CA2883139C - Compositions for oral administration to animals, production methods thereof and uses of same - Google Patents

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, THEIR METHODS OF OBTAINING AND THEIR USES
The present invention relates to the field of the preparation of compositions appetizing for therapeutic purposes more particularly to improve the oral intake and guarantee the treatment, formulated in a solid form, by animals (domestic, farmed or wild).
We are currently witnessing an evolution in the care provided to animals, and the oral route becomes a preferred route for drug administration speak professional or by the owner, and this is more especially true for nutraceutical products. Indeed, the routes of administration usual parenterals (intramuscular, subcutaneous, intradermal or intravenous) in particular from drugs have some drawbacks. The intramuscular or under-skin can, for example, be the cause of hematomas or abscesses. The way intravenous often requires the intervention of a specialist (veterinarian).
As for the way intradermal, it requires the use of solvents to pass the skin barrier to active molecules. These parenteral routes of administration require also the restraining animals. In addition, some active substances are difficult to formulate in parenteral dosage forms. Finally, some substances active will only exert their therapeutic action in the animal if they arrive directly in the digestive system. To have the composition taken by the animal he he must be attracted and that it absorbs the latter we will then note the satisfaction of the animal which will manifest by solicitation of the animal in order to obtain another composition. It is this satisfaction that will please the owner of the animal and he's looking for.
It is known that natural acceptance and consumption by an animal of a composition is based on its dosage form mainly on two characteristics, the palatability and texture of said composition, and with less importance of form and the size of the latter.
Two more must be added to these parameters:
- perfect control of the quantity of one or more active substances as well well if the composition is a drug or nutraceutical or food supplement, and - the cost of the composition, particularly if it is a nutraceutical or one dietary supplement.
Galenic formulations suitable for the administration of compositions by oral or orally are usually in liquid form (such as syrups, solutions or drinkable suspensions, drops, etc.), in semi-solid form (such as than pasta for oral administration) or in solid form. Solid forms commonly used per os in the animal kingdom, come in various formulations of nature

2 different and are obtained by different processes. We distinguish for example the tablets, cachets, capsules, hard capsules, chewing gums, pills lozenges, tablets. Mainly for treatment compliance administered by oral route (i.e. compliance with the instructions and directives of the health professional concerning the taking of drugs), it is observed that the treatment is not always properly monitored, due to the difficulty of administering all of the treatments To animals. Indeed, the administration to animals of drugs in the form solid oral dosage is often difficult due to the bad taste some active substances or certain excipients constituting the medicinal product and very sense developed animal smell and taste. In animals, it has been observed that the main reason that makes it very difficult, if not impossible, to observe a oral treatment is the lack of palatability caused by the drug. It is the same with from 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.
Appetite is defined as the psychological state corresponding to a desire to absorb a food or drink in response to the perception of traits organoleptics this product. The ability to arouse appetite is called appetite. The combination of these characteristics determines the attractiveness of a product to be taken by the way oral on normally fed animals. More particularly the appetite of a medication greatly participates in the refusal or acceptance by the animal of the catch spontaneous treatment and repeating the intake over sometimes long periods.
In the framework of of certain treatments, the treatment may be taken daily or even life.
The appetite of a drug, nutraceutical or food supplement given orally leads to acceptance and voluntary ingestion by the animals. This appetite can be measured in a general test appetite taking into account different parameters of the composition formulated under a form solid, such as its spontaneous grip in the hand or on the ground, or its consumption, even if it is given in several times or taken at regular intervals by the animal.
Texture is defined as a physical state corresponding to a formulation arranged in a way by obtaining technology. It's texture than depend on the hardness, friability, softness, elasticity, color of the composition.
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 settings major or even others have been proposed to facilitate absorption mainly medication by an animal.

3 Regarding palatability, several avenues have been proposed:
A first option is to mask the unpleasant taste and / or odor of the or from constituents, mainly one or more active substances, by encapsulation or by coating of the latter.
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 3,037,911, describe how encapsulate or coat one or more constituents as well as the techniques for to arrive.
These solutions require numerous 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 flavors where the palatable matters.
Another option to facilitate oral administration is to encompass the composition, mainly the drug, in palatable materials.
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, provide lures made with palatable materials.
The disadvantage of these lures is that their use requires manipulation to know 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 to be treated. Of more, their large volume (necessarily larger than the drug) ask for a large quantity of material and their manufacture must be adapted to their form complex; thus these decoys often prove to be expensive.
Yet another option, the active substances are isolated in the middle of a matrix obtained by compressing the dry constituents, comprising a substance appetizing in order to mask their taste and facilitate their intake and consumption.
Patent application EP 0 320 320 describes a tablet for domestic animals characterized in that it consists of at least one core containing one or various active substances totally enclosed in a matrix palatable for the animal. In with such compositions it is the texture which constitutes the major drawback.
Indeed the tablet or tablet form gives hard shapes little appreciated by animals.
Of more, great rigor is required in the manufacture of this type of tablets to kernel for be sure to perfectly encompass the central part.
The following patent applications EP 0 725 570, EP 0 725 627, propose compositions made up of two parts, one central containing the constituents to taste and / or with an unpleasant odor, the other exterior encompassing the central part.
Those are baits and their purpose is to attract the animal to bite it so that it be vaccinated.
Several disadvantages appear:

= when the matrix is made, an increase in temperature, for get the fusion of certain constituents, is necessary to melt the polymer in order to he is intimately mixed, this can constitute a strong constraint for the stability the active substance, = the production of such matrices is complex and expensive, = storage under special conditions to guarantee the integrity of the pharmaceutical form.
Patent application FR 2 709 420 describes a shape and a size for a tablet so that it is more graspable by animals, in particular cats.
The following patent applications: IE 2004 0393, and GB 2 432 506, describe items palatable chews, obtained by extrusion or extrusion molding. The main disadvantage of these items is that they are consumed for several minutes see abandoned and taken back to be chewed again before being consumed. It is therefore not possible to follow a treatment regimen with certainty.
Patent application US 2011/0183036 describes appetizing rewards, obtained by extrusion-molding. The main disadvantage of these rewards is what are obtained hot, temperature above 82 C, from an extruded dough molded therefore a lack of regularity of the weight. In addition, this paste contains water one part, between 3 and 15%, remains in the reward after its conformation. The request is talking about a reward and not about a medicinal object.
US Patent 6,455,083 describes edible chewable objects obtained by extrusion-molding. The main disadvantage is that they are thermoplastics that is that is, in the extruder there is mainly protein polymerization with water (10 to 20%). Given their texture these objects will not be absorbed by a single cut but chew at the risk of being abandoned. The patent describes many objects to to chew nutritional and no medicinal objects.
The following patent applications: FR 2 154 424, and US 5,894,029 refer to the production of pet food. The production processes put in works are in no way suitable for the production of medicinal products particularly. They can seriously affect the stability of the active substances by water use in formulas or processes, by the use of heat with or without of the pressure.
Patent application US 5,637,313 describes particular compositions but especially one particular production process for obtaining coated tablets, namely the matrix after mixing is rolled into a bead of a certain diameter and cut to a length certain length to obtain the desired weight. This production does not allow guarantee a perfect control of the weight therefore of the quantity of active substance per unit ce who is antinomic with a drug.

Concerning the texture knowing that it is strongly linked to the composition therefore also at palatability three methods of obtaining have been mainly proposed:
The first, the oldest, the 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 3,037,911, FR 2,709,420 describe hard dry forms little appreciated by animals and many refusals by 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 appetizing extruded shapes having a relatively soft texture very appreciated by animals especially domestic animals like dogs and cats.
Considering of the production mode i.e. the use of an extruder, there is an output online so continuous die which is then cut to the desired length for have the weight therefore required the constant amount of active substance (s) to be in particular one medication. This requires perfect control of the extrusion parameters.
Unfortunately we know that with this technique we are not at the shelter a variation in density of the extrudate which inevitably leads to length constant at a variation in weight. To overcome this, you have to weigh the tablets one by one to chew and rule out non-standard items that cannot be recycled under penalty of seeing the update disposal of the modified active substance by further extrusion. This technical does not prove to be economical. In conclusion it would not be retained by the man Art to make a drug or nutraceutical or supplement food where the quantity of active substance (s) must be perfectly controlled.
Patent application US 2004/151759 describes chewable tablets obtained by from conventional techniques, the compression of dry granulated powder or extrusion with drying at 50 C. Both manufacturing processes involve water to carry out granulation, water removed before compression to obtain tablets classics or after extrusion to obtain chewable tablets. The inconvenients both techniques that have already been mentioned are present.
The third, last proposed, is the production of soft tablets by molding with a squeezing equipment for burgers, steaks, nuggets, cookies (before cooking) (patty pressing machine in English). Thus the following patent applications:
US 2005/0226908 and patent applications of the same family WO 2009/064859 and US 7,955,632, US 8,293,265, WO 2012/049156, US 8,114,455, and US 2012/0141574 describe chewable tablets obtained by molding a dough with little or no no pressure (explicit in applications WO 2009/064859, US 7,955,632, US
8,293,265, US 8,114,455, US 2012/0141574) prepared with water (application WO 2012/049156)

6 or presence of water (application US 2005/0226908), use of heat (US requests 2005/0226908, WO 2012/049156) all applications advocating the same equipment from Formax Corporation: the Formax F6TM. Taking into account the mode of production at to know the use of hamburger squeezing machine powered by a paste although being able to be homogeneous presents a random density which induces a amount random in the mold therefore a random quantity of substance (s) active for in particular be a drug. This requires a perfect control of characteristics physics of the dough. Unfortunately we know that we are not at the shelter a variation of the density with a very not very fluid dough because it is molded cold. In this disadvantage is added the mold feeding system which aerates the dough, it leads to inevitably to a variation in the weight of the shelves. To overcome this he must weigh one to one the chewable tablets and remove the non-standard ones that cannot be recycled under penalty of seeing the availability of the active substance modified by a new one formatting. This technique does not prove to be economical. In conclusion she does not will not be used by those skilled in the art to make a drug or nutraceutical or food supplement where the amount of active substance (s) must be perfectly controlled.
The plaintiff has set itself the goal of alleviating the drawbacks of Art Previous and by developing compositions and finding a process for confer to the compositions, homogeneity, and stability over time, of the one or more active substances for administration in solid form having a texture appreciated and a better palatability for animals. In particular, she worked on put in point a veterinary composition for simple oral administration adapted and appreciated by each animal species, economic, the manufacture of which is easily industrializable and that the quantity of each component is perfectly controlled more particularly for the active substance (s) in the case of a medicinal product or nutraceutical or dietary supplement.
In the work that led to the development of the composition appetizing according to the invention, the Applicant has observed that obtaining this composition appetizing containing the maximum of appetizing materials by the compression technique from formulas with a high fat content led to compositions veterinarians at oral administration in solid form containing one or more substances active perfectly consumed by all animal species. This technique allows choose a composition that is perfectly suited and therefore appreciated by each of the cash target animals by carefully choosing the components of the formula by seeking to what they are mostly appetizing materials, the texture as well as the shape and size specific to the target animal species. This technique also makes it possible to choose the

7 components of the composition so that they are not the cause of instability specifically degradation of the active substance (s). Moreover, it was, of manner surprisingly, discovered that the introduction into the mixture last of the or from active substances has made it possible to better preserve their integrity and stability throughout of the retention period of the solid form. This technique allows produce very homogeneous compositions and guarantee with great precision the number of active substance (s) it contains during manufacture and over time.
This technique is also very economical and easily industrialized.
The invention relates to a method of manufacturing a solid composition, stable in time, perfectly dosed in active substance, to this composition and its use, in particular as appetizing compositions for oral administration for animals where the active substance (s) are introduced at the last stage of the preparation by addition to an aggregate previously obtained with all the other components (advantageously these other components do not include any substance active). TO
the introduction of the active substance (s), advantageously of all substances active, the aggregate is advantageously cold, i.e. it is at the temperature ambient, which can vary from 15 C to 30 C, advantageously 15 C to 25 C, and that he does not contains no water.
By stable over time, we mean that after at least one year of conservation of composition at 25 C (+ 1- 5 C), under varying relative humidity conditions from 30% to 70%, the mixture remains homogeneous because the dosage values of active substance se all found in the dose range. The dose interval corresponds to the target dose + 1- 5%, the percentages being expressed by weight.
The compositions have a texture, shape and size appreciated by cash animal. The present composition is advantageously in the form of a cube perfectly dosed and stable over time, appetizing very well accepted by all animals, whatever the species, absorbed rapidly, whether given way occasional or repeated.
The description of the invention will be given below in particular with reference to from examples given by way of illustration and with reference to the latest annexed to which :
Figure 1 is a schematic representation of a tablet compression press.
formulas at high fat content, and Figure 2 illustrates schematically a demotor-calibrator advantageously mounted on the supply tank of the press compress high fat formulas.

8 More particularly, the subject of the invention is a process for preparing of a solid appetizing composition, stable over time, characterized in that the composition includes:
To.
3 to 30%, preferably 5 to 15% by weight of at least one fat, chosen from a fatty substance or a wax, or a liquid oil, or a liquid oil thickened, or a mixture thereof, liquid oil, from liquid oil or from oil thickened, not being able to represent more than 8% by weight of the composition, I. 0.001 to 57% by weight of at least one active substance, z. 40 to 96.999% by weight of at least one appetizing material, when the active substance is also an appetizing ingredient, the content in active substance can be up to 97% by weight, advantageously up to 85%
by weight, and the composition may comprise as an appetizing material this single active substance or a mixture of the active substance with at least less another appetizing material, oh.
optionally one or more additives, advantageously chosen from fillers, binders, solvents, absorbent / gelling substances, flavors, surfactants, flavor enhancers, sweeteners, anti-oxidants, chelating agents, preservatives, colorants, and the pH regulators, a) the liquid or thickened oil is chosen from olive oil, oil peanut oil rapeseed, sunflower oil, capric acid triglycerides and caprylic, the propylene glycol of dicapric / dicaprylic acids, and mixtures thereof;
b) the fatty substance is chosen from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, oil possibly hydrogenated palm, cetyl palmitate, walnut oil coco hydrogenated, the triglycerides of capric, caprylic, myristic and stearic, and their mixtures;
c) the wax is chosen from beeswax, carnauba wax, wax candelilla, and their mixtures;
d) the appetizing material is chosen from meat, meat meal, the flours fish, cheese powders, milk derivatives, liver powder, the extracts of these animal substances or their derivatives; beer yeast ; fibers vegetable; plant products or by-products such as fenugreek apple, carrot, fodder beet, sugar beet, thyme, alfalfa, the sugar cane, and grains such as oats, wheat, rice and corn, soybeans, their derivatives such as flour, and mixtures thereof; sugar (sucrose) under all his forms, crystallized, powdered, ice, glucose, invert sugar, la molasses, honey or its derivatives, and their mixtures, salt (sodium chloride), and their mixtures ;

9 e) the solid appetizing composition has a unit weight of more or less than 3%
of the theoretical value of the required weight, and preferably more or less by 2%
the theoretical value of the required weight;
f) the solid appetizing composition is stable for more than one year when it is kept at ambient temperature ;
and in that the method comprises the following successive steps:
i. preparation of homogeneous aggregates comprising, or advantageously consistent in, the appetizing material (s), the fat and possibly a Where several additives, ii. addition, with stirring, at room temperature without adding water or heat, the cold aggregates obtained following step i) of the substance (s) active, advantageously of all the active substances, iii. calibration of the mixture of aggregates obtained following step ii), dry and fluid, for retain aggregates with a granulation between 50 and 1000 µm, of preferably between 200 and 800 μm, even more preferably between 200 and 600 pm, iv. compression of dry aggregates and calibrated fluids, obtained following step iii), with a tableting press for formulas with a high fat content, y. recovery, following step iv) of the solid appetizing composition.
The fat is advantageously in solid or waxy or pasty form.
Step i) advantageously comprises the following successive steps:
he. mixture of the appetizing material (s) and optionally one or various additives, appetizing materials and any additives being form powdery;
i2. Addition of the fat to the mixture obtained following step i);
i3. then mixing or trituration without adding water or heat until obtaining homogeneous aggregates.
It is preferable that in step ii) appetizing materials and possible additives have a particle size of less than 200 μm, advantageously less than 100 pm. the mixing can be carried out in a mixer-granulator.
According to a preferred embodiment, the fat is in the form of solid or waxy or pasty or thickened liquid.
To ensure the stability of the compositions obtained, the substance (s) active are introduced once the other components, advantageously all of the others components, mixtures and granules. When adding the substance (s) active, the aggregate from step iii) is cold and does not contain water. By cold, we hears that he 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 it is meant that the water content is less than 5%
by weight, relative to the total weight of the aggregate. Said active substances can be present in the form:
- powders, or solubilized in a suitable non-aqueous solvent for vaporization or pouring on the aggregate from step i), or - solubilized in a suitable non-aqueous solvent then transformed into a gel or powder by adding an absorbent substance, or - in the form of a granule, after a coating operation for example.

10 The active substance (s) can simply be distributed as a powder within the cube to eat, or be sprayed beforehand on all or part aggregate after having been solubilized in a suitable non-aqueous solvent, or transformed into solid after gelation of a solution, or granulated or coated with 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 upon perception olfactory or taste of the animal.
When in the form of a powder, the active substance has advantageously a particle size less than 200 µm, more preferably less than 100 µm.
When in the form of a granulate, the active substance has advantageously a particle size at most equivalent to that of the aggregate from step iii), granulation included between 50 and 1000 pm, preferably between 200 and 800 pm, even more preferentially between 200 and 600 pm.
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 granulometry between 50 and 1000 pm, preferably between 200 and 800 pm, even more preferably between 200 and 600 μm. Then, a compression of the mixture, fluid and calibrated, with standard equipment such as tablet presses formulas at high fat content of Fette, Bonals, IMA or Corazza (figure 1:
diagram of operating principle of the press), giving compact masses and homogeneous.
Said equipment being advantageously modified:
= by adding a demoulder-calibrator on the supply tank of the press at compress formulas with high fat content which allows to improve filling the cell with a constant volume, i.e. making the volume of aggregate therefore the weight introduced into the cell is as constant as possible in order to ensure a very low variation in the weight of the resulting eat / chew cube by relative to the theoretical fixed weight, as a consequence of which the quantity of substance active present in the cube will be perfectly constant (figure 2: demotor-calibrator), and

11 = to improve the extraction of the eating / chewing cube, but also to avoid all heating which could be detrimental to the cube / substance stability active, the compression stage is refrigerated.
Thus, the tablet press for formulas with high fat content is advantageously equipped with a demoulder-calibrator and / or a stage of compression refrigerated.
During step iv), the compressive force is advantageously included between 5 and 80 kN, more preferably between 20 and 60kN, even 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 top and bottom surfaces flat.
Advantageously, the composition has the shape of a cube or a parallelepiped, whose side advantageously varies from 10 mm to 40 mm, more preferably from 12.5 mm to mm (depending in particular on the mammal for which the composition is intended). the process according to the invention makes it possible to obtain compositions exhibiting a unit weight very homogeneous not deviating by more or less than 3% from the theoretical value weight required and preferably more or less than 2% of the theoretical value of the weight required.
The compositions according to the present invention are typically presented under the made of eating / chewing cubes used to facilitate oral intake by animals, of preferably mammals. Even if the appetizing composition oral administration in solid form for animals is referred to as "eat / chew cube", also other shapes can be considered, while respecting the constraints of equipment to know that at least the two upper and lower faces of the cube to eat / chew are planes.
The hardness of the eating / chewing cubes can be controlled by adjusting the pressure exerted by the tableting press on formulas with a high material content fat 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 tableting press the formulas with high content fat, by banning all equipment working continuously like extrusion or involving a continuous manufacturing step such as an extrusion molding, or working from dough or heterogeneous mixture such as hamburger squeezing equipment, with or without heat or humidity.

12 The compression technique using a tableting press for formulas strong fat content is widely used in food field human as evidenced by the following patent applications: US 6,126,979, WO 2004/1125

13, WO 2006/063694, WO 2007/085609, WO 2009/068378, OA 12967 describing compositions and the use of compression to form broth cubes also called bouillon tablets. Their employment is not direct, it must first dissolve them in water or an aqueous and preferably hot vehicle or to less lukewarm. In addition, these bouillon cubes are very crumbly because they must could be easily crumbled on cooking dishes. As a result, the skilled person would turn step towards these formulations and their production process in order to obtain a composition appetizing solid with desired texture.
The compression process for high fat formulas is known to prior art, and is used in particular in the field of food human. Those products are typically bouillon cubes. However the compositions, obtained by this method of compressing formulas with a high fat content, have until now never been used in the veterinary field, that is to say data directly to animals, especially mammals by plug direct by way oral with the exception of humans who consume them indirectly is dissolved in water hot or lukewarm or crumbled on its dishes before cooking.
Moreover, 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, previously mixed and granules.
Compared to other oral product manufacturing techniques for the animal described in the prior art including in particular the compression of dry powder, extrusion, and molding, compression of high fat formulas allow to obtain products richer in fat and appetizing what leads to a perfect palatability, that is to say to a total catch even if it is repetitive by the animal. All the compositions contain an active substance, this process of compression allows to perfectly control the weight of the eating / chewing cube and so the amount of active substance present in each unit of the final product and to guarantee thus 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 materials, having a texture appreciated by animals, = the extrusion and extrusion-molding processes do not allow fabricate products sufficiently rich in fat that do not exude, while dosing perfectly the product, = hamburger molding processes do not make it possible to manufacture products sufficiently rich in fat that do not exude, while dosing perfectly the product.
Thus, products manufactured in particular by extrusion or molding exhibit in general large variations in weight. These variations are due to different factors such as feeding the equipment with a mixture, but also with the mixture itself even under paste form forming in the screws of the extruder or directly for the molding, paste which presents a strong heterogeneity. These variations can be compensated by sorting products leaving the production lines but such sorting is associated at a loss significant product resulting in a significant additional cost. Calibration of products is particularly decisive with regard to compositions incorporating a active substance. To allow the administration of a constant amount of substance active, the final product must be perfectly calibrated in terms of its weight. This calibration is advantageously obtained by manufacturing the compositions according to the present invention by compression of high fat formulas.
Comprising one or more active substances, the solid compositions appetizing obtained are advantageously used for administration to animals for a therapeutic treatment either drug, nutraceutical or supplement food, the animals being more particularly mammals.
By active substance is meant a medicinal substance, nutraceutical Where food supplement, having a therapeutic effect or having an activity biological.
The content of active substance is adapted in the composition according to the principle active ingredient chosen and the animal to be treated.
The amount of an active substance per solid composition depends on its efficiency. So it can be very weak, close to a few tens of micrograms at various grams.
The minimum content of active substance (s), expressed by weight relative to the weight total of the composition, may be at least 0.001% or at least 0.01% or at less 0.1%, or at least 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%
at 57% in weight, preferably 0.001 to 50% by weight, more preferably 0.001 To 40% by weight or 0.001 to 30% by weight.

14 However, these ranges may be different when one of the substances active is at the same time an appetizing substance. This is because the active substance can be too an appetizing material which allows to have a content of up to 97%
in weight, advantageously up to 85% by weight.
Preferably, the active drug substance is chosen from anti-infectious such as antibiotics and sulfonamides, cardiotonics; the pest control internal and external; insecticides; growth inhibitors insects ; the anti-arthritis; steroidal anti-inflammatory drugs or not; the antihistamines; the hormones such as prostaglandins; digestive therapy substances such as gastrointestinal dressings and sedatives, antiulcer drugs and flora of substitution ; anti-diarrheal drugs; hepato-protectors; the antispasmodics; the laxatives; intestinal antiseptics; therapy substances respiratory such as respiratory analeptics, cough suppressants, bronchodilators, thinners bronchial and mucolytics, and respiratory antiseptics; the active substances on the nervous system such as pain relievers, sedatives and tranquilizers; the antiepileptics; anesthetics; orexigens; appetite suppressants, substances immune therapy such as interleukins and in particular interferon; the anticancer therapy substances such as antimitotics and cytostatics;
macro-, micro- and trace elements; vitamins; plant extracts or organs animals; and their mixtures.
In an advantageous embodiment, the active substance is chosen from the antibiotics such as amoxicillin, clavulanic acid, cephalexin, rifaximin; the antiparasitics such as ivermectin, moxidectin, milbemycin the pyrantel, and its derivatives such as pamoate, praziquantel, benzimidazoles, their salts or their derivatives; insecticides such as fampronil; cardiotonics such as levosimendan;
anti-arthritis drugs such as diacerein.
Preferably, the nutraceutical active substance or food supplement is chosen among extracts of plants or animal organs for their anti-infectious, antibacterial, antifungal, anti-diarrheal, hepato-protective, anti-spasmodic, laxative, intestinal anti-septic; on respiratory problems such as cough, as as bronchodilators, bronchial and mucolytic fluidifying, antiseptic respiratory, analgesic, sedative, tranquilizer, anti-arthritis, insecticide, pest control, anti-ulcer, anti-stress; and substitution flora; macro-, micro- and trace elements ; the vitamins; and their mixtures.
In an advantageous embodiment, the nutraceutical active substance or food supplement is chosen from plant or organ extracts animals for their anti-osteoarthritis action such as chondroitin sulfate, chitosan and its derivatives; for their anti-ulcer and / or anti-stress action such as the extract soybean fermented; for their insecticidal or insect repellent action such as pyrethrums ; the vitamins such as vitamin C, vitamin D3; the flora of substitution tel as Enterococcus faecium; microelements such as selenium provided by a 5 strain of Saccharomyces cerevisiae.
It will be understood that an active substance can have several functions as well extract from fermented soybean can be both an active substance and a material appetizing.
The compositions according to the present invention comprise at least one material 10 appetizing in large quantities contributing to organoleptic characteristics of the composition according to the invention and its palatability for animals.
The content of appetizing material is advantageously at least 40% by weight, more advantageously at least 50% by weight, even more advantageously at least 60%
by weight, relative to the total weight of the composition. The composition can understand

15 up to 96.999% by weight, preferably up to 90% by weight of matter appetizing.
When the appetizing ingredient is also the active ingredient, the content in matter appetizing can be 97% by weight.
Appetizing substances for the target animal are, for example, substances original animal or vegetable, directly powdered after treatments such as drying or dehydration, grinding, sizing but also after processing with addition other components to promote conservation for example. The components appetizing are chosen from the substances of choice which have a strong palatability for target species, in particular domestic carnivores such as dogs and cats or herbivores such as horses.
In the uses and compositions according to the invention, the material appetizing is chosen either in the animal kingdom or in the plant kingdom depending on the animal species target of preference among meat, meat meal, fish meal, powders cheese, milk derivatives, liver powder, extracts of these animal substances or their derivatives; beer yeast ; vegetable fibers; the products or by-products plants such as fenugreek, apple, carrot, beet fodder, the sugar beet, thyme, alfalfa, sugar cane, and grains such as oats, wheat, rice and corn, soybeans, their derivatives such as flour, and their mixtures; the sugar (sucrose) in all its forms - crystallized, powdered, ice, glucose invert sugar, molasses, honey or its derivatives; and their mixtures; that is in the world mineral salt (sodium chloride).
It will be understood that any component of the formulation can also be a material appetizing for animals.

16 The compositions according to the present invention comprise at least one material oily.
The fat content is at least 3% by weight, based on the weight total of the composition, preferably at least 5% by weight, more preferably at least less 10% by weight. The fat content in the composition, expressed in weight relative to the total weight of the composition can be up to 30% or less, preferably up to 20%, more preferably up to 15%.
By fat is meant a material containing one or more lipids.
By fatty substance is meant a substance mainly composed of triglycerides.
In the uses and compositions according to the invention, the fatty substance is preference chosen either in the animal kingdom or in the plant kingdom depending on the species target animal among pasty or hard fats chicken fat, fat from duck, the lard, tallow, butter, palm fat, palmitic stearin, margarine, optionally hydrogenated palm oil, cetyl palmitate, palm oil coconut hydrogenated, the triglycerides of capric, caprylic, myristic and stearic; and their mixtures.
By waxes is meant waxes authorized in food and in particular in animal feed.
In the uses and compositions according to the invention, the wax is chosen preference either in the animal kingdom or in the plant kingdom depending on the animal species target among the beeswax, carnauba wax, candelilla wax, and mixtures thereof.
By oil is meant a fat which is liquid at the temperature ambient. In In general, the oil is of vegetable origin, although it may be of animal or mineral. Depending on the target species, preference will go to oils of vegetable origin or animal.
According to the invention, the eat / chew cube can contain liquid oil acceptable having no degrading activity vis-à-vis the other components chosen in particular the active substance.
In the uses and compositions according to the invention, the liquid oil or thickened is preferably chosen from olive oil, peanut oil, rapeseed oil sunflower, triglycerides of capric and caprylic acids, propylene glycol dicapric / dicaprylic acids; and their mixtures.
In the uses and compositions according to the invention, the fatty substances or waxes or thickened oils will allow granulation of the powdery components for lead to a homogeneous mixture.
It will be understood that a thickened oil, that a fat, that a wax can be also appetizing materials for animals.
The composition further comprises one or more additives selected from preferably either in the animal kingdom or in the plant kingdom depending on the target animal species from

17 fillers, binders, solvents, absorbent / gelling substances, aromas surfactants, flavor enhancers, sweeteners, anti-oxidants, agents of chelation, preservatives, dyes, and pH regulators.
Preferably, the filler is chosen from maltodextrins; the cyclodextrins; the lactose; talc; silicates; phosphates, cellulose powder;
cellulose microcrystalline; mica and carbonates. Advantageously, when it is present, the filler represents 1 to 25% by weight of the composition relative to the weight total of the composition.
The compositions according to the present invention comprise at least one binder. the binder is advantageously chosen from polyvinyl alcohol polymers, the polyvinylpyrrolidone, copolymers of vinylpyrrolidone and acetate of vinyl, the carboxymethylcellulose, its salts and derivatives, polyethylene glycols solid and their derivatives, gelatins, alginic acid and its salts, zein, pectins, gum arabic, acacia gum, tragacanth, karaya gum, gum xanthan, carrageenans, pullulan polymers, agar polymers, starches and their derivatives, sugars and their derivatives such as molasses, carbomers, acid acrylic crosslinked with polyalkenyl ethers, polycarbophils, and their mixtures.
Advantageously, when it is present, the binder represents 1 to 25% by weight of the composition relative to the total weight of the composition.
Preferably, the solvent is chosen from ethanol, propylene glycol, glycerine, cetyl alcohol, benzyl alcohol, liquid polyethylene glycols; and their mixtures.
Advantageously, when it is 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 acid stearic derivatives and its salts such as glyceryl stearates, stearates aluminum or magnesium, hydrogenated castor oil, bentonite, silica derivatives like the colloidal silica, precipitated silica, fumed silica, cellulose and these derivatives like methyl or ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, atomized whey, starches; and their mixtures. Advantageously, when she 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 a scent principle of a certain substance (of synthetic origin Where natural) which will only be perceived by smell. It won't produce a sensation on the organ taste and therefore will not have flavor. Advantageously, when it is present, the aroma represents 0.01 to 5% by weight of the composition relative to the total weight of the composition.
Preferably, the aroma is chosen from essential oils, derivatives terpene such as menthol, and mixtures thereof.

18 Preferably, the surfactant is chosen from glycol esters such as monostearate glycerol, sorbitan and fatty acid esters, fatty acid esters polyoxyethylenates and sorbitan; polyoxyethylenated vegetable oils such as the polyoxyethylenated castor oils, hydrogenated vegetable oils polyoxyethylenated such as polyoxyethylenated hydrogenated castor oils; lecithin and its derived from soy or egg like phosphatidylcholine, phosphatidylcholine hydrogenated lysophosphatidylcholine, hydrogenated lysophosphatidylcholine, as well as their mixtures. Advantageously, when it is present, the surfactant represents 0.1 to 10% in weight of the composition relative to the total weight of the composition.
In a preferred embodiment, the flavor enhancer is sodium.
Advantageously, when it is present, the flavor enhancer represents 0.1 to 10% in weight of the composition relative to the total weight of the composition.
In a preferred embodiment, the sweetener is chosen from aspartame ; the sodium saccharinate; taumatin; polyols such as sorbitol, xylitol, isomalt, maltitol, mannitol, and lactitol; and their mixtures. Advantageously, when it is present, the sweetener represents 0.1 to 10% by weight of the composition by in relation to total weight of the composition.
Preferably, the antioxidant is chosen from ascorbic acid, its salts and its derivatives, sodium or potassium metabisulphite, sodium bisulphite, butylhydroxyanisol, butylhydroxytoluene, gallic acid and its derivatives such as propyl gallate, and mixtures thereof. 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, acid tartaric and its salts, and mixtures thereof. Advantageously, when it is present, the agent of chelation represents 0.01 to 5% by weight of the composition relative to the weight total of the composition.
Preferably, the preservative 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 by relative to the total weight of the composition.
Preferably, the dye is chosen from iron oxides, iron oxide.
titanium curcumin, caramel, carotenes, and mixtures thereof. Advantageously, when it is present, the colorant represents 0.1 to 5% by weight of the composition by in relation to weight total composition.
Preferably, the pH regulator is chosen from citric acid, its salts and its derivatives, sodium carbonates, delta glucono lactone, and mixtures thereof.

19 Advantageously, when it is present, the pH regulator represents 0.01 to 10% in weight of the composition relative to the total weight of the composition.
In a preferred embodiment, the additive (s) represents (s) 0.01 to 25%, of preferably 0.1 to 15% by weight of the composition relative to the total weight of the composition. In another variant, the additive (s) represents (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 load can have several functions as well as a product or under-vegetable product such as cereal flour or sugar can also be well one inert load than an appetizing material.
A subject of the invention is also a solid, stable appetizing composition.
in the time, obtainable by the method according to any one of the preceding claims, characterized in that the composition comprises:
To. 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 body fat or wax, or liquid oil, or thickened liquid oil, or a mixed of these ; liquid oil or liquid oil based on thickened oil should not can represent more than 8% by weight of the composition, I. 0.001 to 57% by weight of at least one active substance, z. 40 to 96.999% by weight of at least one appetizing material, when the active substance is also an appetizing ingredient, the content in active substance can be up to 97% by weight, advantageously up to 85%
by weight, and the composition may comprise as an appetizing material this single active substance or a mixture of the active substance with at least less another appetizing material, oh. optionally one or more additives, advantageously chosen from fillers, binders, solvents, absorbent / gelling substances, flavors, surfactants, flavor enhancers, sweeteners, anti-oxidants, chelating agents, preservatives, colorants, and the pH regulators, a) the liquid oil is chosen from olive oil, peanut oil, rapeseed oil, oil of sunflower, the triglycerides of capric and caprylic acids, propylene glycol dicapric / dicaprylic acids, and mixtures thereof;
b) the fatty substance is chosen from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, oil possibly hydrogenated palm, cetyl palmitate, walnut oil coco hydrogenated, the triglycerides of capric, caprylic, myristic and stearic, and their mixtures;
c) the wax is chosen from beeswax, carnauba wax, wax candelilla, and their mixtures;
5 d) the appetizing material is chosen from meat, meat meal, the flours fish, cheese powders, milk derivatives, liver powder, the extracts of these animal substances or their derivatives; beer yeast ; fibers vegetable; plant products or by-products such as fenugreek apple, carrot, fodder beet, sugar beet, thyme, alfalfa, 10 the sugar cane, and grains such as oats, wheat, rice and corn, soybeans, their derivatives such as flour, and mixtures thereof; sugar (sucrose) under all his forms, crystallized, powdered, ice, glucose, invert sugar, la molasses, honey or its derivatives, and their mixtures, salt (sodium chloride), and their mixtures ;
e) the solid appetizing composition has a unit weight of more or less than 3%
15 of the theoretical value of the required weight, and preferably more or less than 2%
the theoretical value of the required weight;
f) the solid appetizing composition is stable for more than one year when it is kept at ambient temperature.

20 The composition, and its components, in particular their contents, are as described previously.
Advantageously, the composition consists of:
a) at least one active drug substance chosen from among antibiotics such as amoxicillin, clavulanic acid, cephalexin, rifaximin, the 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 the levosimendan, and anti-arthritis drugs such as diacerein; a substance active nutraceutical or food supplement chosen from the extracts animals for their anti-osteoarthritis action such as chondroitin sulfate, the chitosan and its derivatives; for their anti-ulcer and / or anti-stress action such than fermented soybean extract; for their insecticidal action or such as pyrethrums vitamins such as vitamin C, vitamin D3, surrogate flora Phone than Enterococcus faecium, microelements such as selenium provided by a strain of Saccharomyces cerevisiae;
b) at least one fat chosen from chicken fat, fat of duck, lard, tallow, butter, palm fat, stearin palmitic, margarine, possibly hydrogenated palm oil, palmitate cetyl,

21 hydrogenated coconut oil, and mixtures thereof; waxes such as wax beeswax, carnauba wax, candelilla wax, and mixtures thereof; the oils such as olive oil, peanut oil, rapeseed oil, coconut oil, sunflower triglycerides of capric and caprylic acids and their derivatives; or their mixtures;
c) at least one appetizing material chosen from meat, flour meat, fish meal, cheese powders, milk derivatives, powder of liver, gelatin, extracts of these animal substances or their derivatives;
the yeast ; vegetable fibers; the products or by-products of plants such as fenugreek, apple, carrot, fodder beet, the sugar beet, thyme, alfalfa, sugar cane, cereals such than oats, wheat, rice and corn, soybeans, their derivatives such as flour, and their mixtures, sugar (sucrose) in all its forms, crystallized, powder, ice, glucose, invert sugar, molasses, honey and its derivatives, and their mixtures, salt (sodium chloride), and mixtures thereof.
The content of active substance is adapted in the composition according to the principle active ingredient chosen and the animal to be treated. Its content can vary from 0.001 to 97% in weight, by relative to the total weight of the composition, advantageously from 0.001 to 57% in weight, more preferably 0.001 to 50% by weight, even more preferably 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 weight total of the composition, preferably at least 5% by weight, more preferably at least less 10% by weight. The fat content in the composition, expressed in weight relative to the total weight of the composition can be up to 30% or less, preferably up to 20%, more preferably up to 15%.
The content of appetizing material is advantageously at least 40% by weight, more advantageously at least 50% by weight, even more advantageously at least 60%
by weight, relative to the total weight of the composition. The composition can understand up to 96.999% by weight, preferably up to 90% by weight, or 97% by weight weight when the appetizing substance is also the active substance, appetizing.
The composition can be used:
¨ as a medicinal product for mammals, except humans, in particular for animals domestic such as dog, cat or horse, or ¨ as a nutraceutical or food supplement for mammals, except humans, in particular for domestic animals such as dogs, cats or horse.

22 Finally, the invention relates to a solid appetizing composition, characterized in that the composition includes:
To. 3 to 30%, preferably 5 to 15% by weight of at least one material oily, advantageously in solid or waxy or pasty form, chosen from a fatty substance or wax, or liquid oil, or thickened liquid oil, or one mixture of these; liquid oil or liquid oil base of oil thickened do which may represent more than 8% by weight of the composition, p. 0.001 to 57% by weight of at least one active substance, z. 40 to 96.999% by weight of at least one appetizing material, when the active substance is also an appetizing ingredient, the content in active substance can be up to 97% by weight, advantageously up to 85%
by weight, and the composition may comprise as an appetizing material this single active substance or a mixture of the active substance with at least less another appetizing material, oh. optionally one or more additives, advantageously chosen from the fillers, binders, solvents, flavors, surfactants, enhancers taste, sweeteners, anti-oxidants, chelating agents, agents preservatives, dyes, and pH regulators;
a) the liquid or previously thickened oil is chosen from oil olive oil peanut, rapeseed oil, sunflower oil, and mixtures thereof;
b) the fatty substance is chosen from chicken fat, duck fat, lard, tallow, butter, palm fat, palmitic stearin, margarine, oil possibly hydrogenated palm, cetyl palmitate, walnut oil coco hydrogenated, and mixtures thereof;
c) the wax is chosen from beeswax, carnauba wax, wax candelilla, and their mixtures;
d) the appetizing material is chosen from meat, meat meal, the flours fish, cheese powders, milk derivatives, liver powder, the extracts of these animal substances or their derivatives; beer yeast ; fibers vegetable; plant products or by-products such as fenugreek apple, carrot, fodder beet, sugar beet, thyme, alfalfa, sugar cane, and cereals such as oats, wheat, rice and corn, soybeans, their derivatives such as flour, and mixtures thereof; sugar (sucrose) under all his forms, crystallized, powdered, ice, glucose, invert sugar, la molasses, honey or its derivatives, and their mixtures, salt (sodium chloride), and their mixtures ;
e) the solid appetizing composition has a unit weight of more or less than 3%
of the theoretical value of the required weight, and preferably more or less by 2%
the theoretical value of the required weight;

23 f) advantageously the solid appetizing composition is stable for more than a year when stored at room temperature;
for its use as a medicine; nutraceutical or supplement food to oral administration to mammals, except man, in particular for the animal domestic such as dog, cat or horse.
In one variant, the composition comprises:
¨ 5 to 30%, preferably 8 to 20% by weight of at least one fat, chosen from a liquid oil, a thickened oil, a fatty substance, a wax Where a mixture of these, 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%, advantageously 20 to 90%, preferably 40 to 70% by weight of less an appetizing material.
According to a preferred embodiment, the fat is in the form of solid or waxy or pasty or thickened liquid.
The additive may also include or consist of the substances absorbent / gelling.
The liquid or previously thickened oil can also be chosen from triglycerides of capric and caprylic acids, propylene glycol of dicapric acids /
dicaprylic, and their mixtures with the other possibilities.
The fatty substance can also be chosen from the triglycerides of the acids capric, caprylic, myristic and stearic, and their mixtures with the others possibilities.
The solid appetizing composition is advantageously capable of being obtained by the method according to the invention.
It should be understood, however, that these examples are given only To by way of illustration of the object of the invention, of which they in no way constitute way one limitation.

24 EXAMPLE 1 ¨ Preparation of a dog food / chew cube 1.1 g eat / chew cubes containing 2.5 mg of milbemycin, 12.5 mg of praziquantel are made with the following composition:
Milbemycin 0.227%
Praziquantel 1.136%
Liver powder 46.00%
Glycerin 18.00%
PEG 4000 12.00%
Gelatin 8.00%
Sugar 8.582%
Glycerol distearate 5.00%
Propylene glycol of dicapric / dicaprylic acids 1.00%
BHA 0.04%
Propyl gallate 0.01%
Precipitated silica 0.005%
a) batch of cubes produced according to the invention In a blender, introduce the liver powder, the glycerol distearate, and to mix together. Add the PEG 4000, the BHA, the propyl gallate, and mix. Add gelatin, sugar, and mix. Pour the glycerin over the homogeneous mixture. To mix together up to obtaining a homogeneous, dry and fluid aggregate. Dissolve milbemycin in the propylene glycol from dicapric / dicaprylic acids and add silica rushed for thicken the solution. Add praziquantel to one tenth of the aggregate, and to mix together. Add thickened milbemycin solution, and mix until a mixed homogeneous. Add the rest of the aggregate in small quantities, continuing to to mix together.
Calibrate the aggregate on an 800 µm sieve. The eating / chewing cubes of form parallelepiped of dimension 12.5 x 12.5 x 7 mm are obtained by compression at 40 kN using a tablet press for formulas with a high content of fat.
Their theoretical weight is 1.1 g.

b) batch of cubes produced with introduction of active ingredients at the start of mixing At the same time, eating / chewing cubes were made with the same formulation but according to the process: in a mixer introduce the powder of liver.
Dissolve the milbemycin in the propylene glycol of the acids beforehand dicapric /

dicaprylic, spray the milbemycin solution, and mix until obtaining a homogeneous mixture. Add the praziquantel, and mix Spray the triglycerides capric / caprylic / myristic / stearic acids previously liquefied, and to mix together.
Add the PEG 4000, the BHA, the propyl gallate, and mix. Add the gelatin, sugar, and mix. Pour the glycerin over the homogeneous mixture. Mix up obtaining 10 of a homogeneous, dry and fluid aggregate. Add the precipitated silica, and mix.
Calibrate the aggregate on an 800 µm sieve. Shape eating / chewing cubes parallelepiped of dimension 12.5 x 12.5 x 7 mm are obtained by compression at 40 kN using a tablet press for formulas with a high content of fat.
Their theoretical weight is 1.1 g.
15 For the two lots, all the eating / chewing cubes were weighed separately, no cube deviated by more than 2 percent from the theoretical mass. That would not have was achievable using the techniques usually implemented in to know extrusion which is a continuous manufacture or molding using a dough.
For the two batches, the determination of the Milbemycin content for the 5 the lightest and 5 heaviest eating / chewing cubes showed that the mix was perfectly homogeneous because the dosage values were all in the interval of doses, accepted for drugs, framing the theoretical dose. This determination, made on a half cube just after obtaining them, was repeated a year later of storage at 25 C on the other half of the cube. for the cubes obtained according to invention,

25 the dosage values, for each cube after one year of storage, do not differ not values obtained just after compressing the cubes by more than 3%, this who is not not the case for the cubes of the second batch where a loss of more than 10% of the active summer recorded.
Taking into account the margins of error of the dosages, degradations during shelf life (variations) allowed for medicinal products, the invention put in evidence of perfect stability of even a sensitive or fragile molecule.
EXAMPLE 2 ¨ Monadic palatability test with eating / chewing cubes A palatability test of the cubes to eat / chew obtained according to the invention of example 1 was carried out on thirty adult dogs, male and female, of breeds varied. The dogs between 5 kg and 25 kg receive 5 cubes, and dogs between 25 and 50 kg receive 10 cubes, The cubes are offered at the same time.

26 This is a monadic test carried out in individual boxes for ten minutes per dogs. Were measured:
- grip by hand / on the ground / or no grip - total / partial / or no consumption.
For each of these criteria is specified the number of individuals, out of all of the panel and by size categories (small / medium / large). Calculation of acceptability is based on the percentage of dogs having consumed the entire eat / chew cube.
Gripping:
dogs from 5 to 25 kg Dogs from 25 to 50 kg By hand 20 10 on the ground 0 0 no plug 0 0 Consumption :
dogs from 5 to 25 kg Dogs from 25 to 50 kg Partial 0 0 Total 20 10 no consumption 0 0 The acceptability and consumption of the eating / chewing cubes according to the invention are total (100%).
EXAMPLE 3 ¨ Preparation of a dog food / chew cube 1.1 g eat / chew cubes containing 68 pg of ivermectin, 57 mg of pyrantel in the form of pamoate, and 57 mg of praziquantel according to the invention are realized with the following composition:
coated lvermectin 2.85%
Coated pyrantel pamoate 5.13%
Praziquantel coated 3.21%

27 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 the liver powder, the PEG 4000, the palm oil hydrogenated Tenox 8 and mix. Add the gelatin, and mix. To pay on the homogeneous mixture of glycerin. Mix until a granulate is obtained homogeneous, dry and fluid. Add the coated ivermectin, the coated praziquantel, the pamoate coated pyrantel, and mix. Calibrate the aggregate on an 800 µm sieve. The cubes at eat / chew parallelepipedal shape of dimension 12.5 x 12.5 x 7 mm are obtained by compression at 40 kN using a tableting press the formulas to strong fat content. Their theoretical weight is 1.1 g.
All the eating / chewing cubes were weighed separately, no cubes are deviated by more than 2 percent from the theoretical mass. The determination of content ivermectin for the 5 lightest and 5 most eating / chewing cubes heavy showed that the mixture was perfectly homogeneous because the dosage values are found all within the range of doses, admitted for drugs, framing the dose theoretical. This determination, made on a half cube just after their obtaining, was repeated one year after storage at 25 C on the other half of the cube. The values of dosage, for each half cube after one year of storage, do not differ from values obtained just after compressing the cubes by more than 3%. Account kept margins of error of the dosages, degradations during the conservation (variations) allowed for medicinal products, the invention demonstrates a perfect even sensitive or fragile molecule stability.
EXAMPLE 4 ¨ comparative test of the homogeneity of the weights between the cubes at eat / chew and chew tablets obtained by extrusion Twenty cubes to eat / chew, obtained according to the invention in accordance with Example 1, taken consecutively at the exit of the machine were weighed.
A batch of chewable tablets was made by extrusion with the formula next :

28 lvermectin 0.001236%
Pyrantel pamoate 2.963636%
Tallow 2.5%
Beef 42.0%
Soy flour 30.932404%
Salt 2.00%
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 at the extrusion outlet were weighings. The weights recorded for the two samples of the twenty objects are given in the next board :
Item number Chewable cube Chewable 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

29 6 5.41 4.86 7 5.53 5.69 8 5.56 6.27 9 5.60 4.78 5.59 4.96 11 5.55 5.67 12 5.48 6.13 13 5.45 6.06 14 5.49 5.19 5.50 5.43 16 5.47 4.99 17 5.57 4.75 18 5.52 5.78 19 5.49 6.01 5.55 5.26 Deviation <2%> 14%
A significant difference, greater than 14%, is observed between the extreme weights of chew tablets and the average weight obtained with the 20 chew tablets obtained by extrusion compared to the weight difference, less than 2%, observed for cubes at 5 eat / chew obtained according to the invention.
These weight differences necessarily entail a variation of at least the same importance of the quantities of active molecules contained in tablets to chew. It is not possible to use the extrusion or molding process for the production of single-dose drugs, except by weighing the chew tablets 10 one by one at the exit of the shaper, and to remove all those which do not did not come back in the weight range guaranteeing a quantity of active molecules such than requires the regulation of drugs. If at first approach, in The example presented, were kept only the chewing tablets whose weight does not don't deviate WO 2014/0332

30 PCT / EP2013 / 067934 of more than 5 percent of the theoretical weight, it would only be kept 6 shelves to chew on the twenty produced, or 30 percent of the production which is not economical and without guarantee of the quantity of active molecules for the chewable tablets of which the weight is close or equivalent to the upper and lower limit weights for select the 5 chewable tablets. Likewise, it is unthinkable to extrude or mold a second once the chewing tablets have been discarded because inevitably the provision from active molecules in the body would be modified and would lead to a modification of therapeutic activity.
10 EXAMPLE 5 ¨ Formulations Other formulations, in accordance with the invention, are described below.
Food / chew cubes containing 68 pg of ivermectin, and 57.5 mg of pyrantel under pamoate form according to the invention are produced with the following composition :
lvermectin 0.001236%
Pyrantel pamoate 2.963636%
Rapeseed oil 5.00%
Suet 10.00%
Beef 40.30%
Soy flour 28.132428%
Salt 2.00%
Molasses 8.00%
Glucono delta lactone 3.30%
Potassium sorbate 0.30%
Propyl gallate 0.0005%
BHA 0.0018%
Citric acid 0.0004%

31 All the eating cubes 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 lvermectin content for the 5 cubes to eat / chew most light and the 5 heaviest showed that the mixture was perfectly homogeneous because the dosage values were all within the accepted dose range for the drugs, framing the theoretical dose.
Eating / chewing cubes, for horses, are made with the composition next :
Fermented soy extract 83%
10% hydrogenated palm oil Crystallized sugar 6%
Titanium oxide 0.9%
BHA 0.1%
Cubes to eat / chew in parallelepiped shape of dimension 31 x 23 x 10 mm are obtained by compression using a cubic broth press. All the cubes at eat / chew were weighed separately. No cube deviated by more than 2 for cent of the theoretical mass.
A palatability test of these eating / chewing cubes was carried out with various owners of horses and ponies and in a horse club. The cube at eat / chew a been presented to the horse or pony on the wide open hand. Acceptability and the consumption of the eating cubes was total (100%). It is necessary to mention the behavior of animals vis-à-vis this cube. Several riders have reported the the great attraction that horses and ponies had for the cube to eat / chew presented in this form size and color. From the first absorbed, they were looking for have others by feeling the pockets of the rider from which these cubes.
3g dog food / chew cubes containing 68 pg of ivermectin, 57 mg of pyrantel in the form of pamoate, and 57 mg of praziquantel according to the invention are made with the following composition:
1.0% coated lvermectin Coated pyrantel pamoate 6.0%
Praziquantel coated 5.0%

32 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%
Cubes to eat / chew in parallelepiped shape of dimension 17 x 17 x 9.6 mm are obtained by compression using a cubic broth press. All the cubes at eat / chew were weighed separately, their theoretical weight is 3.0 g.
No cube did not deviate by more than 2 percent from the theoretical mass.

Claims (81)

33 1. A process for preparing a solid, stable appetizing composition in time, where the composition includes:
To. 3 to 30%, by weight of at least one fat, chosen from a fatty substances or a wax, or a liquid oil, a thickened liquid oil, or a mixture of those-this ; liquid oil, from liquid oil or thickened oil, do not can represent more than 8% by weight of the composition, R. 0.001 to 57% by weight of at least one active substance, x. 40 to 96.999% by weight of at least one appetizing material, when the active substance is also an appetizing ingredient, the content in active substance can be up to 97% by weight, and the composition can understand as an appetizing material this only active substance or a mixture of the active substance with at least one other appetizing substance O. optionally one or more additives, a) the liquid or thickened oil is chosen from olive oil, oil peanut, rapeseed oil, sunflower oil, triglycerides of capric and caprylic acids, propylene glycol dicapric / dicaprylic acids, and mixtures thereof;
b) the fat is chosen from chicken fat, fat from duck, lard, tallow, butter, palm fat, palmitic stearin, margarine, Palm oil possibly hydrogenated, cetyl palmitate, coconut oil hydrogenated, the triglycerides of capric, caprylic, myristic and stearic acids, and their mixtures;
c) the wax is chosen from beeswax, carnauba wax, candelilla wax, and their mixtures;
d) the appetizing material is chosen from meat, flour meat, flour fish, cheese powders, milk derivatives, liver powder, extracts from these animal substances or their derivatives; beer yeast ; fibers vegetable; the plant products or by-products; sugar (sucrose) in all its forms, crystallized, powdered, iced, glucose, invert sugar, molasses, honey or its derivatives, and their mixtures; salt (sodium chloride); and their mixtures;
Date Received / Date Received 2020-11-13 e) the solid appetizing composition has a unit weight of more or less than 3% of the theoretical value of the required weight;
f) the solid appetizing composition is stable for more than one year when is kept at ambient temperature ;
the method comprising the following successive steps i. preparation of homogeneous aggregates comprising the material (s) appetizing, the fat and possibly one or more additives, ii. addition, with stirring, at room temperature without adding water or heat, the cold aggregates obtained following step i) of the substance (s) active, iii. calibration of the mixture of aggregates obtained following step ii), dry and fluid, for retain aggregates with a granulation between 50 and 1000 pm, iv. compression of dry aggregates and calibrated fluids, obtained following step iii), with a tableting press for formulas with a high fat content, v. recovery, following step iv) of the solid appetizing composition. 2. The method of claim 1, wherein the composition comprises 5 to 15% in weight of said at least one fat. 3. The method of claim 1 or 2, wherein said at least one material fat is under solid or waxy or pasty form. 4. A method according to any one of claims 1 to 3, wherein when the active substance is also an appetizing material, the content of the active substance may go up to 85% in weight. 5. A method according to any one of claims 1 to 4, wherein said one or several additives is chosen from fillers, binders, solvents, substances absorbent / gelling, flavors, surfactants, flavor enhancers, sweeteners, anti-oxidants, agents chelation agents, preservatives, dyes, and regulators pH. 6. Method according to any one of claims 1 to 5, wherein the products or the sub-plant products are chosen fenugreek, apple, carrot, fodder beet, the sugar beet, thyme, alfalfa, sugar cane, and grains. 7. The method of claim 6, wherein the cereals are selected from oats, wheat, rice and mats, soybeans, derivatives thereof and mixtures thereof.
Date Received / Date Received 2020-11-13 8. The method of claim 7, wherein the cereal derivatives are flour. 9. A method according to any one of claims 1 to 8, wherein the appetizing composition solid has a unit weight of more or less than 2% of the value theoretical weight required. 10. A method according to any one of claims 1 to 9, wherein step iii. includes the calibration of the mixture of aggregates obtained following step ii), dry and fluid, to retain the aggregates having a granulation between 200 and 800 μm. 11. A method according to any one of claims 1 to 10, wherein step i) includes the following successive steps:
he. mixture of the appetizing material (s) and optionally one or various additives, appetizing materials and any additives being powder form;
i2. addition of the fat to the mixture obtained following step i);
i3. then mixing or trituration without adding water or heat until obtaining homogeneous aggregates. 12. The method of claim 11, wherein in step ii) the materials appetizing and possible additives have a particle size of less than 200 μm. 13. The method of claim 12, wherein in step ii) the materials appetizing and any additives have a particle size of less than 100 μm. 14. A method according to any one of claims 1 to 13, wherein during step ii) the active substance is in the form:
- powders, or - solubilized in a suitable non-aqueous solvent to be vaporized or paid on the aggregate from step i), or - solubilized in a suitable non-aqueous solvent then transformed into a gel or powder by adding an absorbent substance, or - in the form of a granule. 15. The method of claim 14, wherein during step ii) the substance active has a particle size at most equivalent to that of the aggregate from step iii).
Date Received / Date Received 2020-11-13 16. A method according to any one of claims 1 to 15, wherein the composition appetizing comes in the form of a compact mass with at least the surfaces upper and lower planes. 17. A method according to any one of claims 1 to 16, wherein the press to compress formulas with a high fat content is equipped with a demoulder-calibrator. 18. A method according to any one of claims 1 to 17, wherein the press to compress formulas with a high fat content is equipped with a stage of refrigerated compression. 19. A method according to any one of claims 1 to 18, wherein when step iv), force compression is between 5 and 80 kN. 20. A method according to any one of claims 1 to 19, where:
= the filler is chosen from maltodextrins, cyclodextrins, lactose, talc, silicates, phosphates, cellulose powder, cellulose microcrystalline, mica, and carbonates;
= the binder is chosen from polyvinyl alcohol polymers, the polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, the carboxymethylcellulose, its salts and its derivatives, solid polyethylene glycols and their derivatives, gelatins, acid alginic acid and its salts, zein, pectins, gum arabic, gum acacia, the tragacanth, karaya gum, xanthan gum, carrageenan, pullulan polymers, agar polymers, starches and their derivatives, sugars and their derivatives and their mixtures;
= the solvent is chosen from ethanol, propylene glycol, alcohol cetyl alcohol benzyl, liquid polyethylene glycols, and mixtures thereof;
= the absorbent / gelling substance is chosen from stearic acid, its derivatives and salts;
= the aroma is chosen from essential oils, terpenic derivatives and their mixtures;
= the surfactant is chosen from glycol esters, acid esters fat and sorbitan, esters of polyoxyethylene fatty acids and of sorbitan; vegetable oils polyoxyethylenated, polyoxyethylenated hydrogenated vegetable oils; the Lecithin and its soya or egg derivatives; as well as their mixtures;
= the sweetener is chosen from aspartame; sodium saccharinate;
taumatin; the polyols; and their mixtures;
Date Received / Date Received 2020-11-13 = the antioxidant is chosen from ascorbic acid, its salts and its derivatives, metabisulfite sodium or potassium, sodium bisulfite, butylhydroxyanisol, butylhydroxytoluene, gallic acid and its derivatives; and their mixtures;
= the chelating agent is chosen from EDTA and its salts, the acid tartaric and its salts, and their mixtures;
= the flavor enhancer is sodium glutamate;
= the preservative is chosen from parabens, benzoic acid and its salts, the acid sorbic 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 its derivatives, carbonates sodium, delta glucono lactone; and their mixtures. 21. The method of claim 20, wherein the sugars and their derivatives are chosen from the molasses, carbomers, acrylic acid crosslinked with polyalkenyls ethers polycarbophils. 22. The method of claim 20, wherein the substance absorbent / gelling agent is chosen from glyceryl stearates, aluminum or magnesium stearates, oil castor hydrogenated, bentonite, derivatives of silica, cellulose and its derivatives, whey atomized, starches, and mixtures thereof. 23. The method of claim 22, wherein the cellulose derivatives are chosen from the methyl or ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethylcellulose. 24. The method of claim 22, wherein the silica derivatives are chosen from silica colloidal, precipitated silica, and fumed silica. 25. The method of claim 20, wherein the flavor is menthol. 26. The method of claim 20, wherein the surfactant is glycerol monostearate. 27. The method of claim 20, wherein the vegetable oils polyoxyethylenates are chosen from polyoxyethylenated castor oils. 28. The method of claim 20, wherein the hydrogenated vegetable oils polyoxyethylenated are chosen from polyoxyethylenated hydrogenated castor oils.
Date Received / Date Received 2020-11-13 29. The method of claim 20, wherein the lecithin and its derivatives soy or egg are chosen from phosphatidylcholine, hydrogenated phosphatidylcholine, lysophosphatidylcholine, and hydrogenated lysophosphatidylcholine. 30. The method of claim 20, wherein the polyols are chosen from sorbitol, xylitol, isomalt, maltitol, mannitol, and lactitol. 31. The method of claim 20, wherein the gallic acid derivatives are the gallate of propyl e. 32. A method according to any one of claims 1 to 31, wherein the one or more additives represent 0.01 to 25%, by weight of the composition relative to the total weight of the composition. 33. The method of claim 32, wherein the additive (s) represent 0.1 to 15% by weight of the composition relative to the total weight of the composition. 34. A method according to any one of claims 1 to 33, wherein the active substance is chosen from among anti-infectives, cardiotonics, antiparasitics internal and external, insecticides, insect growth inhibitors, anti-arthritis, anti-inflammatory drugs or not, antihistamines, hormones, substances digestive therapy, respiratory therapy substances, substances acting on the nervous system, immune therapy substances, therapy anticancer agents, macro-, micro- and trace elements, vitamins, plant extracts, extracts of animal organs, and mixtures thereof. 35. The method of claim 34, wherein the anti-infectives are chosen from antibiotics and sulfonamides. 36. The method of claim 34, wherein the hormones are selected from the prostaglandins. 37. The method of claim 34, wherein the therapy substances digestive are chosen among gastrointestinal dressings and sedatives, antiulcer drugs and substitution flora, anti-diarrheal drugs, hepato-protectors, antispasmodics, laxatives, and intestinal antiseptics.
Date Received / Date Received 2020-11-13 38. The method of claim 34, wherein the therapy substances respiratory are chosen from respiratory analeptics, cough suppressants, bronchial dilators, bronchial and mucolytic thinners, and respiratory antiseptics. 39. The method of claim 34, wherein the substances acting on the the nervous system are chosen from pain relievers, sedatives and tranquilizers, antiepileptics, anesthetics, orexigens, and anorectics. 40. The method of claim 34, wherein the therapy substances immune are chosen from interleukins and interferon. 41. The method of claim 34, wherein the therapy substances anticancer drugs are chosen from antimitotics and cytostatics. 42. A method according to any one of claims 1 to 33, wherein the composition includes an active drug substance chosen from antibiotics, pest control insecticides, cardiotonics, and anti-arthritis drugs. 43. The method of claim 42, wherein the antibiotics are chosen among amoxicillin, clavulanic acid, cephalexin, and rifaximin. 44. The method of claim 42, wherein the antiparasitics are chosen among ivermectin, moxidectin, milbemycin, pyrantel, and its derivatives. 45. The method of claim 44, wherein the derivatives of antiparasitics are chosen from pamoate, praziquantel, benzimidazoles, and their salts or derivatives. 46. The method of claim 42, wherein the insecticides are fampronil. 47. The method of claim 42, wherein the cardiotonics are the levosimendan. 48. The method of claim 42, wherein the anti-arthritis drugs are diacerein. 49. A method according to any one of claims 1 to 48, wherein the composition includes a nutraceutical active substance or food supplement chosen from among extracts from plants, animal extracts, substitution flora, macro-, micro-and trace elements, vitamins, and mixtures thereof.
Date Received / Date Received 2020-11-13 50. The method of claim 49, wherein the nutraceutical active substance or complement food is chosen from animal extracts for their anti-arthritis; for their anti-ulcer and / or anti-stress action fermented soybean extract; for their insecticidal action or insect repellent, vitamins, replacement flora Enterococcus faecium, and microelements. 51. The method of claim 50, wherein the animal extracts for their anti- action osteoarthritis are chosen from chondroitin sulfate, chitosan and its derivatives. 52. The method of claim 50, wherein the animal extracts for their anti-ulcer action and / or anti-stress are fermented soybean extract. 53. The method of claim 50, wherein the animal extracts for their insecticidal action or insect repellent are pyrethrums. 54. The method of claim 50, wherein the vitamins are selected from vitamin C and vitamin D3. 55. The method of claim 50, wherein the substitution flora are Enterococcus faecium. 56. The method of claim 50, wherein the microelements are selenium provided by a strain of Saccharomyces cerevisiae. 57. Solid appetizing composition, stable over time, obtained by process according to Claim 1, wherein the composition comprises:
To. 3 to 30% by weight of at least one fat, chosen from a body fat or wax, or a liquid oil, or a thickened liquid oil, or a mixture thereof;
liquid oil or the liquid oil base of thickened oil not being able to represent more than 8%
in weight of the composition, R. 0.001 to 57% by weight of at least one active substance, x. 40 to 96.999% by weight of at least one appetizing material, when the active substance is also an appetizing material, the content of the active substance may go up to 97% by weight, and the composition may comprise as a material appetizing this single active substance or a mixture of the active substance with at least one other appetizing material, O. optionally one or more additives, Date Received / Date Received 2020-11-13 a) the liquid oil is chosen from olive oil, peanut oil, rapeseed oil, sunflower, triglycerides of capric and caprylic acids, propylene glycol dicapric / dicaprylic acids, and mixtures thereof;
b) the fat is chosen from chicken fat, fat from duck, lard, tallow, butter, palm fat, palmitic stearin, margarine, Palm oil possibly hydrogenated, cetyl palmitate, coconut oil hydrogenated, the triglycerides of capric, caprylic, myristic and stearic acids, and their mixtures;
c) the wax is chosen from beeswax, carnauba wax, candelilla wax, and their mixtures;
d) the appetizing material is chosen from meat, flour meat, flour fish, cheese powders, milk derivatives, liver powder, extracts from these animal substances or their derivatives; beer yeast ; fibers vegetable; the plant products or by-products; sugar (sucrose) in all its forms, crystallized, powdered, iced, 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 more or less than 3% of the theoretical value of the required weight;
f) the solid appetizing composition is stable for more than one year when is kept at ambient temperature. 58. A composition according to claim 57, wherein the composition comprises 5 to 15%
in weight of said at least one fat. 59. A composition according to claim 57 or 58, wherein said at least one fat is in solid or waxy or pasty form. 60. A composition according to any one of claims 57 to 59, wherein when the substance active is also an appetizing ingredient, the content of active ingredient can go up to 85% by weight. 61. A composition according to any one of claims 57 to 60, wherein said one or more additives are chosen from fillers, binders, solvents, substances absorbents / gelling agents, flavors, surfactants, enhancers taste, sweeteners, Date Received / Date Received 2020-11-13 anti-oxidants, chelating agents, preservatives, dyes, and pH regulators. 62. A composition according to any one of claims 57 to 61, wherein the products or sub-plant products are chosen fenugreek, apple, carrot, fodder beet, the sugar beet, thyme, alfalfa, sugar cane, and grains. 63. A composition according to claim 62, wherein the cereals are chosen among oats, wheat, rice and mats, soybeans, derivatives thereof and mixtures thereof. 64. A composition according to claim 63, wherein the derivatives are flours. 65. A composition according to any one of claims 57 to 64, wherein the composition appetizing solid has a unit weight of more or less than 2% of the theoretical value of required weight 66. A solid appetizing composition according to any one of claims 57 to 65, which consists of:
a) at least one active drug substance chosen from among antibiotics antiparasitics, insecticides, cardiotonics, and anti-arthritis; a nutraceutical active substance or food supplement chosen from among excerpts animals for their anti-arthritic action, for their anti-ulcer action and / or anti-stress, or for their insecticidal action, vitamins, replacement flora, and micro-elements;
b) at least one fat chosen from chicken fat, duck fat, the lard, tallow, butter, palm fat, palmitic stearin, margarine, oil optionally hydrogenated palm, cetyl palmitate, walnut oil coco hydrogenated, and mixtures thereof; waxes chosen from beeswax, wax carnauba, candelilla wax, and mixtures thereof; oils chosen from olive oil, peanut oil, rapeseed oil, sunflower oil, triglycerides capric acids and caprylic and their derivatives; and their mixtures;
c) at least one appetizing material chosen from meat, flour of meat, fish meal, cheese powders, milk derivatives, liver, the gelatin, extracts of these animal substances or their derivatives; the yeast beer; the vegetable fibers; plant products or by-products; sugar (sucrose) Date Received / Date Received 2020-11-13 in all its forms, crystallized, powdered, iced, glucose, sugar invert, the molasses, honey and its derivatives, and mixtures thereof; salt (chloride of sodium); and their mixtures. 67. A solid appetizing composition according to claim 66, wherein the animal extracts for their anti-arthritic action are chosen from chondroitin sulfate, chitosan and its derivatives. 68. A solid appetizing composition according to claim 66, wherein the animal extracts for their anti-ulcer and / or anti-stress action is the fermented soy extract. 69. A solid appetizing composition according to claim 66, wherein the animal extracts for their insecticidal or insect repellent action are pyrethrums. 70. A solid appetizing composition according to claim 66, wherein the vitamins are chosen among vitamin C and vitamin D3. 71. A solid appetizing composition according to claim 66, wherein the substitution flora are Enterococcus faecium. 72. A solid appetizing composition according to claim 66, wherein the micro-elements are the selenium provided by a strain of Saccharomyces cerevisiae. 73. A solid appetizing composition according to claim 66, wherein the products or sub-plant products are chosen fenugreek, apple, carrot, fodder beet, the sugar beet, thyme, alfalfa, sugar cane, and grains. 74. A solid appetizing composition according to claim 73, wherein the cereals are chosen from oats, wheat, rice and mats, soybeans, derivatives thereof and their mixtures. 75. A solid appetizing composition according to claim 74, wherein the cereal derivatives are flours. 76. A solid appetizing composition according to claim 66, wherein the antibiotics are selected from amoxicillin, clavulanic acid, cephalexin, and rifaximin. 77. A solid appetizing composition according to claim 66, wherein the antiparasitics are selected from ivermectin, moxidectin, milbemycin, pyrantel, and its derivatives.
Date Received / Date Received 2020-11-13 78. A solid appetizing composition according to claim 66, wherein the derived from antiparasitics are chosen from pamoate, praziquantel, benzimidazoles, and their salts or their derivatives. 79. A solid appetizing composition according to claim 66, wherein the insecticides are the fam pronil. 80. A solid appetizing composition according to claim 66, wherein the cardiotonics are the levosimendan. 81. A solid appetizing composition according to claim 66, wherein the anti-arthritis are diacein.
Date Received / Date Received 2020-11-13