in the mineral world salt (sodium chloride).

It will be understood that any component of the formulation may also be an appetizing material for animals. The compositions according to the present invention comprise at least one fat. The fat content is at least 3% by weight, based on the total weight of the composition, preferably at least 5% by weight, more preferably at least 10% by weight. The fat content in the composition, expressed by weight relative to the total weight of the composition may be up to 30% or less, advantageously up to 20%, more preferably up to 15%.

By "fat" is meant a material containing one or more lipids.

By "fat" is meant a substance predominantly composed of triglycerides. In the uses and compositions according to the invention, the fatty substance is preferably chosen either in the animal kingdom or in the plant kingdom according to the target animal species among the pasty fats or hard chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, optionally hydrogenated palm oil, cetyl palmitate, hydrogenated coconut oil, triglycerides of capric, caprylic, myristic and stearic; and their mixtures.

By "waxes" we mean the waxes authorized in food and in particular in animal feed.

In the uses and compositions according to the invention, the wax is preferably chosen either in the animal kingdom or in the plant kingdom according to the target animal species among beeswax, carnauba wax, candelilla wax, and their mixtures.

By "oil" is meant a fat which is liquid at room temperature. In general, the oil is of plant origin, although it may be of animal or mineral origin. Depending on the target species, preference will be given to oils of plant or animal origin. According to the invention, the cube to eat / chew may contain an acceptable liquid oil having no degrading activity vis-à-vis other selected components in particular the active substance.

In the uses and compositions according to the invention, the liquid or thickened oil is preferably chosen from olive oil, peanut oil, rapeseed oil, sunflower oil, triglycerides, capric and caprylic acids, propylene glycol of dicapric / dicaprylic acids; and their mixtures.

In the uses and compositions according to the invention, the fatty substances or the waxes or the thickened oils will allow a granulation of the pulverulent components to lead to a homogeneous mixture.

It will be understood that a thickened oil, a fat, a wax may also be appetizing material for animals.

The composition further comprises one or more additives preferably chosen either in the animal kingdom or in the plant kingdom according to the target animal species among the fillers, binders, solvents, absorbing / gelling substances, flavorings, surfactants, flavor enhancers, sweeteners, antioxidants, chelating agents, preservatives, dyes, and pH regulators .

Preferably, the filler is selected from maltodextrins; cyclodextrins; lactose; talcum; silicates; phosphates, cellulose powder; microcrystalline cellulose; mica and carbonates. Advantageously, when present, the filler represents 1 to 25% by weight of the composition relative to the total weight of the composition.

The compositions according to the present invention comprise at least one binder. The binder is advantageously chosen from polyvinyl alcohol polymers, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and of vinyl acetate, carboxymethylcellulose, its salts and derivatives, solid polyethylene glycols and their derivatives, gelatins, and the acid. alginic and its salts, zein, pectins, gum arabic, acacia gum, gum tragacanth, karaya gum, xanthan gum, carrageenans, pullulan polymers, agar polymers, starches and their derivatives, sugars and their derivatives such as molasses, carbomers, acrylic acid crosslinked with polyalkenyl ethers, polycarbophils, and mixtures thereof. Advantageously, when present, the binder represents 1 to 25% by weight of the composition relative to the total weight of the composition.

Preferably, the solvent is selected from ethanol, propylene glycol, glycerine, cetyl alcohol, benzyl alcohol, liquid polyethylene glycols; and their mixtures. Advantageously, when present, the solvent represents 1 to 25% by weight of the composition relative to the total weight of the composition.

Preferably, the absorbent / gelling substance is chosen from stearic acid, its derivatives and its salts such as glyceryl stearates, aluminum or magnesium stearates, hydrogenated castor oil, bentonite, derivatives of silica such as colloidal silica, precipitated silica, pyrogenic silica, cellulose and these derivatives such as methyl or ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, atomized whey, starches; and their mixtures. Advantageously, when it is present, the absorbent / gelling substance represents 0.1 to 10% by weight of the composition relative to the total weight of the composition.

An aroma is an odorant principle of certain substance (of synthetic or natural origin) that will only be perceived by the sense of smell. It will not produce a sensation on the organ of taste and therefore will have no flavor. Advantageously, when present, the aroma represents 0.01 to 5% by weight of the composition relative to the total weight of the composition.

Preferably, the flavor is chosen from essential oils, terpene derivatives such as menthol, and mixtures thereof. Preferably, the surfactant is selected from glycol esters such as glycerol monostearate, esters of fatty and sorbitan acids, esters of polyoxyethylenated fatty acids and sorbitan; polyoxyethylenated vegetable oils such as polyoxyethylenated castor oils, polyoxyethylenated hydrogenated vegetable oils such as polyoxyethylenated hydrogenated castor oils; lecithin and its soy or egg derivatives such as phosphatidylcholine, hydrogenated phosphatidylcholine, lysophosphatidylcholine, hydrogenated lysophosphatidylcholine, and mixtures thereof. Advantageously, when it is present, the surfactant represents 0.1 to 10% by weight of the composition relative to the total weight of the composition.

In a preferred embodiment, the flavor enhancer is sodium glutamate. Advantageously, when present, the flavor enhancer represents 0.1 to 10% by weight of the composition relative to the total weight of the composition.

In a preferred embodiment, the sweetener is selected from aspartame; sodium saccharinate; taumatine; polyols such as sorbitol, xylitol, isomalt, maltitol, mannitol, and lactitol; and their mixtures. Advantageously, when present, the sweetener represents 0.1 to 10% by weight of the composition relative to the total weight of the composition.

Preferably, the antioxidant is chosen from ascorbic acid, its salts and derivatives, sodium or potassium metabisulfite, sodium bisulfite, butylhydroxyanisol, butylhydroxytoluene, gallic acid and its derivatives such as propyl gallate , and their mixtures. Advantageously, when it is present, the sweetener represents 0.01 to 5% by weight of the composition relative to the total weight of the composition.

Preferably, the chelating agent is chosen from EDTA and its salts, tartaric acid and its salts, and mixtures thereof. Advantageously, when present, the chelating agent represents 0.01 to 5% by weight of the composition relative to the total weight of the composition.

Preferably, the preserving agent is chosen from parabens, benzoic acid and its salts, sorbic acid and its salts, and mixtures thereof. Advantageously, when it is present, the preservative represents 0.01 to 5% by weight of the composition relative to the total weight of the composition.

Preferably, the dye is chosen from iron oxides, titanium oxide, curcumin, caramel, carotenes, and mixtures thereof. Advantageously, when present, the dye represents 0.1 to 5% by weight of the composition relative to the total weight of the composition.

Preferentially, the pH regulator is chosen from citric acid, its salts and derivatives, sodium carbonates, delta glucono lactone, and mixtures thereof. Advantageously, when present, the pH regulator represents 0.01 to 10% by weight of the composition relative to the total weight of the composition.

In a preferred embodiment, the additive or additives represent (s) 0.01 to 25%, preferably 0.1 to 15% by weight of the composition relative to the total weight of the composition. In another variant, the additive or additives represent (s) 0.01 to 56.999%, preferably 0.1 to 47% by weight of the composition relative to the total weight of the composition.

It will be understood that a filler may have several functions, such as a product or by-product of plants such as cereal flour, or the sugar may be both an inert filler and an appetizing material.

The invention also relates to a solid appetizing composition, stable over time, obtainable by the method according to any one of the preceding claims, characterized in that the composition comprises:

at. 3 to 30%, preferably 5 to 15% by weight of at least one fat, advantageously in solid or waxy or pasty form chosen from a fatty substance or a wax, or a liquid oil, or a thickened liquid oil, or a mixture of these; the liquid oil or the liquid oil based on the thickened oil can not represent more than 8% by weight of the composition,

β. 0.001 to 57% by weight of at least one active substance,

χ. 40 to 96.999% by weight of at least one appetizing material,

a) the liquid oil is chosen from olive oil, peanut oil, rapeseed oil, sunflower oil, triglycerides of capric and caprylic acids, propylene glycol of dicapic acids / dicaprylic, and mixtures thereof;

b) the fat is selected from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, possibly hydrogenated palm oil, palmitate cetyl, coconut oil hydrogenated triglycerides of capric, caprylic, myristic and stearic acids, and mixtures thereof;

d) the appetizing material is selected from meat, meat flours, fishmeal, cheese powders, milk derivatives, liver powder, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apple, carrot, mangels, sugar beet, thyme, alfalfa, sugar cane, and cereals such as oats, wheat rice and corn, soybeans, their derivatives such as flours, and mixtures thereof; sugar (sucrose) in all its forms, crystallized, powdered, ice-cream, glucose, invert sugar, molasses, honey or its derivatives, and mixtures thereof, salt (sodium chloride), and mixtures thereof;

e) the solid appetizing composition has a unit weight of plus or minus 3% of the theoretical value of the required weight, and preferably of plus or minus 2% of the theoretical value of the required weight;

f) the solid appetizing composition is stable for more than one year when stored at room temperature. The composition, and its components, especially their contents, are as described above.

Advantageously, the composition consists of:

a) at least one drug-active substance chosen from antibiotics such as arnoxicillin, clavulanic acid, cephalexin, rifaximin, antiparasitic agents such as ivermectin, moxidectin, milbemycin, pyrantel, and its derivatives such as pamoate, praziquantel, benzimidazoles, their salts or derivatives, insecticides such as fampronil, cardiotonics such as levosimendan, and anti-arthritics such as diacein; a nutraceutical active substance or food supplement selected from animal extracts for their anti-osteoarthritic action such as chondroitin sulfate, chitosan and its derivatives; for their anti-ulcer and / or anti-stress action such as fermented soy extract; for their insecticidal action or such as pyrethrum, vitamins such as vitamin C, vitamin D3, substitute flora such as Enterococcus faecium, microelements such as selenium provided by a strain of Saccharomyces cerevisiae;

b) at least one fat selected from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, optionally hydrogenated palm oil, palmitate cetyl, hydrogenated coconut oil, and mixtures thereof; waxes such as beeswax, carnauba wax, candelilla wax, and mixtures thereof; oils such as olive oil, peanut oil, rapeseed oil, sunflower oil, triglycerides of capric and caprylic acids and their derivatives; or their mixtures;

c) at least one appetizing material selected from meat, meat flours, fishmeal, cheese powders, milk derivatives, liver powder, gelatin, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apples, carrots, fodder beet, sugar beet, thyme, alfalfa, sugar cane, cereals such as oats, wheat, rice and corn, soybeans, their by-products such as flour, and mixtures thereof, sugar (sucrose) in all its forms, crystallized, powdered, ice-cream, glucose, invert sugar, molasses, honey and its derivatives, and mixtures thereof, salt (sodium chloride), and mixtures thereof.

The content of active substance is adapted in the composition according to the active ingredient chosen and the animal to be treated. Its content may range from 0.001 to 97% by weight, relative to the total weight of the composition, advantageously from 0.001 to 57% by weight, more preferably from 0.001 to 50% by weight, still more advantageously from 0.001 to 40% by weight. or 0.001 to 30% by weight if the active substance is not at the same time an appetizing substance.

The fat content is at least 3% by weight, based on the total weight of the composition, preferably at least 5% by weight, more preferably at least 10% by weight. The fat content in the composition, expressed by weight relative to the total weight of the composition may be up to 30% or less, advantageously up to 20%, more preferably up to 15%.

The appetizing material content is advantageously at least 40% by weight, more preferably at least 50% by weight, or even more preferably at least 60% by weight, relative to the total weight of the composition. The composition may comprise up to 96.999% by weight, advantageously up to 90% by weight, or 97% by weight when the appetizing material is also the active substance, of appetizing material. The composition can be used:

- as a mammalian drug, except for humans, in particular for domestic animals such as dogs, cats or horses, or

- as a nutraceutical or food supplement for mammals, except for humans, in particular for domestic animals such as dogs, cats or horses. Finally, the subject of the invention is a solid appetizing composition, characterized in that the composition comprises:

at. 3 to 30%, preferably 5 to 15% by weight of at least one fat, advantageously in solid or waxy or pasty form, chosen from a fatty substance or a wax, or a liquid oil, or a thickened liquid oil, or a mixture thereof; the liquid oil or the liquid oil based on the thickened oil can not represent more than 8% by weight of the composition,

β. 0.001 to 57% by weight of at least one active substance,

χ. 40 to 96.999% by weight of at least one appetizing material,

δ. optionally one or more additives, advantageously chosen from fillers, binders, solvents, flavorings, surfactants, flavor enhancers, sweeteners, antioxidants, chelating agents, preservatives, dyes, and pH regulators;

a) the liquid or previously thickened oil is chosen from olive oil, peanut oil, rapeseed oil, sunflower oil, and mixtures thereof;

b) the fat is selected from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, possibly hydrogenated palm oil, palmitate cetyl, hydrogenated coconut oil, and mixtures thereof;

e) the solid appetizing composition has a unit weight of plus or minus 3% of the theoretical value of the required weight, and preferably of plus or minus 2% of the theoretical value of the required weight; f) advantageously the solid appetizing composition is stable for more than one year when it is stored at room temperature;

for use as a medicine; nutraceutical or dietary supplement, administered orally to mammals, except humans, especially for domestic animals such as dogs, cats or horses.

In a variant, the composition comprises:

- 5 to 30%, preferably 8 to 20% by weight of at least one fat, selected from a liquid oil, a thickened oil, a fatty substance, a wax or a mixture thereof, the liquid oil not being able to represent more than 8% by weight of the composition,

0.001 to 85% by weight of at least one active substance, and

- 20 to 95%, preferably 20 to 90%, preferably 40 to 70% by weight of at least one appetizing material.

The additive may also comprise or consist of absorbent / gelling substances.

The liquid or previously thickened oil can also be chosen from triglycerides of capric and caprylic acids, propylene glycol of dicapric / dicaprylic acids, and their mixtures with the other possibilities.

The fatty substance may also be chosen from the triglycerides of capric, caprylic, myristic and stearic acids, and their mixtures with the other possibilities.

The solid appetizing composition is advantageously capable of being obtained by the process according to the invention. It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they in no way constitute a limitation.

EXAMPLE 1 - Preparation of a cube for eating / chewing for dogs

1 g / l chewing / chewing cubes containing 2.5 mg of milbemycin and 12.5 mg of praziquantel are made with the following composition:

a) batch of cubes produced according to the invention

In a blender introduce liver powder, distearate glycerol, and mix. Add PEG 4000, BHA, propyl gallate, and mix. Add the gelatin, the sugar, and mix. Pour on the homogeneous mixture the glycerine. Mix until a homogeneous, dry and fluid granulate is obtained. Dissolve milbemycin in propylene glycol of dicapric / dicaprylic acids and add the precipitated silica to thicken the solution. Add one tenth of the granulate praziquantel, and mix. Add the thickened milbemycin solution and mix until a homogeneous mixture is obtained. Add the rest of the granulate in small amounts while continuing to mix. Calibrate the granulate on a screen of 800 μηη. The cubes to eat / chew parallelepiped shape of size 12.5 x 12.5 x 7 mm are obtained by compression at 40 kN using a press to compress formulas with high fat content. Their theoretical weight is 1.1 g. b) lot of cubes realized with introduction of the assets at the beginning of the mixture

In parallel cubes to eat / chew were made with the same formulation but according to the method: in a mixer introduce the liver powder. Dissolve the milbemycin in the propylene glycol of the dicapric / dicaprylic acids beforehand, vaporize the milbemycin solution, and mix until a homogeneous mixture is obtained. Add praziquantel, and mix Spray triglycerides with previously liquefied capric / caprylic / myristic / stearic acids and mix. Add PEG 4000, BHA, propyl gallate, and mix. Add the gelatin, the sugar, and mix. Pour on the homogeneous mixture the glycerine. Mix until a homogeneous, dry and fluid granulate is obtained. Add the precipitated silica, and mix. Calibrate the granulate on a screen of 800 μηη. The cubes to eat / chew parallelepiped shape of size 12.5 x 12.5 x 7 mm are obtained by compression at 40 kN using a press to compress formulas with high fat content. Their theoretical weight is 1.1 g.

For both lots, all the cubes to be eaten / chewed were weighed separately, no cube deviated by more than 2 percent from the theoretical mass. This would not have been feasible using the techniques usually used namely extrusion which is a continuous manufacture or molding using a paste.

For both batches, determination of Milbemycin content for the lighter and heavier 5 cubes to eat / chew showed that the mixture was perfectly homogeneous because the assay values were all in the range of doses. , admitted for the drugs, framing the theoretical dose. This determination, made on a half cube just after obtaining, was repeated one year after storage at 25 ° C on the other half of the cube, for the cubes obtained according to the invention, the dosage values for each cube. after one year of storage, do not differ from the values obtained just after compression of the cubes by more than 3%, which is not the case for the cubes of the second batch where a loss of more than 10% of the active been recorded.

Given the margins of error assays, impairments during the shelf life (variations) allowed for drugs, the invention demonstrates a perfect stability of even sensitive or fragile molecule.

EXAMPLE 2 - Monadic appetence test with cubes to eat / chew A palatability test of the cubes to eat / chew obtained according to the invention of Example 1 was carried out with thirty adult dogs, male and female, of varied breeds. Dogs from 5 kg to 25 kg receive 5 cubes, and dogs from 25 to 50 kg receive 10 cubes, The cubes are offered at the same time. This is a monadic test performed in individual boxes for ten minutes per dog. Have been measured:

- grasping by hand / on the ground / or not taking

- the total / partial consumption / or no consumption.

For each of these criteria is specified the number of individuals, on the whole panel and by size categories (small / medium / large). The calculation of acceptability is based on the percentage of dogs that consumed the entire cube to eat / chew.

Gripping:

The acceptability and consumption of the cubes to eat / chew according to the invention are total (100%).

EXAMPLE 3 - Preparation of Dog Eating / Chewing Cube

1.1 g eating / chewing cubes containing 68 μg of ivermectin, 57 mg of pyrantel in the form of pamoate, and 57 mg of praziquantel according to the invention are produced with the following composition:

Ivermectin coated 2.85%

Coated pyrantel pamoate 5.13%

Praziquantel coated 3.21% Liver powder 44,80%

Hydrogenated palm oil 6,00%

Glycerin 18.00%

PEG 4000 12.00%

Gelatin 8.00%

Tenox 8 0, 01%

In a blender introduce liver powder, PEG 4000, hydrogenated palm oil, Tenox 8, and mix. Add the gelatin, and mix. Pour on the homogeneous mixture the glycerine. Mix until a homogeneous, dry and fluid granulate is obtained. Add coated ivermectin, coated praziquantel, coated pyrantel pamoate, and mix. Calibrate the granulate on a screen of 800 μηη. The cubes to eat / chew parallelepiped shape of size 12.5 x 12.5 x 7 mm are obtained by compression at 40 kN using a press to compress formulas with high fat content. Their theoretical weight is 1.1 g.

All the cubes to be eaten / chewed were weighed separately, no cube deviated by more than 2 percent from the theoretical mass. Determination of the ivermectin content for the lighter and heavier 5 cubes to eat / chew showed that the mixture was perfectly homogeneous because the assay values were all within the dose range, allowed for the drugs. , framing the theoretical dose. This determination, made on a half cube just after they were obtained, was repeated one year after storage at 25 ° C on the other half of the cube. The dosage values, for each half cube after one year of preservation, do not differ from the values obtained just after compression of the cubes by more than 3%. Given the margins of error assays, impairments during the shelf life (variations) allowed for drugs, the invention demonstrates a perfect stability of even sensitive or fragile molecule.

EXAMPLE 4 - Comparative test for the homogeneity of the weights between the cubes to be eaten / chewed and chewable tablets obtained by extrusion

Twenty cubes to eat / chew, obtained according to the invention according to Example 1, taken consecutively at the machine outlet were weighed.

A batch of chewing tablets was made by extrusion with the following formula: Ivermectin 0.001236%

Pyrantel Pamoate 2.963636%

Tallow 2.5%

Beef 42.0%

Soy flour 30.932404%

2.00% salt

Molasses 8.00%

Propylene glycol 5.0%

Glucono delta lactone 3.30%

Potassium sorbate 0.30%

Propyl gallate 0.0005%

BHA 0.0018%

Citric acid 0.0004%

Similarly twenty tablets, taken consecutively extrusion output were weighed. The weights taken for the two samples of the twenty objects are given in the following table:

Item # Cube chewing chewing tablet

Weight in grams Weight in grams

1 5.53 5.55

2 5.56 4.83

3 5.51 5.92

4 5.49 5.49

5 5.42 6.24 6 5.41 4.86

7 5.53 5.69

8 5.56 6.27

9 5.60 4.78

10 5.59 4.96

1 1 5.55 5.67

12 5.48 6.13

13 5.45 6.06

14 5.49 5.19

15 5.50 5.43

16 5.47 4.99

17 5.57 4.75

18 5.52 5.78

19 5.49 6.01

20 5.55 5.26

Distance <2%> 14%

A significant difference, greater than 14%, is observed between the extreme weights of the chewable tablets and the average weight obtained with the 20 chewing tablets obtained by extrusion compared to the difference in weight, less than 2%, observed for the cubes to eat / chew obtained according to the invention.

These differences in weight necessarily result in a variation of at least the same importance of the amounts of active molecules contained in the chewing tablets. It is inconceivable to use the extrusion or molding process for the production of unit-dose drugs, except by weighing the chewing tablets one by one at the output of the shaper, and to discard all those that do not did not enter the field of weight guaranteeing a quantity of active molecules as required by the regulation of drugs. If at first approach, in the example presented, were kept only chewing tablets whose weight does not deviate by more than 5 percent of the theoretical weight, only six chewing tablets of the twenty produced, or 30 percent of the production, would be kept, which is not economical and without guarantee of the quantity of active molecules for the tablets. to chew whose weight is near or equal to the upper and lower limit weights to select chewable tablets. Similarly it is unthinkable to extrude or mold a second time chewing tablets apart because inevitably the provision of active molecules in the body would be modified and would lead to a change in therapeutic activity. EXAMPLE 5 - Formulations

Other formulations according to the invention are described below.

Cubes to eat / chew containing 68 μg of ivermectin, and 57.5 mg of pyrantel in the form of pamoate according to the invention are made with the following composition:

Ivermectin 0.001236%

Pyrantel Pamoate 2.963636%

Canola oil 5.00%

Tallow 10.00%

Beef 40.30%

Soy flour 28,132428%

2.00% salt

Molasses 8.00%

Glucono delta lactone 3.30%

Potassium sorbate 0.30%

Propyl gallate 0.0005%

BHA 0.0018%

Citric acid 0.0004% All the cubes to be eaten were weighed separately, their theoretical weight is 5.5 g. No cube deviated by more than 2 percent from the theoretical mass.

Determination of the Ivermectin content for the lighter and heavier 5 cubes to eat / chew showed that the mixture was perfectly homogeneous because the assay values were all in the range of doses allowed for the drugs. , framing the theoretical dose.

Cubes to eat / chew, for horses, are made with the following composition:

The cubes to eat / chew parallelepiped shape of size 31 x 23 x 10 mm are obtained by compression using a cubic broth press. All cubes to eat / chew were weighed separately. No cube deviated by more than 2 percent from the theoretical mass.

An appetence test of these cubes to eat / chew was made with several owners of horses and ponies and in a horse club. The cube to eat / chew was presented to the horse or pony on the open hand. The acceptability and consumption of the cubes to eat were total (100%). It is worth mentioning the behavior of animals with respect to this cube. Several riders reported the great attraction that horses and ponies had for the cube to eat / chew presented in this size and color form. From the first absorbed, they sought to have others by feeling the pockets of the rider from which these cubes had emerged.

Dog eating / chewing cubes of 3 g containing 68 μg of ivermectin, 57 mg of pyrantel in pamoate form, and 57 mg of praziquantel according to the invention are made with the following composition:

Ivermectin coated 1, 0%

Pyrantel pamoate coated 6.0%

Praziquantel coated 5.0% Liver powder 46.00%

Hard fat 8.00%

Glycerin 12.00%

PEG 4000 12.00%

Gelatin 6.00%

Sugar 3.54%

Sorbic acid 0, 40%

BHA 0, 04%

Propyl gallate 0, 02%

The cubes to eat / chew parallelepiped shape of size 17 x 17 x 9.6 mm are obtained by compression using a cubic broth press. All cubes to eat / chew were weighed separately, their theoretical weight is 3.0 g. No cube deviated by more than 2 percent from the theoretical mass.

Claims

A process for the preparation of a solid appetizing composition, stable over time, characterized in that the composition comprises:

at. 3 to 30%, preferably 5 to 15% by weight of at least one fat, preferably in solid or waxy or pasty form, selected from a fatty substance or a wax, or a liquid oil, a thickened liquid oil, or a mixture of these; the liquid oil, from the liquid oil or the thickened oil, can not represent more than 8% by weight of the composition, β. 0.001 to 57% by weight of at least one active substance,

χ. 40 to 96.999% by weight of at least one appetizing material,

d) the appetizing material is selected from meat, meat flours, fishmeal, cheese powders, milk derivatives, liver powder, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apple, carrot, mangels, sugar beet, thyme, alfalfa, sugar cane, and cereals such as oats, wheat rice and corn, soybeans, their derivatives such as flours, and mixtures thereof; sugar (sucrose) in all its forms forms, crystallized, powdered, ice-cream, glucose, invert sugar, molasses, honey or its derivatives, and mixtures thereof, salt (sodium chloride), and mixtures thereof;

and in that the method comprises the following successive steps:

i. preparation of homogeneous aggregates comprising the appetizing substance (s), the fat and optionally one or more additives, ii. addition, with stirring, at room temperature without addition of water or heat, cold aggregates obtained following step i) of the active substance (s), iii. calibration of the mixture of aggregates obtained after step ii), dry and fluid, to retain the aggregates having a granulation of between 50 and Ι ΟΟΟμηη, preferably between 200 and δθθμηι, compression of the dry aggregates and calibrated fluids, obtained following step iii), with a press to compress the formulas with high fat content,

iv. recovery, following step iv) of the appetizing solid composition.

2. Method according to claim 1, characterized in that step i) comprises the following successive steps:

M. mixing the appetizing material (s) and optionally one or more additives, the appetizing materials and any additives being in pulverulent form;

i2. Addition of the fat to the mixture obtained following step i);

i3. then mixing or triturating without adding water or heat until homogeneous aggregates are obtained.

3. Method according to claim 2, characterized in that during step M) the appetizing materials and optional additives have a particle size less than 200 μηη, preferably less than 100 μηη.

4. Method according to any one of the preceding claims, characterized in that during step ii) the active substance is in the form:

- powders, or

solubilized in a suitable non-aqueous solvent to be vaporized or poured onto the granulate of step i), or solubilized in a suitable non-aqueous solvent and then converted into a gel or powder by the addition of an absorbent substance, or

in the form of a granule.

5. Method according to claim 4, characterized in that during step ii) the active substance has a particle size at most equivalent to that of the granulate of step iii).

6. Method according to any one of the preceding claims, characterized in that the appetizing composition is in the form of a compact mass with at least the upper and lower plane surfaces.

7. Method according to any one of the preceding claims, characterized in that the press to compress the formulas with high fat content is equipped with a demo-calibrator.

8. Method according to any one of the preceding claims, characterized in that the press to compress the formulas with high fat content is equipped with a refrigerated compression stage.

9. Method according to any one of the preceding claims, characterized in that during step iv), the compression force is between 5 and 80 kN.

10. Method according to any one of the preceding claims, characterized in that:

The filler is chosen from maltodextrins, cyclodextrins, lactose, talc, silicates, phosphates, cellulose powder, microcrystalline cellulose, mica, carbonates;

The binder is chosen from polyvinyl alcohol polymers, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and of vinyl acetate, carboxymethylcellulose, its salts and derivatives, solid polyethylene glycols and their derivatives, gelatins, acid alginic and its salts, zein, pectins, gum arabic, acacia gum, gum tragacanth, karaya gum, xanthan gum, carrageenans, pullulan polymers, agar polymers, starches and their derivatives, sugars and their derivatives such as molasses, carbomers, acrylic acid crosslinked with polyalkenyl ethers, polycarbophils; and their mixtures;

• that the solvent is selected from ethanol, propylene glycol, cetyl alcohol, benzyl alcohol, liquid polyethylene glycols, and mixtures thereof; The absorbent / gelling substance is chosen from stearic acid, its derivatives and its salts, such as glyceryl stearates, aluminum or magnesium stearates, hydrogenated castor oil, bentonite, silica derivatives such as that colloidal silica, precipitated silica, fumed silica, cellulose and these derivatives such as methyl or ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, atomized whey, starches; and their mixtures;

The aroma is chosen from essential oils, terpene derivatives such as menthol; and their mixtures;

The surfactant is chosen from glycol esters such as glycerol monostearate, esters of fatty and sorbitan acids, esters of polyoxyethylenated fatty acids and of sorbitan; polyoxyethylenated vegetable oils such as polyoxyethylenated castor oils, polyoxyethylenated hydrogenated vegetable oils such as polyoxyethylenated hydrogenated castor oils; lecithin and its soy or egg derivatives such as phosphatidylcholine, hydrogenated phosphatidylcholine, lysophosphatidylcholine, hydrogenated lysophosphatidylcholine; as well as their mixtures;

The sweetener is chosen from aspartame; sodium saccharinate; taumatine; polyols such as sorbitol, xylitol, isomalt, maltitol, mannitol, and lactitol; and their mixtures;

The antioxidant is chosen from ascorbic acid, its salts and derivatives, sodium or potassium metabisulfite, sodium bisulfite, butylhydroxyanisol, butylhydroxytoluene, gallic acid and its derivatives such as propyl gallate; and their mixtures;

· The chelating agent is selected from EDTA and its salts, tartaric acid and its salts, and mixtures thereof;

• the flavor enhancer is sodium glutamate;

The preservative is chosen from parabens, benzoic acid and its salts, sorbic acid and its salts; and their mixtures;

The dye is chosen from iron oxides, titanium oxide, curcumin, caramel, carotenes; and their mixtures;

The pH regulator is chosen from citric acid, its salts and derivatives, sodium carbonates, delta glucono lactone; and their mixtures.

11. Method according to any one of the preceding claims, characterized in that the additive or additives represent 0.01 to 25%, preferably 0.1 to 15% by weight of the composition relative to the total weight of the composition.

12. Method according to any one of the preceding claims, characterized in that the active substance is selected from anti-infectives such as antibiotics and sulfonamides, cardiotonics, internal and external antiparasitics, insecticides, growth inhibitors insects, anti-arthritics, anti-inflammatory steroids or not, antihistamines, hormones such as prostaglandins, digestive therapy substances such as dressings and gastrointestinal sedatives, antiulcer and surrogate flora, anti -diarrheic, hepatoprotective, antispasmodic, laxative, intestinal antiseptic, respiratory therapy substances such as respiratory analgesics, antitussives, bronchodilators, bronchial and mucolytic fluidifiers, and respiratory antiseptics, substances acting on the nervous system such as painkillers, sedatives and tranquillizers, antiepileptics, anesthetics, orexigenes, anorectics, immune therapy substances such as interleukins and interferon, anticancer therapeutic substances such as antimitotics and cytostatics, macro-, micro - and trace elements, vitamins, plant extracts, animal organ extracts, and mixtures thereof.

13. Method according to any one of the preceding claims, characterized in that the composition comprises a medicinal active substance chosen from antibiotics such as arnoxicillin, clavulanic acid, cephalexin, rifaximin, antiparasitic agents such as ivermectin, moxidectin, milbemycin, pyrantel, and its derivatives such as pamoate, praziquantel, benzimidazoles, their salts or derivatives, insecticides such as fampronil, cardiotonics such as levosimendan, and anti-arthritics such as diacein.

14. Method according to any one of the preceding claims, characterized in that the composition comprises a nutraceutical active substance or food supplement selected from plant extracts, animal extracts, substitute flora, macro-, micro- and trace elements, vitamins, and mixtures thereof.

15. The method of claim 14, characterized in that the nutraceutical active substance or food supplement is selected from animal extracts for their anti-osteoarthritic action such as chondroitin sulfate, chitosan and its derivatives; for their anti-ulcer and / or anti-stress action such as fermented soy extract; for their insecticidal or insect repellent action such as pyrethrum, vitamins such as vitamin C, vitamin D3, substitute flora such as Enterococcus faecium, microelements such as selenium provided by a strain of Saccharomyces cerevisiae.

16. Solid appetizing composition, stable over time, obtainable by the method according to any one of the preceding claims, characterized in that the composition comprises:

β. 0.001 to 57% by weight of at least one active substance,

χ. 40 to 96.999% by weight of at least one appetizing material,

the solid appetizing composition has a unit weight of plus or minus 3% of the theoretical value of the required weight, and preferably of plus or minus 2% of the theoretical value of the required weight;

the appetizing solid composition is stable for more than one year when stored at room temperature.

17. Solid appetizing composition according to claim 16, characterized in that it consists of:

c) at least one appetizing material selected from meat, meat flours, fishmeal, cheese powders, milk derivatives, liver powder, gelatin, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apples, carrots, fodder beet, sugar beet, thyme, alfalfa, sugar cane, cereals such as oats, wheat, rice and corn, soybeans, their derivatives such as flours, and their mixtures, sugar (sucrose) in all its forms, crystallized, powdered, ice-cream, glucose, invert sugar, molasses, honey and its derivatives, and mixtures thereof, salt (sodium chloride), and mixtures thereof .

18. Appetizing solid composition, characterized in that the composition comprises: a. 3 to 30%, preferably 5 to 15% by weight of at least one fat, advantageously in solid or waxy or pasty form, chosen from a fatty substance or a wax, or a liquid oil, or a thickened liquid oil, or a mixture thereof; the liquid oil or the liquid oil based on the thickened oil can not represent more than 8% by weight of the composition,

β. 0.001 to 57% by weight of at least one active substance,

χ. 40 to 96.999% by weight of at least one appetizing material,

d) the appetizing material is selected from meat, meat flours, fishmeal, cheese powders, milk derivatives, liver powder, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; plant products or by-products such as fenugreek, apple, carrot, mangels, sugar beet, thyme, alfalfa, sugar cane, and cereals such as oats, wheat , rice and corn, soybeans, their derivatives such as flours, and mixtures thereof; sugar (sucrose) in all its forms, crystallized, powdered, ice-cream, glucose, invert sugar, molasses, honey or its derivatives, and mixtures thereof, salt (sodium chloride), and mixtures thereof;

f) advantageously the solid appetizing composition is stable for more than one year when it is stored at room temperature;

19. Composition according to claim 18, characterized in that the solid appetizing composition is obtainable by the method according to any one of claims 1 to 15.