FR2963239A1 - SOLAR EFFERVESCENT GALENIC FORMS FOR ANIMALS - Google Patents

Abstract

The present invention relates to effervescent solid dosage forms, especially pebbles, for the collective treatment of animals through their drinking water. The effervescent solid galenic form according to the invention is based on an effervescent couple releasing carbon dioxide when it comes into contact with water, comprising at least one active substance or at least one active ingredient, a compression adjuvant , and at least one lubricating substance.

Description

The present invention relates to solid effervescent galenic forms for animals, providing supplements in terms of diet, health, comfort or well-being.

There are now several fairly common forms of distribution of supplements for animals, either in treatment or isolated supply, or collectively, which may be mentioned: - solutions in liquid form, for example vitamins, minerals, trace elements , presented in drums or bottles to be diluted or dissolved in drinking water; - powder forms: complementary foods, mineral or vitaminic foods, presented in bags, pots or buckets, to be dispersed in the food ration that must be distributed daily to the animals; - granular forms: to be incorporated and mixed with food; - stones and / or blocks to lick, based on vitamins, oligo and macro-elements. Even if these different forms of contribution are conventionally used today by the majority of the users, they present however many disadvantages: - they are most of the time impractical of employment, because sometimes heavy or bulky, and require operations transportation and handling; - they must be adapted to food rations to be distributed daily, hence the need to be mixed manually, then dispersed at the right dose of incorporation, and this homogeneously; - moreover, their incorporation and their mixing in the food rations are a source of potential error, this operation being sometimes carried out approximately by the breeders, who do not always respect the recommended doses; - their daily intake is not necessarily constant by the animal, in relation to its physiological needs: in breeding conditions in fact, the animals are 1

strongly influenced by group phenomena and / or dominant-dominated relationships. As regards pharmaceutical or para-pharmaceutical formulation, the effervescent galenic forms are very widely known, for example, vitamins in the form of effervescent tablets sold in tubes or in boxes, or analgesics, or corticosteroids, also presented in the form of tablets, possibly scored, effervescent. However, it would seem that such products have not been designed or adapted for use with community animals, especially farm animals, for example, so-called "cash" animals, or domesticated animals. Indeed, the difficulty in the preparation of such products seems to lie in the fact that the active substances or active principles that one wishes to integrate therein are in a form that makes them incompatible with a large scale distribution system or at large volumes for many animals simultaneously, controlled, and for which the necessary amounts of intake can be met in a reproducible and secure manner. The same problem does not arise for example in human treatments, since the dosages are calculated and administered individually, and the dosage forms correspond to this individual use. There is also the problem of the size and volume of the adapted galenic form. In fact, it is a matter of human therapy to have galenic forms comprising relatively low doses of active principle, which naturally limits it. the size and volume of the final dosage form. On the other hand, for collective animals, for example equidae or so-called "cash" animals, such as ruminants, or other intensive farm animals, such as pigs, rabbits, or poultry, the galenic form must be adapted to the mass not only of the animal, but also to the way in which are distributed and ingested by the animals in collective or raising the other foods or complements. The invention therefore relates more particularly to a new form, intended for collective use and in particular to animals in community, providing active substances or active principles, highly concentrated, such as nutritional supplements, dietary supplements, antibiotics, pro-biotics or pre-biotics, vitamins, plant solids and / or plant-derived active ingredients, and the like, which can be used safely, conveniently and effectively, based on a strong and effervescent dosage form. By "active plant derived" is meant here either 2

isolated phytochemical molecules or concentrated and purified fractions thereof having a recognized physiological activity. The form of delivery according to the invention consists in incorporating the active substances or active ingredients in concentrated form into an effervescent matrix presented for example in the form of a pebble to be dissolved in the drinking water of the animals in community or rearing. Preferably, the solid effervescent galenic form according to the invention has at least one, several or all of the following characteristics: a weight of the order of a few tens of grams, for example 15 g, at about 200 grams, depending the number and nature of the target animal, eg cattle, sheep, goats, pigs, poultry, fish, leporidae, rabbits, domestic animals such as cats and dogs; it is perfectly soluble in water at ambient temperature and very quickly dispersible in the drinking water, with effervescence and complete dissolution of the order of 5 minutes to a few tens of minutes at most, and preferably 30 minutes at maximum. For the pharmaceutical form of the invention to work, it must of course be effervescence in contact with the drinking water. Such an effect is generally obtained by an effervescence pair, which is a combination of an organic acid, generally a double functional carboxylic group, for example citric acid, and a base capable, on contacting with water, to release a gas such as carbon dioxide, for example a bicarbonate or a carbonate. These couples are generally known to those skilled in the art as effervescent tablets. The preferred effervescent couple of the solid dosage forms of the invention is the citric acid-sodium bicarbonate pair. The solid dosage form according to the invention comprises, with regard to the active ingredient or the active substance, preferably and advantageously: a mixture or a composition based on trace elements in the form of water-soluble or even water-dispersible salts, or in the form of amino acid chelates, preferentially glycinates, constituting intakes of highly bioavailable trace elements; 3

a mixture or a composition based on plant extracts, preferably in the form of dry extracts, of plant active principles, for example the fraction or the purified molecules, such as saponins, polyphenols, flavonoids, alkaloids, etc., which are water-soluble or water-dispersible; in the case where these plant extracts are rather liposoluble or of hydrophobic nature, it is preferred to make them water-dispersible by encapsulation or adsorption on a support such as cyclodextrins, gum arabic, silicas, maltodextrins, inulin, etc. before integration; one or a mixture of several essential oils, based on monoterpenes and sesquiterpenes and / or purified aromatic molecules, of natural origin or of synthesis, preferably adsorbed on a support, coated or encapsulated, so as to be rendered water-soluble or water dispersible; a mixture or a combination of several water-soluble plant extracts, or purified fractions or molecules, obtained using a suitable extraction solvent of high or medium polarity, such as water, alcohol, hydro-alcoholic or hydro-acetonic mixture low title; one or more "dry" extracts of plants of a lipophilic nature, acetone extracts or of lower polarity, or else obtained by extraction with supercritical CO2, or another apolar solvent, rendered dispersible in water after adsorption or encapsulation on a support; a mixture or a composition based on vitamins, or provitamines, or their salts, perfectly hydro-soluble, and / or liposoluble vitamins rendered water-dispersible in water after adsorption and / or encapsulation on a support prior to their incorporation into the effervescent solid dosage form; a mixture or a composition based on minerals, such as macro-elements containing calcium, potassium, magnesium and / or phosphorus, and more particularly calcium and magnesium pidolate; a mixture or a composition containing pre-biotics; a mixture or a composition comprising one or more pro-biotics; 4

a mixture or a composition containing active ingredients used in the case of curative treatments, such as antibiotic therapy; - a mixture, combination or combination of the substances and active ingredients indicated above.

The advantages of the solid dosage forms according to the invention are numerous, among which may be mentioned: rapid diffusion and dispersion of the various constituents, which are released homogeneously in the drinking water under the effect of the effervescence ; - Nutrients or concentrated active ingredients, inside the solid dosage form; thus, in the context of group treatments, it is possible with the solid dosage forms of the invention to collectively treat several animals simultaneously or herds; a dosage security corresponding to the needs of each animal of the different forms of nutrient or active ingredient intake, which are dissolved very rapidly in the drinking water: 100% of the animals drink according to their physiological needs, which ensures a particularly precise individualized contribution, according to the body weight of the animals; for example, a calf of 50 kg drinks less than a calf of 200 kg; in the same vein, a cow of 600 kg will drink less than a bull of 800 kg; it is also very light and compact, which avoids the problems of storage and handling; for an equivalent supply of micronutrients in the form of blocks to be licked, for example, the total weight to be stored is of the order of thirty times greater than the galenic forms according to the invention for the same number of animals; the gain in terms of management of storage and handling is obvious; - The solid dosage forms according to the invention release only little or no active substances in the environment: trace elements, for example, directly released under the effect of effervescence in the drinking water are perfectly water soluble or hydrodispersible, and therefore directly assimilable; 5

the active substances are protected by the matrix into which they are incorporated; this is particularly interesting in the case of unstable forms of active substances, which have a limited shelf life in liquid solution; this is particularly the case with vitamins, growth factors, probiotics, for example.

Preferably, if the active ingredient (s) are trace element salts, they are chosen to be substantially water-soluble or water-dispersible, of organic or mineral nature based on copper, zinc, iodine, cobalt, manganese, iron, selenium and molybdenum. Indeed, it has been found that the use of salts with reduced solubility in water tends to form precipitates once the dosage form comes into contact with water, leaving solid deposits at the end effervescence. It has also been found that the presence of such deposits, apart from the dry loss of active ingredient not ingested by the animal, also has a tendency to reduce the attraction of the animal for its drinking water. Examples of suitable trace elements include ferrous carbonate, ferrous chloride tetrahydrate, ferric chloride hexahydrate, ferrous citrate hexahydrate, ferrous fumarate, ferrous lactate tetrahydrate, ferrous sulfate monohydrate, ferrous sulfate heptahydrate, ferric acid chelate, hydrated, glycine iron chelate, hydrated, calcium iodate hexahydrate, anhydrous calcium iodate, sodium iodide, potassium iodide, cobalt acetate tetrahydrate, basic carbonate of cobalt monohydrate, cobalt carbonate hexahydrate, cobalt sulfate heptahydrate, cobalt sulfate monohydrate, cobalt nitrate hexahydrate, cupric acetate monohydrate, basic copper carbonate monohydrate, cupric chloride dihydrate , copper methionate, cupric sulfate pentahydrate, cuprous chelate of amino acids, hydrated, cuprous glycine chelate, hydrated e, the copper chelate of hydroxy-methionine analogue, manganous carbonate, manganous chloride tetrahydrate, manganese acid phosphate trihydrate, manganous sulfate tetrahydrate, manganous sulfate monohydrate, manganese chelate of amino acids, hydrated, manganese chelate of glycine, hydrated, manganese chelate of hydroxy-methionine analogue, zinc lactate trihydrate, zinc acetate dihydrate, zinc carbonate, zinc chloride monohydrate, sulfate of zinc heptahydrate, zinc sulphate monohydrate, zinc chelate of amino acids, hydrated, glycine zinc chelate, hydrated, zinc chelate of hydroxy-methionine analogue, ammonium molybdate, sodium molybdate, sodium selenite, sodium selenate, the organic form of selenium produced by saccharomyces cerevisiae, selenomethionine (selenium-inactivated yeast), and selenomethionine pro Saccharomyces cerevisiae (selenium-inactivated yeast). As regards the vitamins, these are preferably in the form of easily dispersible powders in water and can be mixed together, the vitamins are of water-soluble or fat-soluble nature, and in this case, for example, after encapsulation and /or

Adsorption on a suitable carrier or, for example, in the form of water-soluble salts. A non-exhaustive list of possible vitamins is indicated below, namely: vitamin A, vitamin D2 (ergocalciferol), 25-hydroxycalciferol, vitamin D3 (cholecaliferol), beta-carotene (pro-vitamin A), vitamin E, vitamin D, vitamin K, vitamin BI, for example in the form of thiamine hydrochloride and / or thiamine mononitrate, vitamin

B2, for example in the form of riboflavin and / or riboflavin phosphate - monosodium salt ester, vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6, for example in the form of pyridoxine hydrochloride, vitamin B12 in the form of cyanocobalamin, vitamin C in the form of L-ascorbic acid, sodium ascorbate, calcium ascorbate, palmityl-6-L-ascorbic acid - calcium salts, sodium ascorbylmonophosphate,

For example in the form of calcium D-pantothenate, or D-pantothenol, vitamin PP, for example in the form of nicotinic acid, niacin, and / or nicotinamideniacinamide, vitamin B9, for example in the form of folic acid, vitamin 112, B7 or BW, in the form of biotin, choline, for example in the form of choline chloride, choline dihydrogen citrate, choline bitartrate, inositol, carnitine, for example in the form of of the-

Carnitine, L-carnitine-L-tartrate, betaine, for example in the form of anhydrous betaine, betaine monohydrate, betaine hydrochloride, taurine, and the like. The expression "pre-biotic", when used in the context of the present invention, should be understood as meaning an oligosaccharide or a polysaccharide, which acts as a substrate for promoting the growth of certain bacteria of the colon (lactobacilli and

25 Bifidobacteria in particular). Oral Absorbed as a Nutritional Supplement in Foods or Food Supplements, Prebiotics are Not Digested in the System

digestive and through the intestines of livestock, but they pass directly into the colon where they play a targeted role, to promote only the beneficial bacteria of the intestinal flora. Pre-biotics can be found naturally in honey, fruits and vegetables, in

30 plants and cereals, and are extractable, an example of which is inulin. Others are commercially produced by hydrolysis of polysaccharides, for example fructooligosides or oligofructoses, or else synthesized by subjecting disaccharides such as lactose to the action of enzymes such as lactases with transferase activities to produce trans-galactooligosaccharides. or by a chemical isomerization reaction which gives lactulose. Currently, trans-galactooligosaccharides and fructans of inulin type are those whose prebiotic effects are recognized, and therefore particularly preferred over the invention. Another example which is also preferred relates to manno-oligosaccharides (MOS), of which MOS-500 is more particularly preferred. MOS-500 is a specific combination of mannooligosaccharides (MOS) and glucose (13-glucans) obtained by natural extraction of the yeast cell wall Saccharomyces cerevisiae. MOS-500 is the result of the autolysis of yeast cells at high temperature and controlled pH. After autolysis, the walls and yeast extracts are separated by centrifugation and dried. MOS are natural oligosaccharides, consisting of a repetition of mannose chains, capable of binding many specific pathogens to prevent their attachment to the walls of the digestive tract and block their colonization. 13-glucans, essential compounds of the cell wall of yeast, are particularly interesting for their ability to stimulate the non-specific immune system in animals. The expression "pro-biotic", when used in the context of the present invention, means living microorganisms, bacteria or yeasts, naturally present in the body, especially in the intestinal flora. Their absorption - orally, in the form of food supplements or directly in food, stimulates the growth of bacteria useful to exert a beneficial effect on health. They contribute to the digestion of fibers, strengthen the immune system, act against diarrhea, atopic eczema, stomach ulcer, etc. Among the preferred pro-biotics, mention may be made of various strains of Saccharomyces cerevisiae, Bacillus cereus var toyoi, Bacillus subtilis alone or in combination with Bacillus licheniformis, or strains of Enterococciaccium. These microorganism strains are generally encapsulated, dispersed and / or adsorbed on a solid support, for example calcium carbonate, dextrose or sorbitol. When the effervescent solid dosage form is intended to be administered in the drinking water of dogs or cats, or other domestic animals, it may be advantageous to add to the formulation one or more palatability factors. In general, the flavors used are of the beef, roast meat, or grilled chicken, ham or umami flavor, or fish or pepper type. They may be incorporated preferentially at concentrations ranging from 0.5% up to 5% relative to the total weight of the solid dosage form according to the invention, in order to

to release an olfactory and gustatory power perceptible by the animal, once the solid form dissolves in the drinking water. These palatability factors are available in water-soluble form, either in hydrodispersible form, for example adsorbed on maltodextrin support, or silica support, or encapsulated in gum arabic or inulin.

Other active ingredients or ingredients are preferably incorporated into the galenic forms of the invention, these include: - proteins and / or water-soluble concentrates of powdered milk proteins, derived from the crackinng of milk such as: colostrum freeze-dried powder or atomized, whey powder, purified or enriched fractions of IgG, lactoferrin, lactoperoxidase; plant or animal enzymes, for example, promutase (SOD), 3-phytase, 6-phytase, endo-1,4-betaglucanases, endo-1,4-betaxylanases, or other enzymes improving or promoting the digestion of the animal; amino acids and peptides, for example L-carnitine, more particularly in its dipeptide form, or other water-soluble peptides of molecular weight greater than a dipeptide; sugars, in particular water-soluble polysaccharides and lower molecular weight sugars, of which the oligosaccharides, mono- or disaccharides such as glucose, lactose, dextrose, used for an energy supply in the form of simple sugars which are rapidly assimilable, also sugars called "slow"; one or more molecules for therapeutic purposes, such as antibacterials, antiparasitics, antihelminthics, including cestocides, nematocides, fasciolicides; tenicides, anti-coccidials and anti-cryptosporidials, antiparamphistomas, anti-protozoa, anti-mycotic agents, especially against actinomycosis and candidiasis; anti-inflammatory, anti-allergic and immunomodulatory agents; central analgesics, and antihistamines; in the field of digestive and hepatology, anti-ulcer and anti-emetic, anti-diarrheal and antispasmodic, digestive enzymes and flora, laxatives, purgatives, meteorifuge and excitants of ruminal motility, modifiers and regulators of liver function digestive regulators of rumination; in the field of cardiology and angiology, vasodilators, 9

active principles for vascular purposes; in the field of the immune system, active ingredients used in immunotherapy; in the supply of immunoglobulin, interferon, and immunomodulators; in the field of metabolism or nutrition: intake of anabolic, anti-anemic, anti-ketotic, oral rehydration agents; in the field of metabolism, the intake of calcium, magnesium, and phosphorus; in the field of lipotropic factors and liver and kidney disease: intake of vitamins and trace elements; intake of active ingredients used in hormonology, endocrinology reproduction: fertility hormones, anti-hyperthyrroid, antigalactogens, abortives, hormone inhibitors; in the field of muscles and the musculoskeletal system: provision of anti-rheumatic, anti-arthritic, muscle and musculoskeletal stimulants, anti-myopathic molecules; in the field of the respiratory system: supply of respiratory analeptics, bronchodilators, mucoregulators and expectorants, antitussives, anti-infectives; in the field of the urinary system: intake of diuretics, urinary acidifiers, urinary antispasmodics; in the field of the neurological system: supply of general anesthetics, analgesics, anticonvulsants, sedatives and tranquilizers, etc. Furthermore, flavor enhancers, for example sodium glutamate, or intense sweeteners such as Sucram N3D (available from the company Pancosma), may be added to the galenic forms according to the present invention, in order to enhance the attractiveness of the product, or possibly mask a bitter taste, thanks to a sweetening power equivalent to 250 times that of sucrose. When the solid dosage form is a pebble, the applicant has discovered that it is problematic to obtain an effervescent pebble weighing several tens of grams by direct compression, this size is not usual in the compression of powders. However, given the water sensitivity of the effervescent couple, direct compression was considered the only possible route. This has therefore required the resolution of adverse phenomena, such as dechaping, called "capping" in English, which results in giving a dosage form which in its upper part is not stabilized and consistent with the rest of the mass , which makes the shape difficult to use and transportable and very friable. Moreover, the applicant has been forced to integrate at least one substance having an effect 10

lubricant, in particular to facilitate the integration of the various components in the form of powder so as to obtain a premix that can flow more easily into the filling hopper of the compression mold. In the absence of incorporation of lubricant in the dosage forms according to the invention, the applicant has observed adverse phenomena of adhesion and sticking to the punches of the compression matrix, especially during the ejection of the dosage form. Preferably, the substance having a lubricating effect is chosen from lubricating substances in solid form, in particular hydrogenated vegetable oils in particulate form, for example hydrogenated soybean oil or hydrogenated cottonseed oil, or the other hydrogenated oils. such as castor oil, etc., or else leucine. Leucine also has the advantage of allowing the production of solid effervescent dosage forms according to the invention which do not form a foam on the surface when brought into contact with water, and which also does not cause the formation of water. retardation effect on the release of the active ingredients, unlike the presence of fatty substances in the composition, which rather have a hydrophobic effect and which therefore tend to limit the entry of water into the matrix of the galenic form. It is thus more particularly preferred that the percentage of the substance having a lubricating effect is equal to or less than 5%. An example of a lubricant known in compression is magnesium stearate. The Applicant has found, however, that it is not possible, with the amounts of magnesium stearate conventionally used as a lubricant in the compression of tablets from dry powders, to arrive at satisfactory finished products.

On the contrary, it has been discovered that too much magnesium stearate can seriously slow the effervescence. Thus, if it is used in the galenic forms of the invention, the percentage by weight of magnesium stearate is less than or equal to 1.5% relative to the total weight of the galenic form according to the invention. The Applicant tested several compression aids during the production of effervescent solid dosage forms according to the invention and discovered that among all those tested, it was preferable to use hydrated dextrates, otherwise known as crystalline dextrose, comprising in very small quantities starch oligosaccharides (for example sold under the name of Emdex), or else compression lactoses (for example sold under the name Flowlac 100, Pharmatose DCL 11 or Lactopress spray dried). Although the Applicant has also tested compressive sorbitols, of the type sold under the name Neosorb, the latter have proved unsatisfactory because they have a tendency to take up water over time once the galenic form is manufactured. 11

In general, the dosage forms according to the invention preferably have a density greater than 1 kg / m 3, otherwise they tend to remain on the surface, which lengthens the dissolution time and does not promote disintegration and homogeneous dispersion of the active ingredients in drinking water.

The present invention will be better understood with reference to the following exemplary embodiments, given for information only. Example 1 Effervescent roller for rearing large ruminants, in particular cattle or other, containing in its composition a mixture of several trace elements in the form of glycine chelates The roller of this example has the following composition: Components Weight% Comments DEXTRATE (EMDEX ) 13 COMPRESSION LACTOSE (FLOWLAC 13 or PHARMATOSE DC) SODIUM BICARBONATE 27% 20.56 HYDROGENATED COTTON 2 VEGETABLE OIL (LUBRITAB) CITRIC ACID ANHYDROUS 8 COBALT ACETATE TETRAHYDRATE 1.6 Micronutrient Salt 23.5% GLYCINE COPPER CHELATE 21% 7.5 Oligonine Glycine Chlorate (PANCOSMA) Element CALCIUM IODATE ANHYDROUS 0.95 Trace Mineral Salt 12 Components Weight% Comments GLYCINE MANGANESE CHELATE 11.5 Glycine Chelate of oligo- 21% (PANCOSMA) element SELENITE OF SODIUM 45% 0.14 Salt of micronutrient CHELATE OF GLYCINE ZINC 22% 21.75 Chelate of Glycine of oligo- (PANCOSMA) element TOTAL 100 The pebble is formed by compression in a matrix different ingredients mixed beforehand. The sparkling pebble weighs about 100 g and has a spherical shape, like hockey puck. It has a diameter of 65.4 mm, and a thickness of about 20 mm depending on the compression force applied. The complete dissolution by the effervescence of the pebble lasts on average 10 to 15 min maximum. The pebble described above can be used in dairy or lactating cattle in curative treatment during periods of drought, reproduction, end of pregnancy, or poor quality forage, for a course of 5 days. Moreover, it can be used for maintenance, for a course of 5 days, with 2 to 3 courses spread over the period of grazing or distribution once a week for 9 to 10 weeks, then renewed 3 months later. Finally, it can also be used in case of collapsed blood status, for a course of 5 days. In each of the cases of use specified above, the roller is dissolved in 10 liters of water, of which 6 liters will be taken, then poured back into 300 liters of drinking water, which represents a sufficient quantity for 8 liters of water. 10 dairy cows, or 12 to 15 suckler cows. In order to verify the effectiveness of the roller according to the invention, a comparative test was carried out with a control roller, of the following composition: 13 Components Weight% Comments DEXTRATE (EMDEX) 13 LACTOSE OF COMPRESSION 13 (FLOWLAC or PHARMATOSE DC) BICARBONATE SODIUM 27% 51.47 HYDROGENATED COTTON 2 VEGETABLE OIL (LUBRITAB) BLUE COLOR 0.2 Placébo CITRIC ACID ANHYDROUS 20.33 TOTAL 100 The test was conducted in a herd of two groups of 12 Limousin suckling heifers, all of good health before starting the test. Heifers were 17 to 24 months old and weighed between about 360 kg to 440 kg (visual approximation). The cows fed a diet consisting of grass silage, hay, straw, cereal concentrates, and grape and prune dries, but had no access to any source of trace elements, for example. example, lick stone. The drinking water was distributed for the purpose of the test in galvanized tanks of 500 liters, the tanks having been filled with 300 liters of water per day. Daily water consumption was 300 liters. A roller was dissolved in 10 liters of water, of which 6 liters were taken and mixed with the 300 liters of the tank. This administration has been repeated for five continuous days since the date of departure of the trial. Blood was taken in the morning on three occasions, (a) at the beginning of the test, (b) one month later, and then (c) four months after the start of the test. Blood samples were analyzed for their contents of copper, zinc, selenium, and iodine. The results of the various analyzes carried out indicated a significant increase in blood levels of copper, zinc, selenium and iodine in the cows which received the roller according to the invention in their drinking water compared to the control wheel. 14

EXAMPLE 2 Effervescent Pebbles for Pig Farming Containing in Their Composition a Mixture of One or More Vegetable Active Ingredients Having Nutritional and / or Functional Properties This roller incorporates vegetable matter, in the form of a hydrodispersible dry powder. This powder is a mixture of carvacrol (5%) and cinnamaldehyde (3%), which are terpenes of identical nature, plus 2% oleoresin capsicum, which is a standardized plant extract capsaicin, all adsorbed on a support of gum arabic type, in order to render the active ingredients water-dispersible, and sold by the company Pancosma under the name XTRACT Instant.

Ingredients Weight% Comments VEGETABLE EXTRACT "Xtract 20% Mixture of nature identical terpenes Instant" (PANCOSMA) (carvacrol 5% + Cinnamaldehyde 3%) with 2% oleoresin capsicum (standardized and titrated in capsaicin) VEGETABLE OIL OF COTTON 2, 00% HYDROGENEE (LUBRITAB) SODIUM BICARBONATE 27% 38% CITRIC ACID ANHYDROUS 15% LACTOSE 25% COMPRESSION (FLOWLAC or PHARMATOSE DC) / DEXTRATE (EMDEX) (50/50) TOTAL 100 The pebble produced according to this composition has a color orange peach / apricot, a weight of about 100 g, a diameter of 65.4 mm and a thickness of about 22 mm. The duration of the effervescence after the launch is 6 minutes and 30 seconds. Pebbles produced according to 15

this composition can be used with pigs and piglets, in instant supply of 20 or 40 g of active substances "XTRACT Instant", to stimulate the appetite and the improvement of the average daily gain (GMQ), for the fattening and finishing. The dosage is 1 to 2 rolls per day to dissolve in 1000 liters of water. Another possible use is with poultry, in instant supply of 40 or 60 g of active substances "XTRACT Instant", to stimulate the appetite, the food intake and the gain of weight, with 2 to 3 pebbles per day to dissolve in 1000 liters of water. EXAMPLE 3 Effervescent pebbles for rearing large ruminants, in particular cattle or the like, containing fat-soluble vitamins rendered water-soluble by encapsulation or adsorption on a support This roller, weighing 100 g, is to be diluted in 1000 liters of water for 10 adult cows ( Approximately 650 kg each). Once put in the water, the pebble rises to the surface after 15 minutes of effervescence, and finally dissolves totally in water after 21 minutes. Ingredients Weight% Comments CITRIC ACID ANHYDROUS 13.8 Beta CAROTENE 20% WD 15 Liposoluble provitamin made water-soluble by encapsulation or adsorption on a support SODIUM BICARBONATE 27% 27.4 DEXTRATE (EMDEX) 26 L LEUCINE 5 (Excipient: Lubricant) VIT A ACETATE POWDER WS 8 Fat soluble vitamin rendering 500 000 IU / g water-soluble by encapsulation or adsorption on a carrier VIT D3 POWDER WS: 500 000 IU / g 0.8 as VIT E POWDER WS 4 idem (Alphatocopheryl acetate) 50% TOTAL 100 16 Example 4: Effervescent pebbles for pig breeding containing a probiotic and a pre-biotic This roller is intended for 30 pigs of 50kg each. The roller weighs 100g and is dissolved in 100 liters of water. Once put in the water, the pebble rises to the surface after 17 minutes and 30 seconds of effervescence, and finally dissolves completely in the water after 19 minutes. Ingredients Weight% Comments CITRIC ACID ANHYDROUS 8.15 SODIUM BICARBONATE 27% 19.85 BIOPLUS 2B Support Sorbitol 4 X 7.5 Pro-biotic consisting of a mixture of B. subtilis and licheniformis DEXTRATE (EMDEX) 25.5 FRUCTOLINE 35 Pre-biotic (fructo-oligosaccharides derived from chicory inulin) L-LEUCINE 4 (Excipient: Lubricant) TOTAL 100 Example 5: Effervescent pebbles for pig breeding containing vitamins and amino acids 10 A 120g roller intended for 300 pigs 50kg each, dissolve in 1000 liters of water. Once put in the water, the pebble rises to the surface after 11 minutes and 45 seconds, and finally dissolves completely in the water after 13 minutes in total. Components Weight% Comments CITRIC ACID ANHYDROUS 17 SODIUM BICARBONATE 41.5 27% CHOLINE CHLORIDE 75% 0.11 Water-soluble Vitamin DEXTRATE (EMDEX) 30 L CARNITINE 99% 0.3 Peptide L LEUCINE 5 (Excipient: Lubricant) LYSINE HC178% 0 , 21 Amino acid METHIONINE DL FEED 0.32 Amino acid GRADE: 99% VITAACETATE POWDER WS 1.62 Fat-soluble vitamin rendered 500 000 IU / g water-soluble by encapsulation or adsorption on a support 17 Components Weight% Comments VIT B 1 THIAMINE 98% 0, 11 Water-soluble vitamin VIT B 2 RIBOFLAVIN 80% 0.26 ditto (Dextrin) VIT B 5 (PANTOTHENENATE Ca) 0.31 ditto 100% VIT B 6 PYRIDOXIN 0.08 ditto (Hydrochloride) 100% VIT B 9 AC FOLIC 96% 0 , 11 idem VIT C: A. Ascorbic 100% 1.02 ditto VIT D3 POWDER WS: 500 000 0.32 Fat-soluble fat rendered water-soluble IU / g by encapsulation or adsorption on carrier VIT E POWDER WS 1.21 ditto (Alphatocopheryl Acetate) 50% VIT H2 BIOTINE 2% 0.1 Water-soluble vitamin VIT K3 MSB (MENADIONE 0.41 fat soluble vitamin BI SULPHITE) 50% water-soluble TOTAL 100 Example 6: Effervescent pebble for poultry breeding containing amino acids and vitamins A 120g pebble is intended for 4000 hens of 3kg each, to dissolve in 1000 liters of water.

5 This pebble rises to the surface after 12 minutes of effervescence, and then is completely dissolved after 14 minutes in total. Ingredients Weight% Comments CITRIC ACID ANHYDROUS 15.83 SODIUM BICARBONATE 27% 38.5 CHOLINE CHLORIDE 75% 0.27 Water-soluble vitamin DEXTRATE (EMDEX) 30 L-LEUCINE 5 (Excipient: Lubricant) LYSINE HC178% 0.39 Amino acid METHIONINE DL FEED GRADE: 99% 0.46 Amino Acid VITAACETATE POWDER WS 500 2 Fat-soluble Vitamin rendered 000UI / g water-soluble by encapsulation or adsorption on support VIT B 1 THIAMINE 98% 0.37 Water-soluble Vitamin 18 Components Weight% Comments VIT B 2 RIBOFLAVINE 80 % (Dextrin) 0.13 ditto VIT B 3 or PP NIACIN 100% 0.75 ditto VIT B 5 (PANTOTHENENATE Ca) 0.62 ditto 100% VIT B 6 PYRIDOXIN (Hydrochloride) 0.15 ditto 100% VIT B 9 AC FOLIC 96% 0.11 idem VIT C: A. Ascorbic 100% 2.53 ditto VIT D3 POWDER WS: 500 000 IU / g 0.2 Fat-soluble vitamin made water-soluble by encapsulation or adsorption on a support VIT E POWDER WS (Alphatocophéryl 2 idem Acetate) 50% VIT K3 MSB (MENADIONE 0.7 Fat-soluble vitamin made BISULFITE) 50% water-soluble TOTAL 100 Exemplary e 7: Effervescent pebbles for raising poultry containing chelates of trace elements (glycinates) A 100g pebble intended for 1000 hens of 3kg each, to dissolve in 1000 liters of water. This roller has a total duration of effervescence of 12 minutes. Ingredients Weight% Comments CITRIC ACID ANHYDROUS 8 SODIUM BICARBONATE 27% 16 COBALT CARBONATE MONOHYDRATE 52% 0.88 Micronutrient salt CHYCINATE CHELATE CU 24% (PANCOSMA) 4.2. Trace Glycine Chelate 18% GLYCINE CHELATE 18% 15 ditto (PANCOSMA) Mn 22% GLYCINE CHELATE (PANCOSMA) 16.4 ditty GLYCINE CHELATE Zn 26% (PANCOSMA) 13.9 ditto DEXTRATE ( EMDEX) 19.19 CALCIUM IODATE ANHYDROUS 64% 0.94 Micronutrient Salt L LEUCINE 5 (Excipient: Lubricant) SELENITE SODIUM 45% OIL 0.45 Micronutrient Salt 19 Components Weight% Comments SUCRAM N3D ( PANCOSMA) 0.04 Sweetener TOTAL 100 Example 8: Effervescent pebbles for poultry breeding containing micronutrient salts Two rolls of 70g each to dissolve in 1000 liters of water, intended for 4000 hens of 3kg each. Once put in the water, the roller finishes to dissolve after 9 minutes. Components Weight% Comments COPPER ACETATE MONOHYDRATE 3.9 Micronutrient Salt 31% ZINC ACETATE ANHYDROUS 35.5% 12.4 Micronutrient Salt CITRIC ACID ANHYDROUS 8 SODIUM BICARBONATE 27% 16 COBALT CARBONATE 0.32 Trace Mineral Salt MONOHYDRATE 52% IRON CHLORIDE TETRAHYDRATE 14.26 Elemental Salt EMDEX (DEXTRATE) 25.16 CALCIUM IODATE ANHYDROUS 64% 0.76 Trace Elemental Salt L-LEUCINE 5 (Excipient : Lubricant) SELENITE SODIUM ANHYDROUS 45% 0.37 SUCRAM N3D (PANCOSMA) trace element classic salt 0.04 SULFATE MANGANESE sweetener 13.8 Micronutrient salt MONOHYDRATE 32% TOTAL 100 Example 9: Effervescent pebbles for breeding Antibiotic swine This roller has a weight of 75g, a diameter of 65.3 mm, and a thickness of 18.23 mm, and is intended to be dissolved in 150 to 190 liters of water for pigs of 50kg each. The time of effervescence, with a rise of the surface roller at 6 minutes and 16 seconds, is 8 minutes and 30 seconds in total.

20 10 Components Weight% Comments CITRIC ACID ANHYDROUS 11.67 AMOXICILLIN 50% 40 Antibiotic SODIUM BICARBONATE 27% 23.33 DEXTRATE (EMDEX) 20 L-LEUCINE 5 (Excipient: Lubricant) TOTAL 100- Example 10: Anti-stress effervescent pebbles The pebble has a weight of 100g, and is intended for 100 rabbits, to dissolve in 10 liters of water. Once put in the water, it rises to the surface after 21 minutes and 30 seconds of effervescence, and the total dissolution is complete at 25 minutes and 30 seconds. Ingredients Weight% - Comments CITRIC ACID ANHYDROUS 13.83 SODIUM BICARBONATE 27% 27.66 EMDEX (DEXTRATE) 16 YUCCA DRY EXTRACT 29% 5 Saponins 29% L-LEUCINE 5 (Excipient: Lubricant) OPC OF GRAPEFRUIT 1, Procyanidolic Oligomers (Polyphenols) PROMUTASE Purified Enzyme (SOD) Extracted from Melon SELENITE SODIUM ANHYDROUS 0.002 Trace Elemental Salt STEVIOSIDE 90% Terpene Heteroside (C15) VIT E POWDER WS (Alphatocopheryl 1 Fat-soluble Vitamin Reactive Acetate) 50% water soluble by encapsulation or adsorption on a substrate TOTAL 100 21 Example 11: Multi-trace elements and multi-vitamins effervescent pebbles for breeding dogs Components Weight% Comments COPPER ACETATE MONOHYDRATE 0.22 Trace element salt 31% ACETATE ZINC ANHYDROUS 35.5 % 2,83 ditto CITRIC ACID ANHYDROUS 17,2 SODIUM BICARBONATE 27% 34,39 IRON GLYCINE CHELATE 21% 1,59 Micronutrient Glycine Chelate (PANCOSMA) EMDEX (DEXTRATE) 19,497 CALCIUM IODATE ANHYDROUS 64 % 0.02 L-LEUCINE Micronutrient Salt 3.33 (Excipient: Lubricant) SERIGEL LP 5.07 Protein Concentrate from Whey SELENITE ANHYDROUS SODIUM 45% 0.01 SUCRAM N3D Micronutrient Salt (PANCOSMA ) 4 Sweetener SULFATE MANGANESE MONOHY- 0.31 Micronutrient salt DRATE 32% VIT AACETATE POWDER WS 500 000 0.03 Fat-soluble vitamin made hy-IU / g soluble by encapsulation or adsorption on carrier VIT B 1 THIAMINE 98% 0 , 07 Water-soluble Vitamin VIT B 2 RIBOFLAVIN 80% (Dextrin) 0.09 same VIT B 3 or PP NIACIN 100% 1.01 same VIT B 5 (PANTOTHENENATE Ca) 100% 0.34 same VIT B 6 PYRIDOXIN (Hydrochloride) 0 , 04 same 100% VIT B 9 AC FOLIC 96% 0.01 same VIT B12 CYANOCOBALIN (PREMIX 1.73 same 1/1000) VIT C: A. Ascorbic 100% 3.37 same 22 Components Weight% Comments VIT D3 POWDER WS : 500 000 IU / g 0.003 Fat-soluble vitamin made water-soluble by encapsulation or adsorption on a support VIT E POWDER WS (Alphatocopheryl Ac-2.67 idemate) 50% - VIT H2 BIOTIN 2% 1.67 Vitam water soluble iPEAT FACTOR 0.5 Flavor encapsulated or adsorbed on powder carrier TOTAL 100 This formulation is intended for breeding dogs to promote their vitality as well as harmonious growth and good recovery after exercise. For small dogs, and medium size, the effervescent pebbles range from 15g to 55g and are spherical in shape, with the appearance of a curved disc surface, about 40 mm in diameter, or otherwise for dogs large, the pebbles are hockey puck type from 65g to 110g, about 60 mm in diameter. The duration of effervescence, whatever the size of the roller, is between 10 and 25 minutes maximum, depending on the compression force applied during manufacture. Matrix Weight of the pebble (g) Target species Time of ascent time (mm: ss) total dissolution (mm: ss) Matrix A -diam. 15.2 g Pinscher 12:36 15:10 40 mm Disk - spherical with curved ends Matrix A 25.2 g Cocker English 8:00 11:50 Matrix B - diam. 66.5 g Saint Bernard 7:35 12:10 60 mm Puck of male and female hockey with flat surfaces Matrix B 94.9 g Saint Bernard 16:00 22:40 female 2310 Matrix Weight of the pebble (g) Target species Time of Recovery time (mm: ss) total dissolution (mm: ss) Matrix B 110.4 g Saint Bernard 20:22 25:00 male Once the tablets are dissolved in water, the resulting solution is translucent yellow, with no deposits. The pebbles are preferably administered according to the following dosage indicated in the table below: The pebbles are to be dissolved in the drinking water, considering that a dog drinks: 50 to 70 ml of water / day / kg of weight lively, in case of normal activity; Up to 100 ml / day / kg body weight, in case of strong heat or after intense exercise. The table below summarizes the preferred dosing regimens: Adult Dog Body Weight Nb of tablets / day to administer Pinscher 4 to 6 Kg 1 15g roller (matrix A), to dissolve in 2 to 4 L of water for 10 Animals Cocker 12,5 to 14,5 Kg 2 to 3 rollers of 25 g (matrix A) for 10 animals to distribute English on the day, a roller is to dissolve in 3 L to 5L of water. Setter 27 to 32 Kg 4 to 5 rollers of 25 g (matrix A) for 10 animals to be distributed over the day, a roller is to dissolve in 3.25 L to 5 L of water; or otherwise a roller of 95 g per day (matrix B), for animals, to dissolve in one single time in 15 L to 20 L of water 24 Dog Adult Weight Body Nb of tablets / day to administer Berger 22 to 32 Kg 3 to 4 rollers of 25 g (matrix A), for 10 animals, to be spread over the day, a roller is to dissolve in 2.5 L to (female) 5L of water; otherwise 1 roller of 95 g (matrix B) for 10 animals, to dissolve at once in 10 'to 20 L of water. Shepherd 30 to 40 Kg 4 to 5 rollers of 25 g (matrix A) for 10 animals, to be distributed in the German day, a roller is to dissolve in 3.75 L to 5 L (male) of water; otherwise 1 roller of 110 g (matrix B) for 10 animals, to dissolve at once in 15 L to 20 L of water. St. 51 to 72 Kg 2 to 3 rollers of 66.5 g (matrix B) for 10 animals, to Bernard spread over the day, a roller is to dissolve in 10 L to (female) 20 L of water; if not 2 rollers of 95g or 110g per day (matrix B) for 10 animals, a roller is to dissolve in 15 L to 20 L of water. Saint-55 to 80 Kg 3 to 4 rollers of 66,5g per day for 10 animals (matrix B) Bernard to distribute during the day, a roller is to dissolve in 10 L (male) to 20 L of water; otherwise 2 rollers of 95g or 110 g (matrix B) for 10 animals, to be distributed during the day, morning and evening, a roller is to dissolve in 15 L to 20 L of water. 25

Claims (20)

1) effervescent solid dosage form based on an effervescent couple releasing carbon dioxide when it comes into contact with water, comprising at least one active substance or at least one active ingredient, a compression adjuvant, and at least one a substance with a lubricating effect. 2) effervescent solid dosage form according to claim 1, which has a weight ranging from a few tens of grams to about 200 grams. 3) Effervescent solid dosage form according to any one of the preceding claims, which is adapted in size and weight for administration to one or more animals selected from the group consisting of cattle, sheep, goats, poultry, poultry, sheep and goats. pigs, sows, piglets, fish, leporids, equines, and domestic animals such as cats and dogs. 4) Effervescent solid dosage form according to any one of the preceding claims, which is perfectly soluble and very rapidly dispersible in drinking water, with effervescence and complete dissolution of the order of 5 min to a few tens of minutes maximum . 5) Effervescent solid dosage form according to any one of the preceding claims, which is in the form of a pebble dissolving in water. 6) Effervescent solid dosage form according to any one of the preceding claims, wherein the active ingredient is a mixture or a composition based on trace elements in the form of water-soluble or water-dispersible salts, of organic or inorganic nature based on copper , zinc, iodine, cobalt, manganese, iron, selenium and molybdenum. 7) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is a mixture or a composition based on trace elements in the form of amino acid chelates, preferably chelates of glycine. 8) effervescent solid dosage form according to any one of claims 1 to 5 26 preceding, wherein the active ingredient is a mixture or a composition based on organic selenium, including selenomethionine and / or selenocysteine. 9) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is a mixture or a composition based on plant extracts, preferably in the form of dry extract, plant active ingredients, for example, the fraction or the purified molecules, such as saponins, polyphenols, flavonoids, alkaloids, whether the latter are water-soluble or water-dispersible in nature, or else liposoluble rendered water-dispersible by encapsulation or adsorption on a support such as cyclodextrins, gum arabic, maltodextrins, silicas or inulin. 10) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is one or more essential oils, based on monoterpenes and sesquiterpenes, or purified aromatic molecules, of natural origin or of synthesis, adsorbed on a support, coated or encapsulated, so as to be rendered water-soluble or water-dispersible. 11) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is one or more water-soluble solids solids, for example a purified fraction or molecule, water-soluble nature, obtained at the using a suitable extraction solvent of high or medium polarity, such as water, alcohol, hydroalcoholic or hydro-acetonic mixture of low titre. 12) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is one or more "dry" extracts of lipophilic nature, acetone extracts or lower polarity, or obtained by supercritical CO2 extraction or another apolar solvent, rendered dispersible in water after adsorption or encapsulation on a support. 13) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is one or more vitamins or provitamins, preferably in the form of powder, perfectly water soluble, or fat-soluble vitamins rendered water-dispersible in water after adsorption and / or encapsulation on a support. 14) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is one or more water-soluble vitamins, including vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), 5 vitamin B5 (pantothenic acid), vitamin B6, vitamin B8 (biotin), vitamin B9 (folic acid), vitamin B12 (cobalamin), vitamin C, choline, taurine and betaine. 15) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is one or more liposoluble vitamins rendered water-dispersible, including encapsulated vitamin E, encapsulated vitamin A, encapsulated pro-vitamin A (beta-carotene), vitamin D, and vitamin K. 16) Effervescent solid dosage form according to any one of the preceding claims 1 to 5, wherein the active ingredient is a mixture or a composition based on minerals, such as macro-elements containing calcium, potassium, magnesium. and / or phosphorus, and more particularly calcium and magnesium pidolate. 17) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is a mixture or a composition comprising one or more prebiotics. 20 18) effervescent solid dosage form according to any one of claims 1 to 5 above, wherein the active ingredient is a mixture or a composition comprising one or more pro-biotics. 19) effervescent solid dosage form according to any one of the preceding claims 1 to 5, wherein the active ingredient is a mixture or a composition containing active ingredients used in the case of curative treatment, such as antibiotic therapy. 20) effervescent solid dosage form according to any one of claims 1 to 19 above, wherein the active ingredient is a mixture, combination or combination of the active substances and principles mentioned in claims 6 to 19. 28) Solid dosage form effervescent fluid according to any one of the preceding claims, wherein the lubricating substance is selected from magnesium stearate, hydrogenated vegetable oils and L-Leucine. 22) Effervescent solid dosage form according to any one of the preceding claims, wherein the lubricant is a hydrogenated vegetable oil in particulate form, of cotton, soybean, palm, or castor, the percentage by weight relative to the weight total is equal to or less than 5%. 23) effervescent solid dosage form according to any one of the preceding claims, wherein the lubricant is magnesium stearate whose percentage by weight relative to the total weight is equal to or less than 1.5%. 24) effervescent solid dosage form according to any one of the preceding claims, wherein the lubricant is L-Leucine, the percentage by weight relative to the total weight is equal to or less than 5%. 25) effervescent solid dosage form according to any one of the preceding claims, wherein the compression aid is selected from compression lactose and crystallized dextrose (dextrates). 26) effervescent solid dosage form according to any one of the preceding claims, wherein the active ingredient is one or more molecules for therapeutic purposes. 27) effervescent solid dosage form according to any one of the preceding claims, which has a density greater than 1 kg / m3. 29