WO2012017363A1

WO2012017363A1 - Effervescent solid galenic forms for animals

Info

Publication number: WO2012017363A1
Application number: PCT/IB2011/053376
Authority: WO
Inventors: Laurent Chery; Jean-Pierre Wajda-Dubos
Original assignee: Vetalis Sarl
Priority date: 2010-08-02
Filing date: 2011-07-28
Publication date: 2012-02-09
Also published as: FR2963239B1; FR2963239A1

Abstract

The present invention relates to effervescent solid galenic forms, in particular stones, intended for the collective treatment of animals by means of the drinking water thereof. The effervescent solid galenic form according to the invention is based on an effervescent couple which releases carbon dioxide when it is brought into contact with water, comprising at least one active substance or at least one active ingredient, a compression adjuvant, and at least one substance with a lubricating effect.

Description

SOLAR EFFERVESCENT GALENIC FORMS FOR ANIMALS

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, including:

- 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 various forms of contribution are classically used today by the majority of users, they nevertheless have many disadvantages:

- they are most of the time impractical of employment, because sometimes heavy or

bulky, and require transport and handling operations;

- they must be adapted to the rations of food to be distributed daily, hence the need to be mixed manually and 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, the animals are 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.

GB2083997A is known, for example, from effervescent tablets with dimensions of between 0.5 cm and 5 cm in diameter, and with a weight of between 0.25 g and 12 g. However, these tablets have been clearly designed for the treatment of individual subjects, and require the use of multiple tablets when one wants to increase the number of subjects to be treated.

Also known from the article entitled "Die Pharmazie, 45, 1990, February, No. 2, pages 89-101", it was possible to prepare effervescent tablets containing vitamin C and having a weight of order of a few grams only.

However, it seems that such products have not been designed or adapted for single-dose use with several animals in community, including farm animals, for example so-called "cash" animals, or domestic animals in breeding. The term "collective" or "community" refers to a group of at least three animals raised together on the same breeding site.

Indeed, the difficulty in preparing products adapted to the problem described above is manifested in the fact that the active substances or active principles that one wishes to integrate therein are in a form that make them incompatible with a distribution system on a large scale or at large volumes for many animals in a simultaneous, controlled manner, and for which the necessary quantities can be

reproducible and secure. 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. Indeed, it is a matter, in human therapy, to have galenic forms comprising doses relatively low active ingredient, which naturally limits 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, that is to say at least three or more animals, providing active substances or active ingredients, highly concentrated , such as nutritional supplements, dietary supplements, antibiotics, pro-biotics or pre-biotics, vitamins, plant and / or herbal active extracts, and the like, usable in a safe, practical and effective manner, based on a solid dosage form and effervescent.

By "active plant derived" is meant here either 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 exhibits 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, so adapted in size and weight for single-dose administration to at least three or more animals, depending on the number and nature of the target animal, eg cattle, sheep, goats, pigs, poultry, fish, rabbits, domestic animals such as cats and dogs; - it is perfectly soluble in water at room temperature and very quickly

dispersible in the drinking water, with effervescence and complete dissolution of the order of 5 min to a few tens of minutes at most, and preferably 30 minutes at most. 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 principle 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;

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, 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 solids, or purified fractions or molecules, obtained using a suitable extraction solvent of high or medium polarity, such as water, alcohol, hydro-alcoholic or hydrophilic mixture; low-grade acetone; 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, 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 integration into a the effervescent solid dosage form;

a mixture or a composition based on minerals, such as macro-elements

containing calcium, 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;

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 liberated homogeneously in the drinking water under the effect of 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;

- dosing safety corresponding to the needs of each animal of the different Forms of nutrients or active ingredients, which are dissolved very quickly in the drinking water: 100% of the animals drink indeed according to their physiological needs, which ensures a particularly individualized contribution, according to the weight animal body; 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 lick blocks, 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;

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. 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, the ferrous chelate of amino acids, hydrated, the glycine iron chelate, hydrated, calcium iodate hexahydrate, anhydrous calcium iodate, sodium iodide, potassium iodide, cobalt acetate tetrahydrate, basic cobalt carbonate

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 chelate of glycine, hydrated, 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, zinc sulphate heptahydrate, zin sulphate c monohydrate, amino acid zinc chelate, hydrated, glycine zinc chelate, hydrated, zinc chelate of hydroxy-methionine analogue, ammonium molybdate, sodium molybdate, selenite sodium, sodium selenate, the organic form of selenium produced by Saccharomyces cerevisiae, selenomethionine (selenium-inactivated yeast), and selenomethionine produced by Saccharomyces cerevisiae (inactivated selenium yeast).

As regards the vitamins, these are preferably in the form of easily dispersible powders in water and which can be mixed together, that the vitamins are water-soluble or fat-soluble in nature, and in this case, for example, after encapsulation and or adsorption on a suitable support or, for example, in the form of salts soluble in water. 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 K, vitamin B 1, 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 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, pantothenic acid for example in the form of calcium D-pantothenate, or D-pantothenol, vitamin PP, for example in the form of acid Nicotine, niacin, and / or nicotinamide-niacinamide, vitamin B9, for example in the form of folic acid, Vitamin H2, B7 or BW, in the form of biotin, choline, for example in the form of choline chloride, dihydrogen chloride citrate, choline bitartrate, inositol, carnitine, for example in the form of L-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

especially bifidobacteria). Orally absorbed as a nutritional supplement in foods or food supplements, pre-biotics are not digested in the digestive system and in the intestines of livestock, but pass directly into the colon where they play a role. targeted, in order to favor only the beneficial bacteria of the intestinal flora. Prebiotics can be found naturally in honey, fruits and vegetables, in plants and cereals, and are extractable, an example of which is inulin. Others are commercially produced by the hydrolysis of polysaccharides, for example fructo _z oligosaccharides or oligofructose, or synthesized by subjecting disaccharides such as lactose to the action of enzymes such as lactase with transferase activity to produce trans- galacto-oligosaccharides or by an isomerization chemical 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 manno- oligosaccharides (MOS) and glucose (β-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. B-glucans, essential compounds of the yeast cell wall, 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 oral absorption, in the form of food supplements or directly in food, stimulates the growth of bacteria that are useful for having 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, various strains of

Saccharomyces cerevisiae, Bacillus cereus var toyoi, Bacillus subtilis alone or in combination with Bacillus licheniformis, or strains of Enterococcus faecium. 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 release an olfactory and gustatory power perceptible by the animal, once the solid form dissolved in the drinking water. These palatability factors are available in the form

water-soluble, 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 in the galenic forms of the invention, these include:

- proteins and / or water-soluble concentrates of powdered milk proteins, derived from

milk crackinng such as: lyophilized or atomized powder colostrum, powdered whey, 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 that improve 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 with a molecular weight greater than one dipeptide;

- sugars, in particular water-soluble polysaccharides and sugars of weight

lower molecular, including oligosaccharides, mono- or disaccharides such as glucose, lactose, dextrose, used for energy input in the form of simple sugars quickly assimilated, but also so-called "slow" sugars;

one or more molecules for therapeutic purposes, such as antibacterials,

antiparasitic, anthelmintic, 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, 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 roller, it can take different three-dimensional configurations, for example spherical, oval, flat, parallelepiped, a predetermined thickness. The applicant has discovered that it is problematic to obtain an effervescent roller according to the invention weighing several tens of grams by direct compression, this size is not usual in powder compression. 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. On the other hand, the direct compression conditions for galenic forms in the weight range provided by the invention are also not the same in terms of mechanical stresses. A small defect without consequences that would manifest itself on small tablets is amplified on a large scale, rendering this form unusable. The applicant nevertheless managed to overcome these technical difficulties of realization with the solid dosage forms according to the invention.

Furthermore, the applicant has been forced to integrate at least one substance having a lubricating effect, in particular to facilitate the integration of the various components in powder form so as to obtain a premix that can flow more easily in 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 effervescent solid dosage forms according to the invention which do not form a foam on the surface when placed in contact with water, and which also does not cause a retarding 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 dosage 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.

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. 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 pebble of this example has the following composition

pebble is formed by compression in a matrix of the various ingredients mixed with prior. 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:

The trial was conducted in a herd of two groups of 12 Limousin suckling heifers, all of good health prior to the start of the trial. 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 pebble 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.

Example 2: Effervescent pebbles for pig farming containing in their composition a mixture of one or more plant active ingredients having nutritional and / or functional properties

This roller incorporates plant materials, being 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.

Components Weight% Comments

Instant (PANCOSMA) (carvacrol 5% + Cinnamaldehyde 3%) with 2% oleoresin capsicum (standardized and titrated with capsaicin)

VEGETABLE OIL OF COTTON 2.00%

HYDROGENEE (LUBRITAB)

SODIUM BICARBONATE 27% 38%

CITRIC ACID ANHYDROUS 15%

LACTOSE OF COMPRESSION 25%

(FLOWLAC or PHARMATOSE DC) /

DEXTRATE (EMDEX) (50/50)

TOTAL 100

The pebble produced according to this composition has a peach / apricot orange color, 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. This one can be used with pigs and piglets, in instant contribution with 20 g of active substances

"XTRACT Instant" to boost appetite and improve average daily gain (ADG) for fattening and finishing. The dosage is 1 tablet per day to dissolve in approximately 650 liters of water for a total of 200 individuals. Another possible use is for poultry, in instant supply of 20 g of active ingredients "XTRACT Instant", to stimulate appetite, food intake and weight gain, at the rate of 1 pebble per day to dissolve in about 400 liters of water for a total of 1600 individuals.

Example 3 Effervescent pebbles for rearing large ruminants, in particular cattle or other, containing fat-soluble vitamins rendered water-soluble by encapsulation or adsorption on a support This roller, weighing 100g, is to be diluted in 1000 liters of water for 10 adult cows (about 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.

Example 4: Effervescent pebbles for pig breeding containing a probiotic and a prebiotic

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.

Components Weight% Comments

chicory)

L-LEUCINE 4 (Excipient: Lubricant)

TOTAL 100

Example 5: Effervescent pebbles for pig breeding containing vitamins and amino acids

A 120g roller intended for 300 pigs of 50kg each, to 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

VIT H2 ΒΙΟΤΓΝΕ 2% 0.1 Water-soluble vitamin

VIT K3 MSB (MENADIONE 0.41 fat soluble vitamin

BISULFITE) 50% water soluble

TOTAL 100

EXAMPLE 6 Effervescent Pebble for Poultry Farming Containing Amino Acids and Vitamins

A 120g pebble is intended for 4000 hens of 3kg each, to dissolve in 1000 liters of water. This pebble rises to the surface after 12 minutes of effervescence, and then is completely dissolved after 14 minutes in total.

Components Weight% Comments

BISULFITE) 50% water soluble

TOTAL 100

Example 7 Effervescent Pebbles for Poultry Farming Containing Trace Mineral Chelates (Glycinates)

A roller of 100g intended for 4000 hens of 3kg each, to dissolve in 1000 liters of water. This pebble has a total duration of effervescence of 12 minutes.

Example 8 Effervescent Pebbles for Poultry Farming Containing Salts

trace elements

A roller of 70g to dissolve in 500 liters of water, intended for 2000 hens of 3kg each. Once put in the water, the roller finishes to dissolve after 9 minutes.

Components Weight% Comments

CITRIC ACID ANHYDROUS 8

SODIUM BICARBONATE 27% 16

COBALT CARBONATE 0.32 Micronutrient salt

MONOHYDRATE 52%

IRON CHLORIDE TETRAHYDRATE 14,26 Micronutrient salt

EMDEX (DEXTRATE) 25.16

CALCIUM IODATE ANHYDROUS 64% 0.76 Micronutrient salt

L-LEUCINE 5 (Excipient: Lubricant)

SELENITE SODIUM ANHYDROUS 45% 0.37 Classic trace mineral salt

SUCRAM N3D (PANCOSMA) 0.04 Sweetener

SULFATE MANGANESE 13,8 Micronutrient salt

MONOHYDRATE 32%

TOTAL 100

Example 9: Effervescent pebbles for pig breeding based on antibiotic

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 a collective treatment of 60 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.

Example 10 Effervescent Effervescent Peels Based on Phytoelements for Leporidae Farms The roller 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.

Example 11: Multi-trace element and multi-vitamin effervescent peels for breeding dogs

Components Weight% Comments

CALCIUM IODATE ANHYDROUS 64% 0.02 Trace element salt

L-LEUCINE 3.33 (Excipient: Lubricant)

SERIGEL LP 5,07 Concentrate of Proteins from

whey

SELENITE SODIUM ANHYDROUS 45% 0.01 Micronutrient Salt

SUCRAM N3D (PANCOSMA) 4 Sweetener

SULFATE MANGANESE MONOHY0,31 Micronutrient salt

DRATE 32%

VIT A ACETATE POWDER WS 500 000 0.03 Fat-soluble vitamin made hy

IU / g soluble by encapsulation or adsorption on a support

VIT B 1 THIAMINE 98% 0.07 Water-soluble vitamin

VIT B 2 RIBOFLAVIN 80% (Dextrin) 0.09 same

VIT B 3 or PP NIACINE 100% 1.01 ditto

VIT B 5 (PANTOTHENENATE Ca) 100% 0.34 ditto

VIT B 6 PYRIDOXINE (Hydrochloride) 0.04 same

100%

VIT B 9 AC FOLIC 96% 0.01 ditto

VIT B12 CYANOCOBALIN (PREMIX 1,73 ditto

1/1000)

VIT C: A. Ascorbic 100% 3.37 same

VIT D3 POWDER WS: 500 000 IU / g 0.003 Fat-soluble vitamin made water-soluble by encapsulation or adsorption on carrier

VIT E POWDER WS (Alphatocopheryl Acet2,67 ditto

tate) 50%

VIT H2 BIOTIN 2% 1.67 Water-soluble Vitamin

FACTOR OF APPETIANCE 0.5 Flavor encapsulated or adsorbed on powder support

TOTAL 100

This formulation is intended for breeding dogs to promote their vitality as well as a harmonious growth and a good recovery after the effort. 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 65 g to 110g, about 60 mm of diameter. The duration of effervescence, whatever the size of the roller, is between minutes maximum, depending on the compression force applied during manufacture.

Once the tablets are dissolved in water, the resulting solution is translucent yellow in appearance with no deposits. The pebbles are preferably administered according to the following dosage indicated in the table below:

The pebbles are to dissolve in the drinking water, considering that a dog drinks:

50 to 70 ml of water / day / kg live weight, 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 regimes

Adult Dog Body Weight Collective Treatments: Examples of Single Doses

Shepherd 30 to 40 Kg 1 roller of 110 g (matrix B) / day for 10 animals, to

German dissolve in one go in 15 liters to 28 liters of water,

(male) or 1 roller of 66.5 g (matrix B) / day for 6 animals to dissolve at once in a volume of water of 9 to 17 liters of water.

St. 51 to 72 Kg 1 roller of 95g per day (matrix B) for 5 animals, to Bernard dissolve in a single time in a volume of 13 liters to (female) 25 liters of water, or 1 roller of 66.5 g per day (matrix B) for 4 animals, to dissolve at once in 10 liters to 20 liters of water.

St. 55 to 80 Kg 1 roller of 110 g per day (matrix B) for 5 animals, to Bernard dissolve in one go in 13.5 liters to 28 liters (male) of water, or 1 roller of 66,5g per day (matrix B) for 3 animals, to dissolve in one go in 8 liters to 17 liters of water.

Claims

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 substance lubricant effect, which is adapted in size and weight for a

single-dose administration to at least three animals or more, and has a weight of from 15 grams to 200 grams.

Effervescent solid dosage form according to claim 1, which has a weight ranging from a few tens of grams to about 200 grams.

An effervescent solid dosage form according to any one of the preceding claims, wherein the animals are selected from the group consisting of cattle, sheep, goats, poultry, pigs, sows, piglets, fish, leporids , equines, and domestic animals such as cats and dogs.

Effervescent solid dosage form according to any one of the preceding claims, which is perfectly soluble 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 maximum.

Effervescent solid dosage form according to any one of the preceding claims, which is in the form of a pebble to be dissolved in water.

Effervescent solid dosage form according to any one of the preceding claims, in which the active principle is a mixture or a composition based on trace elements in the form of water-soluble or water-dispersible salts, of organic or mineral nature based on copper, zinc , iodine, cobalt, manganese, iron, selenium and molybdenum.

Effervescent solid dosage form according to any one of the preceding claims 1 to 4, wherein the active ingredient is a mixture or a composition based on trace elements in the form of amino acid chelates, preferably glycine chelates. 8) effervescent solid dosage form according to any one of claims 1 to 4 above, 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 4 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 purified fraction or molecules, such as saponins, polyphenols, flavonoids, alkaloids, whether the latter are of a water-soluble nature or

hydrodispersible, or even 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 4 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 the preceding claims 1 to 4, in which the active ingredient is one or more water-soluble solids, for example a purified fraction or molecule, of a kind

water-soluble, obtained using a suitable extraction solvent of high or medium polarity, such as water, alcohol, hydroalcoholic mixture or hydro-acetonic low titre.

12) effervescent solid dosage form according to any one of claims 1 to 4 above, wherein the active ingredient is one or more extracts "dry" 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 4 above, wherein the active ingredient is one or more vitamins or

provitamines, preferentially in powder form, perfectly hydrophilic soluble or liposoluble vitamins rendered water-dispersible after adsorption and / or encapsulation on a support.

14) effervescent solid dosage form according to any one of claims 1 to 4 above, wherein the active ingredient is one or more water-soluble vitamins, including vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), 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 4 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 claims 1 to 4 above, 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 4 above, wherein the active ingredient is a mixture or a composition comprising one or more prebiotics.

18) effervescent solid dosage form according to any one of claims 1 to 4 above, wherein the active ingredient is a mixture or a composition comprising one or more pro-biotics.

1) effervescent solid dosage form according to any one of claims 1 to 4 above, 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, an association or a combination of the substances and active principles mentioned in claims 6 to 19.

21) Effervescent solid dosage form according to any one of the claims

in which 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 claims

in which the lubricant is a hydrogenated vegetable oil in particulate form, of cotton, soybean, palm, or castor oil, the percentage by weight relative to the total weight is equal to or less than 5%.

23) Effervescent solid dosage form according to any one of the claims

in which the lubricant is magnesium stearate whose weight percentage relative to the total weight is equal to or less than 1.5%.

24) Effervescent solid dosage form according to any one of the claims

in which 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 claims

wherein the compression aid is selected from compression lactose and crystalline dextrose (dextrates).

26) Effervescent solid dosage form according to any one of the claims

in which the active ingredient is one or more molecules for therapeutic purposes.

27) Effervescent solid dosage form according to any one of the claims

previous, which has a density greater than 1 kg / m ³ .