EP2646004A2 - Galenic composition suitable for administration to a non-human animal, uses thereof, and associated methods - Google Patents

Abstract

The present invention relates to a galenic composition suitable for administration to a non-human animal, including at least the following three components: one or more active principles; an agent for accelerating delitescence; an agent for delaying delitescence, wherein the agent for accelerating delitescence and the agent for delaying delitescence are integrated in the composition so as to form a matrix with the controlled release of the active principle(s). The invention also relates to the uses of said compositions, as well as to a method for measuring the in vitro delitescence thereof.

Description

 GALENIC COMPOSITION SUITABLE FOR NONHUMAN ANIMAL DISINFERENCE, USES THEREOF AND METHODS RELATED THERETO

The present invention relates to pharmaceutical compositions adapted for administration to a non-human animal, both monogastric animals and ruminants. In general, galenic compositions suitable for administration to animals already exist in different galenical forms, including, for example, tablets, boli, pellets, granules, injections, or even the provision of compositions intended to be administered to animals. to be dispersed in their drinking water, etc. In ruminants such as cows or bulls, for example, the galenic compositions are often administered as a bolus, introduced into the rumen of the animal where the composition can disintegrate under the effect of mechanical friction with the rumen walls. and foods, digestive juices and native microbial flora. When the animal is monogastric, for example with pigs, they can be ingested the galenic compositions by adding the composition, in tablet form for example, to their food or added to their drinking water or given directly. One of the major problems of all these different galenic forms remains the difficulty of controlling, or predicting with a degree of certainty, the duration of decomposition, release or disintegration of the galenic composition once ingested. Until then, and taking into account the variability of the components and active ingredients used in these galenic compositions, this has not been satisfactory either only in a very specific field or with a certain type of animal. In addition, it has not heretofore been possible to determine in advance the lifetime of the composition once in the stomach or rumen of the animal. However, this is important from an economic point of view and general health of the animal, because with the existing solutions, the animals receive either too much or not enough active ingredients, because one is unable to know with certainty when the previous administration has ceased to produce its effects. The applicant of the present application, however, has succeeded in developing a galenic composition which makes it possible to satisfy these various problems and in doing so has discovered other interesting properties and uses of the compositions as well as certain active principles incorporated therein. These different objects will be identified in the detailed description of the invention which will be given below. In a first step, the applicant has been able to develop a pharmaceutical composition suitable for administration to an animal, preferably breeding, comprising at least the following three components: one or more active ingredients;

an accelerating agent of disintegration;

a disintegrating agent for disintegration; composition in which the disintegration control agent is different in function of the disintegrating agent and both are integrated into the composition so as to form a controlled release matrix of the active ingredient (s).

By "one or more active ingredients" is meant one or more substances capable of having a beneficial effect on the physiology or biological state of the farmed animal. Thus, and according to the present invention, different active principles can be integrated therein. A discussion of these will be made below.

For example, and preferably, micronutrients, in the form of water-soluble or water-dispersible or even very slightly soluble or almost insoluble salts of organic or inorganic nature based on copper, zinc, iodine, cobalt, manganese, will be chosen. iron, selenium and molybdenum. Thus, those selected from the group consisting of ferrous carbonate, ferrous chloride tetrahydrate, ferric chloride hexahydrate, ferrous citrate hexahydrate, ferrous fumarate, ferrous lactate tetrahydrate, ferric oxide, ferrous sulfate monohydrate, ferrous sulphate heptahydrate, ferric chelate of amino acids, hydrated, glycine iron chelate, hydrated, iron pidolate, calcium iodate hexahydrate, anhydrous calcium iodate, sodium iodide, potassium iodide, cobalt acetate tetrahydrate, basic cobalt carbonate monohydrate, cobalt carbonate hexahydrate, cobalt chloride hexahydrate, cobalt sulfate heptahydrate, cobalt sulfate monohydrate, cobalt nitrate hexahydrate, pidolate of cobalt, cupric acetate monohydrate, basic copper carbonate monohydrate, cupric chloride dihydrate, copper methionate, cupric oxide, sulphate cupric pentahydrate, cuprous chelate of amino acids, hydrated, cuprous glycine chelate, hydrated, copper chelate of hydroxy-methionine analogue, copper pidolate, manganous carbonate, manganous chloride tetrahydrate, phosphate Manganese acid trihydrate, manganous oxide, manganic oxide, manganous sulfate tetrahydrate, manganous sulfate monohydrate, manganese chelate of amino acids, hydrated, glycine manganese chelate, hydrated, manganese chelate hydroxy-methionine analogue, manganese pidolate, zinc lactate trihydrate, zinc acetate dihydrate, zinc carbonate, zinc chloride monohydrate, zinc oxide, zinc sulfate heptahydrate, zinc sulfate monohydrate, zinc amino acid chelate, hydrated, glycine zinc chelate, hydrated zinc chelate of hydroxy-methionine analogue, zinc pidolate, ammonium molybdate, sodium molybdate, sodium selenite, sodium selenate, organic form of selenium produced by Saccharomyces cerevisiae, selenomethionine (inactivated selenium yeast), and selenomethionine produced by Saccharomyces cerevisiae (inactivated selenium yeast).

In addition, it may be advantageous to include in the galenic compositions according to the invention a composition or a mixture based on one or more vitamins, provitamines, or their salts, which are perfectly hydro-soluble, hydrodispersible, or very slightly soluble. even insoluble, for example liposome-rich vitamins normally insoluble in water but rendered water-dispersible after adsorption and / or encapsulation on a support prior to their incorporation into the galenic form, but also water-soluble vitamins protected by encapsulation in a matrix of nature hydrophobic, in order to delay their escape into the external environment. As regards the vitamins, these are preferably in the form of powders that can be easily mixed with each other: that the vitamins are of a water-soluble or fat-soluble nature, after, for example, encapsulation and / or adsorption, either in a matrix or on a appropriate powder carrier.

Thus vitamin A, vitamin D2 (ergocalciferol), 25-hydroxycalciferol, vitamin D3 (cholecaliferol), beta-carotene (pro-vitamin A), vitamin E, vitamin K, are preferred as vitamin. example in the form of bisulphitic menadione, vitamin B1, 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, acid 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 nicotinic acid, niacin, and / or nicotinamide-niacinamide, vitamin e 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, choline dihydrogen 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.

Among other desirable active ingredients, mention may also be made of macro-elements which are generally based on one or more minerals containing calcium, magnesium, sodium and / or phosphorus, potassium or sulfur. The latter are preferably in powder form and correspond to inorganic salts either of organic nature or of a totally inorganic nature, that is to say inorganic salts, and have a solubility in water greater than 0.25. g in 100 g of water. Preferably, the apparent density of these powders is greater than 0.45 and they have a particle size of less than 800 microns. Soluble and highly bioavailable salts will then be favored, the macronutrients having to be brought in large quantities, generally in the form of immediate input over relatively short periods, of the order of a few days at most. Preferably, the macroelement is selected from the group consisting of calcium and magnesium L-pidolates, calcium and magnesium amino acid chelates, calcium or magnesium glycinates, or any other calcium complex or chelate or magnesium containing in its structure an organic ligand, calcium and magnesium lactates, calcium and magnesium gluconates, calcium and magnesium formates, calcium and magnesium citrates, magnesium sulfate and calcium sulphate.

The galenic compositions according to the present invention may also contain other active principles, in particular one or more pre-biotics in powder form. In general, 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 in the body. colon, including lactobacilli and bifidobacteria. Orally absorbed as a nutritional supplement or dietary supplement, 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 targeted role. to favor only the beneficial bacteria of the intestinal flora.

Thus, and according to the present invention, it is preferred that the pre-biotic (s) be selected from the group consisting of fructo-oligosaccharides (FOS), inulin and / or inulin derivatives, manno-oligosaccharides (MOS) and / or combinations of MOS and glucose (β-glucans), for example MOS 500, which is a specific combination of manno-oligosaccharides and B-glucans, obtained by natural extraction of the cell wall from yeasts Saccharomyces cerevisiae. Another possibility of a preferred active ingredient is the pro-biotics. 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. These pro-biotic strains when used in the context of the present invention are generally encapsulated, dispersed and / or adsorbed on a solid support of powder type, for example calcium carbonate, dextrose or sorbitol, for reasons of practicality and convenience of use. Thus, the probiotics that can be used according to the present invention are preferably selected from the group consisting of Saccharomyces cerevisiae, Enterococcus faecium, Bacillus cereus var. toyoi, Bacillus subtilis, Bacillus lichreniformis, Bacillus amyloliquefaciens, Clostridium butyricum, Pediococcus acidilacti, Lactobacillus rhamnosus, Lactobacillus farciminis, and Kluyveromyces marxianus-fragilis.

According to a preferred embodiment of the present invention, the pharmaceutical composition also comprises one or more active ingredients in the form of powder in the form of proteins, peptides, enzymes and / or free amino acids, which can be either of origin plant, or derived from the biofermentation of microorganisms, or of synthetic origin, and in particular proteins and / or water-soluble concentrates of milk proteins in powder form, resulting from the cracking of milk such as colostrum lyophilized or atomized powder, whey in powder form, immunogobulins such as fractions purified or enriched in IgG, lactoferrin, lactoperoxidase, animal or plant enzymes, and more particularly, 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. When amino acids are integrated as active principle in the present composition, it is preferred to use the free amino acids or in the form of salts, or peptides, especially L-carnitine, more particularly in its dipeptide form, or any another water-soluble peptide of molecular weight greater than a dipeptide. Advantageously, the compositions according to the present invention also comprise one or more active ingredients of vegetable origin, for example, powders or a mixture of dried, ground, and / or micronized plant powders, or one or more plant extracts, of preferably in the form of dry extract, of vegetable active ingredients, for example the fraction or the purified molecules, such as saponins, polyphenols, flavonoids, alkaloids, etc.,

water-soluble or water-dispersible, obtained with the aid of a suitable extraction solvent of high or medium polarity, such as water, alcohol, or a hydroalcoholic or hydro-acetonic mixture of low titre; in this same group of active ingredients, one can also find one or more plant extracts of liquid type, for example one or more mother tinctures, previously dispersed on a suitable powder support.

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 powder support such as cyclodextrins, gum arabic, silicas, maltodextrins, inulin, etc. , before integration. Moreover, it is also possible to integrate one or more essential oils, containing monoterpenes and sesquiterpenes, and / or one or more purified aromatic molecules of natural or synthetic origin, preferably adsorbed - encapsulated or encapsulated on a powder support, of to be made water-soluble or water-dispersible. In the same group of active principles, it is also possible to include "dry" extracts of plants of a lipophilic nature, such as acetone extracts or of lower polarity, or extracts obtained by supercritical CO2 extraction, or by another apolar solvent. , but rendered dispersible in water after adsorption or encapsulation on a powder-type support.

Finally, it is also possible to include, as active ingredient in the compositions according to the present invention, active principles used in the case of curative treatments, such as antibiotic treatment, in particular 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-inflammatories, antiallergics and immunomodulators, such as central analgesics, oral anti-inflammatories, 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, angiology, vasodilators, active principles for vascular purposes; in the immune system, active ingredients used in immunotherapy, immunoglobulin intake, interferon, immunomodulators; in the field of metabolism, or nutrition, anabolic, antianemic, anti-ketotic, oral rehydration, calcium metabolism, magnesium and phosphorus, lipotropic factors and liver and kidney disease, vitamin therapy and oligotherapy; the active ingredients used in hormonology, reproductive endocrinology, fertility hormones, anti-hyperthyrroidians, antigalactogens, abortives, hormone inhibitors; in the field of muscles / locomotor system, anti-rheumatic, anti-arthritic, muscle and musculoskeletal stimulants, anti-myopathy; in the field of the respiratory system, respiratory analeptics, bronchodilators,

mucoregulators and expectorants, antitussives, anti-infectives; in the urinary system, diuretics, urinary acidifiers, urinary antispasmodic; in the neurological system, general anesthetics, analgesics, anticonvulsants, sedatives and tranquilizers, etc. Preferably, the active ingredients are present in the compositions of the present invention in amounts of between 0.5% to 90% by weight relative to the total weight of the composition.

The compositions according to the present invention also comprise a disintegration accelerating agent. By "accelerating agent of disintegration" is meant one or more substances that function to facilitate the entry of water into the composition according to the invention, once it is in an aqueous medium, for example in the stomach or rumen of an animal; the depositor has furthermore discovered that by choosing a certain type of accelerator of disintegration, it is possible to accelerate the disintegration according to the desired result; examples of suitable disintegration accelerating agents will be given below. Indeed, the applicant has chosen his preferential choice on lignosulfites or lignosulphonates as the preferred accelerating agent for disintegration. Lignosulfonates are water-soluble mono or poly-electrolytic anionic polymers from the pulp and wood processing industry, obtained by treating lignin under the action of a bisulphitic acid solution. The sulphonated lignins thus obtained are neutralized under the action of a base and then concentrated to dryness to obtain lignosulphonates in powder form. Lignosulphonates are generally in the form of fine powders which are highly soluble in water and are strongly hygroscopic, demonstrating a tendency to caking and moisture uptake. Lignosulphonates or lignosulphonates have a very wide range of molecular weight, being very polydispersed, and can even be repolymerized under certain conditions, with molecular weights of between 10,000 and 200,000 Daltons. The cations which are attached to the sulphonic groups are, in general, a mixture of NH ₄ ⁺ and Ca ₂ ⁺ - or even simple ions such as Na ⁺ , Ca ₂ ⁺ , K ⁺ , and NH ₄ ⁺ . Lignosulphonates are generally known for their use as a colloidal agent in nutrition compositions animal, or even as a retarder for the mortar compositions, but a priori not as an accelerator of the disintegration as in the compositions according to the present invention.

Preferably, the applicant has chosen lignosulphonates based on calcium and ammonium, or a mixture thereof, or based on sodium or potassium. They advantageously have a metal ion content of between 3 and 15%, and a total sulfur content of between 7% and 7.5%, with a residual moisture content of less than or equal to 7%. Even more preferably, the lignosulphonates used in the present invention are:

acid mixed lignosulphonates, available for example from the company Tembec, for example lignosulphonate ARBO C12 NH4 / Ca;

acid single lignosulphonates, available from Borregaard under the name Borresperse AM 320 (NH4), Lignobond DD (Ca), also available from Borregaard, or Arbo Tl 1 N5 (NH4), available from Tembec; neutral simple lignosulphonates, such as Ultrazine Ca available from Borregaard;

simple basic lignosulfonates, such as Arbo NI 8 (Na) from Tembec,

 Borresperse (Na) from Borregaard, Ultrazine Na from Borregaard and Arbo Kl 8 (K) from Tembec. Preferably, the delitescence accelerating agent is present in the compositions according to the present invention in amounts of between 3% and 25% by weight relative to the total weight of the composition, in a preferred variant of between 3% to 16%. and according to another variant between 3% to 8% by weight relative to the total weight of the composition.

By way of an accessory, the applicant has observed that there may be, in certain cases, a fairly significant dose effect with regard to the amount of accelerating agent, especially when the active ingredients are, by their nature, moderately water-soluble or very little water-soluble, that is to say that the disintegration is significantly accelerated when increasing the amount of accelerating agent in the composition. Although it is undoubtedly also present in the compositions based on very water-soluble active ingredients, the demonstration of this phenomenon in this type of composition is much more difficult because of the too rapid dissolution of the very water-soluble active ingredients. As mentioned above, the compositions according to the invention also comprise a disintegration retarder. By "disintegration retarder" is meant one or more substances that function to prevent water from entering the composition, and thus delay disintegration; it should be noted that the function of the retarding agent is very different from that of the accelerator of disintegration. The applicant has discovered that the use of a fatty substance is well suited to fulfill this role of disintegrating agent. Thus, it is preferred that the disintegration-delaying agent be a solid fat substance at room temperature, preferably in the form of fine powders with a particle size of less than or equal to 800 microns.

Preferred fatty substances of plant origin and / or derived from chemical synthesis, for example catalytic hydrogenation of vegetable oils. Thus, the preferred solid particulate fats are selected from the group consisting of hydrogenated rapeseed oil, hydrogenated soybean oil, hydrogenated cottonseed oil, hydrogenated palm oil, palm kernel oil hydrogenated, hydrogenated castor oil, vegetable waxes, esters of fatty acids and alcohol, cerides, cetyl palmitate, for example derived from whale-white, carnauba wax, beeswax candellila wax, stearin, stearic acid, glycerol trihydroxystearate, microcrystalline wax, solid paraffin, and white melamine wax.

Preferably, the disintegrating agent is present in the compositions according to the present invention in amounts of between 1% and 12%, preferably 1% to 8%, more preferably between 2% and 10%, and more preferably between 3% to 12% by weight relative to the total weight of the composition.

Moreover, the composition may advantageously, but not necessarily, and depending on the destination of the pharmaceutical composition, comprise a weighting agent. By "weighting agent" is meant one or more substances or mixtures thereof which have only a densifying function at the level of the composition, the purpose of which is to maintain the composition in the stomach or rumen of the animal. The weights that can be used in the context of the present invention are essentially in the form of fine powders that are insoluble in water, preferably with a particle size of less than 500 microns. The weight powders used should preferably have an apparent density greater than or equal to 2.40 g / cm ³ , thus fully fulfilling their role of densifying agent, which makes it possible to avoid regurgitation and a rise when the pharmaceutical composition is in the form of a bolus, since the rumen.

Indeed, it is preferable that when the composition is in the form of a bolus, the latter has a density, once the compression of the components made, greater than 1.5 g / cm ³ , plus preferably greater than 1.8 g / cm ³ or close to 2.0 g / cm ³ , or even more preferably greater than 2.0 g / cm ³ .

Thus, the weights that can be used in the context of the present invention are therefore chosen

preferentially among the metals or among the metal alloys having such characteristics. It is especially and preferably, the case of iron, steel, cast iron, bronze, copper, brass, nickel, tungsten, zinc, constantan, which is a copper alloy and nickel, chromium, manganese, ferro-nickel. It is also preferred that the ballast be free of all toxic metals, such as lead, arsenic, cadmium, and mercury, to be compatible with use in the context of animal health or nutrition.

Among the various preferred weights indicated above, the most preferred example is that of iron powder. Among the various iron powders that may be used in the context of the present invention, mention may be made of the following commercial specialties: Nutrafme RS from HOGANAS, MH4024 from the same company, Carbonyl Iron Powders from BASF, 42 DR ELTRO 400/30 or the ATOMET 110 marketed by ECKA GRANULES, etc.

Yet another example tested in the context of the present invention is that of an atomized powder of zinc, marketed by CASTOLIN under the trade reference ROTOTEC 29230.

The amount of weight present in the compositions according to the present invention may vary rather widely, and thus its percentage by weight relative to the total weight of the composition is preferably between 0% to 50%. Preferably, the weighting agent is in the form of particulate iron in amounts of between 7% and 25% by weight relative to the total weight of the composition. Even more preferably, the weighting agent is in the form of particulate iron in amounts of between 9% and 25% by weight relative to the total weight of the composition.

When it is desirable, for example, to increase the hardness of the composition according to the invention in tablet or bolus form, it may be advantageous that a compressing agent is present in said composition according to the invention. Thus, by "compression agent" is meant a compression medium of inorganic nature, inert, which does not provide an active ingredient. In the context of the present invention, the applicant has discovered, quite surprisingly, that unlike various pharmaceutical excipients and / or compression supports conventionally used in the pharmaceutical industry, which disintegrate very slowly. rapidly in the water after a few hours, some raw materials of mineral origin could be used judiciously for galenic purposes as a compression support, to better control the disintegration on the one hand and / or to lengthen in some cases significantly the disintegration time of the composition when it was in the form of a bolus, whose disintegration was otherwise short-lived. Thus, the addition of a compression support could increase the duration of disintegration from a few hours to several days, or even weeks. As mentioned above, these bulking agents are not those conventionally used in the pharmaceutical industry as regards compression: such as, for example, modified starches, EMDEX-type dextrates, compression lactose of the Flowlac type, Pharmatose, or else Compression sorbitols of the NEOSORB type.

Indeed, these have proved far too soluble, or facilitating too much dispersion in water, or having a disintegrating effect, to be useful as a compression agent in the present invention. In the same vein, coating agents or coating agents such as:

hydroxypropylcellulose (HPC in its highly substituted version) or

hydroxypropylmethylcellulose (HPMC in its highly substituted version), known for their filmogenic properties, were tested, leading to poor results with at most disintegration times of a few hours. Thus, the applicant has preferred to retain mineral raw materials as compression agent, and even more preferably those based on calcium, magnesium, and / or phosphorus in the form of an inorganic salt of origin. mineral. The preferred compression agent according to the present invention is therefore chosen from oxides,

hydroxides, carbonates and phosphates, the content or contribution of which in the compositions according to the present invention do not have a regulated daily maximum, unlike conventional mineral salts based on trace elements whose maximum daily doses are set by regulations. Preferably, the chosen salts are in the form of fine powder with a particle size less than or equal to 800 microns, making them compatible with mixing operations that are homogeneous with the other ingredients of the composition. The chosen compression agents also have, and preferably, a solubility in water very low, or almost zero, that is to say less than 0.25 g in 100 g of water, and preferably lower to 0.15 g in 100 g of water. As regards the other preferred characteristics of the compressing agents according to the present invention, mention may also be made of a density of powder apparent greater than 0.45, allowing the realization of a sufficiently dense bolus while reducing the amount of agent ballast, which has the additional advantage of leaving room in the formula for the other ingredients, including the active ingredients and other possible excipients. It is particularly advantageous that the squeezing agent has a wet granulation and compression ability, i.e., the ability to form grains which are sufficiently resistant to crushing once. dried. Of all the possible compressing agents, applicants prefer that those used in the invention be selected from the group consisting of magnesia, quicklime, dolomite lime, slaked lime, magnesia hydroxide, anhydrous dicalcium phosphate, tricalcium phosphate, natural or precipitated calcium carbonate, high density calcium carbonate, litothamne, magnesium carbonate, basic heavy magnesium carbonate, or a mixture thereof, and preferably is magnesia oxide. Even more preferably, these compressing agents are all used in powder form.

According to a particularly advantageous aspect, the compressing agent is present in the composition according to the invention in amounts ranging from 0% to 70%, preferably from 0% to 60%, more preferably from 0% to 40%. %> by weight relative to the total weight of the composition.

During the preparation of the compositions according to the present invention, the applicant has also discovered that a number of other parameters than those already mentioned could have an influence on the time of disintegration to varying degrees. Thus, the determination of these parameters allowed him to develop another definition of the compositions according to the present invention as a function of the desired or actual disintegration in vitro or in vivo of the composition, also valid, and verified by statistical modeling. One of these parameters is the solubility index, which is an absolute value obtained by summing the relative solubility contributions of a given component in the composition, calculated by multiplying the known solubility in grams in 100 g of water of said component with the percentage by weight of said component in the composition:

Solubility Index = SUM 1 to N (Solubility Component X *% Incorporation Component X). The solubility values of the components are those:

- be available in the official documentation of the supplier of the component or its data sheets; - obtained from reference works, such as:

- the "Nuffïeld Book of Data" - Rev. ed. Section 5.3 (inorganic compounds: Physical and thermochemical data), pages 61 to 101;

- The CRC Handbook of Chemistry and Physics, 88th Edition (2007-2008) by David R. Lide;

the reference "Solubilities: inorganic and metal-orga c compounds: a compilation of sohibiiity data from the periodical. Hterature, Linke, Wiiiiam, Seideil, Atherton, ACS

1958-1965;

- The Perry 's Chemical Engineers Handbook, 7 * Ed. Robert H. Peny, 1977; - the "Usual of General and Mineral Chemistry", 1920-today, Bernard, M, and

 Busnot, F.

- or calculated in the laboratory, for soluble active ingredients, whose solubility data are not indicated by suppliers and / or available in the literature. The solubility determination protocol for these components was as follows:

A beaker comprising 200 g of cold water at a temperature between 18 to 25 ° C is placed on a stirring magnetic plate. A given quantity of substance whose solubility is to be measured is incorporated with stirring and in very large excess, until saturation. After stirring for one hour, the saturated solution is filtered on a funnel provided with a filter paper (the undissolved being retained on the filter). The filtrate is collected. The latter is analyzed using a desiccator / moisture meter of the Sartorius MA 150 type: test portion = 2 to 3 g of filtrate, spread and distributed uniformly on a metal cup, and brought to a temperature of 105 ° C. , in order to measure the dry residue at constant weight, after evaporation of the water. The value of the dry residue is given by the apparatus in grams in 100 g of solution. By difference, the water content is thus determined. Then, by calculation, we deduce the solubility of the substance to be analyzed, expressed in grams in 100 g of water.

Indeed, applicants have found that a high solubility index value leads to compositions that generally disintegrate rather quickly, whereas a low solubility index value tends to lead to very disintegrating compositions. slowly. This determination could be confirmed by a statistical analysis and modeling done on different compositions prepared by the applicant during the development of the invention.

Thus, according to a first aspect, there is provided a pharmaceutical composition according to the invention, which comprises:

One or more active ingredients; An index of solubility in water at room temperature of between 4.5 and 38;

A lignosulfonate-based component in amounts of between 3% and 25% by weight relative to the total weight of the composition;

- A fat-based component in amounts between 1% to 8% by weight relative to the total weight of the composition, which composition has a disintegration of between one hour and less than or equal to 30 days.

According to a second aspect, there is provided a pharmaceutical composition, which comprises:

One or more active ingredients;

An index of solubility in water at ambient temperature of between 2.5 and 11.5; A lignosulphonate-based component in amounts of between 3% and 16% by weight relative to the total weight of the composition;

A component based on fatty substances in amounts of between 2% and 10% by weight relative to the total weight of the composition; which composition has a disintegration greater than 30 days and less than or equal to 90 days.

According to a third aspect, there is provided a pharmaceutical composition, which comprises:

One or more active ingredients;

A solubility index in the range of from 2 to 4;

A lignosulfonate-based component, in amounts of between 3% and 8% by weight relative to the total weight of the composition;

A fat-based component, in amounts of between 3% and 12% by weight relative to the total weight of the composition; which composition has an in vivo disintegration greater than 90 days and less than or equal to 180 days.

Advantageously, the compositions thus defined may also comprise a compressing agent in amounts of between 0% to 70% by weight relative to the total weight of the composition, preferably between 0%> and 60%>, and preferably more preferred between 0%) to 40% by weight relative to the total weight of the composition. According to a fourth aspect, there is provided a galenic composition, which comprises:

One or more active ingredients;

An index of solubility in water at ambient temperature of between 2 and 4;

A lignosulphonate-based component in amounts of between 3% and 8% by weight relative to the total weight of the composition; A fat-based component in amounts of between 3% and 12% by weight relative to the total weight of the composition;

A compression agent, in amounts of between 4% and 30% by weight relative to the total weight of the composition; which composition has a disintegration greater than 180 days. The applicant has also observed another phenomenon, when the compositions according to the invention comprise zinc oxide alone as active principle, namely that it is necessary to include in the composition a compressing agent, preferably magnesia, failing which the composition did not behave as expected and tended to disintegrate or even disintegrate erratically, rather than disintegrating. Apart from the components given above, the composition may of course comprise adjuvants and excipients, for example, binders, flavors, sweeteners, flavor enhancers, lubricants serving to aid compression when the composition is present under form of bolus or tablet, and the like. Examples of these adjuvants are given below as an indication:

binders: water-soluble cellulose ethers, povidones, gum arabic, etc., in amounts of between 3% and 7% by weight relative to the total weight of the

 composition;

compressive aid lubricants: magnesium stearate, in amounts of between 1% and 6% by weight of the total weight of the composition;

sweeteners, flavorings, flavor enhancers, in amounts of between 0.05% and 2%. In general, the total amount of adjuvants and excipients is between 1% to 10%.

During the preparation of the compositions described above, the applicant has made surprising discoveries, since it has been found that one of the active ingredients, namely calcium pidolate and / or magnesium has remarkable effects on animals. having ingested it. In particular, calcium pidolate, as well as magnesium pidolate, optionally in admixture with calcium pidolate, had a remarkable effect on the non-human female animals, which had just given birth, and milk producers, as well as their offspring that fed on milk produced. In fact, the applicant found particularly in the postpartum cow, for example, that it began to produce significant amounts of milk much earlier and in larger quantities than other cows in the same situation, but receiving only a classic calcium intake. A similar effect was observed in the sow, in particular that piglets fed under the mother, whose mother had received peri-partum calcium pidolate and / or magnesium, had a weight gain greater than one batch of corresponding piglets of which the feeding sow had not received a contribution of these salts. An acceleration of farrowing has been observed, with the result that the sow can produce more litters per year, and in addition require less monitoring time because of the reduced farrowing time.

Beyond, therefore, the effect of calcium intake, the applicant discovered that the pidolate ion, in salt form with calcium and / or magnesium, could not only bring calcium to the non-animal. but also induce the mobilization of endogenous calcium ions in the animal in question. This effect was never previously revealed or demonstrated. When the animal is a milk-producing cow, this effect has the effect of stimulating the recovery of production much earlier than in a cow that has not received such a contribution, which in turn makes the cow more productive in the long run in terms of the amount of milk produced. Thus, the applicant has discovered a surprising use of calcium and / or magnesium pidolate and, from a physiological and economic point of view, very interesting for the breeder of these animals. This has led to the development of other uses of calcium and / or magnesium pidolate, as indicated below.

According to one aspect, the invention preferably relates to the use of calcium and / or magnesium pidolate for the supply of calcium and / or magnesium, for a non-human animal, preferably for breeding. Preferably, the use of calcium pidolate and / or magnesium is made to stimulate milk production in a female non-human animal, preferably, postpartum. Even more preferably, the non-human animal is a ruminant, and even more preferably the non-human animal is selected from the group consisting of cattle, sheep, goats, deer, camelids, and preference is a cattle. According to another preferred use, the non-human animal is monogastric, preferably selected from the group consisting of pigs, leporids, equines, pets, preferably dogs and cats, and more preferably still is a pig.

It will be noted here that the use of calcium pidolate and / or magnesium can be done in any suitable composition or vehicle, for example, simply by adding the active ingredient or a mixture of two active ingredients in question to feeding of the animal in question. However, it is preferred that the calcium and / or magnesium pidolate be used in its L-pidolate form, and preferably integrated as an active ingredient in a

galenic composition according to the invention.

According to another aspect of the present invention, provision is made for the use of calcium pidolate and / or magnesium as a feedstock of non-human animal macroelements, preferably cultured. In this case, it is preferred that this contribution is made through a composition according to the invention, preferably in the form of a bolus, and that the non-human animal is a ruminant. As before, it is preferable then that the non-human animal is selected from the group consisting of cattle, sheep, goats, deer, camelids, and preferably is a cow, when the animal in question is a ruminant. However, this use can also be done for other animals, and in other forms of presentation, for example in the form of tablets, for example, chewable tablets. In this case, it will be preferred that the non-human animal be selected from the group consisting of pigs, leporids, equines, pets, preferably cats and dogs, and preferably is a porcine animal.

According to another aspect of the invention, provision is made for the use of calcium and / or magnesium pidolate to stimulate milk production in post-partum non-human mammalian animals, preferably breeding animals. Preferably, this animal is a cow, although other non-human animals could be taken into account. In this case, it is preferred that the pidolate in question be incorporated in a composition according to the invention, and more

preferentially in tablet form and that the animal is a sow. The calcium and / or magnesium pidolate can then be administered as it is, but preferably will take the form of a tablet, which will dissolve in the animal's diet, or a chewable tablet by the animal.

According to yet another aspect of the invention, there is provided a use of a composition according to the invention containing an active ingredient based on calcium pidolate and / or magnesium, to stimulate, around a farrowing, a general mobilization of calcium ions in a mammalian animal non-human female, preferably farmed. More preferably, the rearing female non-human mammalian animal is a cow and the composition is in the form of a bolus. According to a preferred variant of this use, the farmed mammalian non-human animal is a sow and the composition is in the form of a tablet.

According to yet another aspect of the present invention, there is provided a use of a composition according to the invention, containing an active ingredient based on calcium pidolate and / or magnesium, to increase the weight gain of a piglet raised under the mother. According to yet another aspect, the invention relates to the use of a composition according to the invention, containing an active ingredient based on calcium pidolate and / or magnesium, to accelerate the farrowing time of the animal. and preferably the sow.

According to two other aspects of the present invention, provision is made for: the use of calcium and / or magnesium pidolate for the maintenance of a peri-partum blood calcium level in the cow greater than 85 mg / l by injection of at least the equivalent of 3.78 g, preferably at least the equivalent of 7.56 g, of calcium in the form of pidolate salt;

- the use of calcium pidolate and / or magnesium for the increase of

peri-partum blood phosphoremia in cows above 55 mg / l by intake of at least the equivalent of 30,24g of calcium pidolate and / or 7,5g of pidolate magnesium.

Thus, as can be seen from the foregoing, the applicant has developed several uses of calcium and / or magnesium pidolate in the field of animal nutrition and animal health. When both pidolates were used together it was determined that it was preferable to use a 4: 1 ratio of calcium pidolate to magnesium pidolate.

In order to support the position of the depositor, it seems important to describe, on the biochemical level, the mechanisms of regulation of blood concentrations of macro-elements such as Ca, P, Mg are called homeostasis. The vital functions of the body are also dependent on the homeostasis of these elements. When it is out of order, pathological events occur.

For example, 99% of organic Ca constitutes the skeleton in the form of complex salts

(hydroyapatite), in ionized form, closely related to P, Ca has multiple functions:

- transmission of nerve impulses

- intervention in muscle contraction (smooth or striated) - regulation of permeability of cell membranes

- regulation of the transduction mechanisms of hormonal messages

- participation in blood coagulation

- enzymatic activation

- control of the use of ΑΤΡ (close relationship with the 3 phosphate groups of the ATP structure).

The regulation of blood calcium, without causing any harm to the cow, particularly with regard to osteoporosis, is dependent on several factors: Parathyroid hormone (PTH), calcitriol (1,25 dihydroxyvitamin D) and secondarily calcitonin thyroid. Thanks to the sensitive transmembrane receptors, when the serum calcium decreases, the secretion of PTH and the synthesis of calcitriol increase significantly. PTH allows bone resorption of Ca and tubular reabsorption of Ca by the kidney. It has an action on the synthesis of calcitriol. Calcitriol, produced by the kidney, stimulates intestinal absorption (duodenumjejunum) of dietary Ca, and regulates bone resorption of Ca. Hypocalcemia and milk fever, or vitreous fever, occur when the original Ca bone can not be moved and that the diet food does not compensate for the loss of lacteal Ca. As serum calcium increases, PTH secretion decreases, there is a decrease in bone resorption and tubular reabsorption, and thus the synthesis of calcitriol decreases due to impaired intestinal absorption. Then there is the production of thyroid calcitonin. There are several factors affecting PTH regulation:

hypomagnesemia impedes the response of the parathyroid. Mg status decreases when K-uptake increases, for example during grazing, resulting in hypocalcemia;

- diets that are overloaded with Ca (alfalfa, excess CMV rich in Ca), during late gestation, inhibit the secretion of PTH. In contrast, diets low in Ca, for example, less than 20g of daily intake of Ca, stimulates the secretion of PTH allowing good osteoclasy and production of calcitriol, which improves the absorption of dietary Ca by enterocytes ;

- Metabolic alkalosis, which is defined by a urine pH greater than 7.8, positive BACA, excess K and chloride deficiency, predisposes to hypocalcemia and vitreous fever;

controlled ruminal acidification and Baca negative (0.15 Ca + at 0 15 Mg = Na + K) - (Cl + at 0.25 S + 0.5 P) = - 200 mEQ / kg. Sulphates are less acidifying than chlorides (Mg, ammonium), allows effective prevention of VF; - liver failure (steatosis) decreases the synthesis of 25 hydroxyvitamin

D who will be deficient at the renal level for the production of 1,25 dihydroxyvitamin D or calcitriol;

- Corticosteroids are aggravating factors of hypocalcemia, especially in cases of muscle disorders or inflammation of the nervous trunks. There are also factors affecting the absorption of dietary Ca

- With the increase in the age of the animal, there is a decrease in the number of PTH receptors decreases which results in a decrease of the animal to maintain its homeostasis;

- the estrogens which increase at the time of share, have a frenating action on the homeostatic response; calcitonin secreted by the thyroid, decreases osteoclasis and increases urinary excretion of Ca;

- If the acidosis is too important, the blood pH decreasing, the osteoclasy will be increased for a better acid-base balance of the blood, by the Ca ion. There are also the factors affecting the calcitriol kidney production, because it is practically similar between a healthy animal and a cow in vitreous neurosis, where the rate is a little higher:

- BACA + reduces the synthesis of calcitriol, because alkaloses reduce its production and the sensitivity of the renal tissue to PTH; - the high blood concentrations in P inhibit its activity and increase the

 hypocalcemia.

Magnesium is known to participate in nucleic acid metabolism, chromatin organization, protein synthesis, and energy production in the cytoplasm and mitochondria. It is a cofactor essential for the activity of many enzymes found in the cell nucleus, mitochondria, endoplasmic reticulum and cytoplasm. It is also involved in the direct or indirect regulation of more than 300 enzymes (ATPases, protein kinase C etc.). It participates in the stabilization of the structure of proteins, acnucleics and cell membranes. It controls the use of ΑΤΡ which serves as substrate or phosphate donor (ΑΤΡ provided with 3 negatively charged phosphate groups is stabilized by the Mg ion). As a divalent cation, it is indispensable for stability

electrochemistry of many charged molecules of the cell and membrane cohesion. The bone reserves of Mg are large, about 70% of body Mg, but short-term mobilizations are low. If Mg dietary intakes are insufficient, ruminal absorption of Mg is impeded by antagonists, the blood status of the cow will be low. Below 18 mg / l, hypomagnesemia will cause hypocalcemia.

Hypomagnesemia also interferes with the ability of Ca target cells to solicit additional production of PTH, which causes a decrease in PTH. During hypocalcemia, this PTH nevertheless increases the reabsorption of Mg by the kidney, because

Γ renal excretion is slowed down.

In summary, PTH is hypercalcemic and hypophoaphatemic, calcitriol is hypercalcemic and hyperphosphatemic, calcitonin is hypocalcemic and

hypophosphatemic (inhibition of bone resorption) and phosphatonin is

hypophosphatémiante.

To regulate serum calcium, phosphoremia and magnesia during the peripartum, it is essential:

- avoid any alkalosis, any fatty liver or kidney damage during the end of

 gestation;

- to respect the mechanisms of production or synthesis of parathyroid hormone and

 calcitriol, in dairy cows at the end of gestation and beyond, optimizing the intakes of Ca, P and Mg not too much or too little.

As has been specified above, the compositions according to the invention can incorporate calcium and / or magnesium pidolate as active ingredients, which can subsequently be used in uses according to the invention. The calcium and / or magnesium pidolates used according to the invention have a maximum digestive bioavailability, making it possible to provide 13.5% of Ca and 8.5% of Mg, for example by means of 2 boli of 75 g, directly metabolizable by enterocytes, and to capture, or chelate, Ca, Mg and P present in the digestive tract, via the protein complex of pidolates. They also make it possible to mobilize bone Ca by means of carboxyglutamic acid and to regulate calcemia and phosphatemias, around the farrowing (peri-partum), as has been demonstrated by zootechnical tests conducted by the depositor. and described below. In addition, the compositions of the invention containing calcium pidolate and / or magnesium bolus provide controlled release for a single dose, thereby avoiding burst effect and falling blood levels. Secondly, they cause a significant increase in the growth hormone, precursor of IGF1 (insulin growth factor) involved in the formation of bone and muscle cells.

Tests in the cow

Assays of administering a bolus-containing composition according to the invention containing calcium and magnesium L-pidolate in a 4: 1 mixture were conducted on cows around the farrowing. These tests were conducted in parallel with tests comparing the effectiveness of two products already marketed and available on the market, namely the Bovicalc and Calform-phosphorus.

The trials concerned 5 groups of 6 multiparous dairy cows, peripartum, high producing, having calved at least once, from the same farm and receiving no products containing Ca or Mg other than those referred to below. One of the 5 groups in the test did not receive any products and is considered the control group.

Each group is identified by a letter, in this case N, O, P, Q and R. The start of operations was about 2 to 3 hours before farrowing. The timing of farrowing was noted, indicated in HO, and blood tests performed around the farrowing and up to 25 hours later. These periods of blood are indicated by reference to the farrowing, therefore the reference H, and are therefore:

- H-4 to 5: 4 to 5 hours before farrowing;

- HO: moment of birth;

- H + 3 to 4: 3 to 4 hours after parturition;

- H + 12 to 13: 12 to 13 hours after parturition; - H + 22 to 25: 22 to 25 hours after the farrowing.

The administration of the different products was done as follows:

group N: two boles according to the invention in a single dose at the first signs of farrowing, immediately after the blood samples, the reference of the bolus according to the invention being 7040-2-13 (13003), that is 7 56 g Ca, and 1.19 g Mg; group O: three boles according to the invention in a single dose at the first signs of farrowing, immediately after blood samples, the reference of the bolus according to the invention being 7040-2-13 (13003), ie 11, 34g of Ca, and 1.78g of Mg;

group P: control group, no administered product;

- group Q: a Bovicalc bolus, at the first signs of farrowing, immediately after

 blood samples, then a second bolus Bovicalc 4 to 5 hours after calving, then finally a third bolus Bovicalc 12 hours after calving, immediately after the blood samples, according to the recommendations of the supplier;

- group R: a 350ml bottle of Calform, at the first signs of farrowing, and after blood samples, a second bottle of 350ml of Calform 4 at 5 hours after calving, and a third bottle of 350ml of Calform 12 hours after calving, immediately after blood sampling, following the recommendations of the supplier.

The three administrations of Bovicalc brought a total of 129 g of Ca contained in the three boli, and the three vials of Calform-phosphorus gave 156 g of Ca. In terms of Mg intake, the 3 vials of Calform-phosphorus were brought 2.4g. The boles according to the invention did not provide phosphorus, compared to 135 g of P 3 bottles of Calform-phosphorus.

The bolus according to the invention, bearing the reference 7040-2-13 (13003), had the following composition:

Table 1: Bolus 7040-2-13 (13003)

H + 12 to

Identity Date Part H-4 to H-1 HO H + 3 to 4 13 H + 22 to 25

8595 20-May 85 85 86 83 83

8662 28-Aug 88 79 80 79 76

5282 02-se 82 82 83 84 74

9467 06-oct 84 76 80 75 69

8855 16-oct 83 82 89 75 80

9576 07-Jan 82 81 78 84 85

Lot N 84.0 80.8 82.7 80.0 77.8

Table 2: Results Calcium Lot N

Table 3: Results Calcemia Lot O H + 12 to

Identity Date Part H-4 to H-1 HO H + 3 to 4 13 H + 22 to 25

9320 26-Aug 91 90 85 86 81

9413 28-oct 81 76 74 73 71

8476 15-Nov 84 85 82 86 80

8489 21 -nov 84 81 74 74 85

9552 22-Nov 84 90 88 84 77

9315 08-Feb 57 53 46 41 56 Lot P 80.2 79.2 74.8 74.0 75.0

Table 4: Results Calcium Lot P

Table 5: Results Calcemia Lot Q H + 12 to

 Identity Date Part H-4 to H-1 HO H + 3 to 4 13 H + 22 to 25

9556 10-oct 92 93 106 93 84

8851 10-Nov 83 81 74 81 73

8590 23-Nov 86 90 88 95 87

9433 25-dec 80 83 81 90 108

9480 25-Jan 84 85 86 82 83

8531 26-Jan 86 87 92 93 90

Lot R 85.2 86.5 87.8 89.0 87.5

Table 6: Results Calcemia Lot R

Comparison of calcemia of lot N versus lot P. Lot 0. Lot R

The calcemias in lot N are slightly higher than those in control group P, but although they are in an area at risk of hypocalcemia, that is to say at a blood calcium level of less than 85 mg / l, blood status in Ca have been maintained at a good level and no morbid event has occurred, unlike the control batch which one cow in six has suffered from fever. The calcemias of lots Q and R are slightly higher (7 to 11%) than those of batch N, whose subjects have had only one bolus administration according to the invention. It is surprising, considering the massive Ca influx of Bovicalc (17 times more) and Calform-phosphorus (20 times more), that the blood levels of Ca hardly exceed 92 mg / 1 for these two products.

Comparison of the Calcemias of lots N and O versus lots P. O. R

Calcium in lot O are at levels higher than those in lot N and lot P, since the blood status of cows collected at H-4 to H-1 is greater than 90 mg / l, thereby presenting a lower risk for the subjects of this batch, but the values show that the blood profile is substantially parallel to that of the lot N. It is therefore certain that the bolus according to the invention based on pidolates of Ca and Mg, whose disintegration occurs about 30 hours, directly affects the homeostasis of Ca and P. Comparison of low calcium levels in each batch

Table 9: Low Calcemia - Lot P Identity Date Part H-4 to H-1 HO H + 3 to 4 H + 12 to 13 H + 22 to 25

9439 05-nov 64 65 72 75 77

9406 27/04 75 83 85 87.7 92

Lot Q 69.5 74 78.5 81.5 84.5

Table 10: Low Calcemia - Lot Q

 Table 11: Low Calcemia - Lot R

The 4 calcemias of lot N are 5 to 12% higher than 5 in lot P, within 4 to 12 hours after calving. Those of lots Q and R mark a good ancestry especially from the twelfth hour, the cysemia of cows in lot Q being very low before farrowing. In addition, those of cow No. 9315 in lot P are representative of the course of a fever, which was observed and treated a dozen hours after calving.

Comparison of the phosphoremias of lots N and O versus lots PQ R: H + 12 to

Identity Date Part H-4 to H-1 HO H + 3 to 4 13 H + 22 to 25

8595 20-May 41.9 38.6 57.2 55.8 48.8

8662 28-Aug 50.9 41.3 48.9 57.7 58.4

5282 02-seven 82.1 69.3 82.2 76.8 72.4

9467 06-oct 43.3 38.5 58.8 52.5 49.3

8855 16-oct 42.3 42.2 51.0 57.4 51.4

9576 07-Jan 83.4 78.9 81.2 61.9 53.5

Lot N 57.3 51.5 63.2 60.3 55.6

Table 12: Phosphoremia -

Table 13: Phosphoremia - Lot O H + 12 to

Identity Date Part H-4 to H-1 HO H + 3 to 4 13 H + 22 to 25

9320 26-Aug. 41, 7 43.5 44.1 43.3 45.9

9413 28-oct 51, 2 54.3 43.8 47.6 50.6

8476 15-nov 54.9 58.1 62.0 66, 1 67.8

8489 21-Nov 58.2 55.8 61, 3 79.3 68.2

9552 22-nov 46.4 54.5 68.2 50.6 45.9

9315 08-Feb 37.7 51, 3 29.3 17.6 33.5

Lot P 48.4 52.9 51, 4 50.7 52.0

Table 14: Phosphoremia -

Table 15: Phosphoremia - Lot Q H + 12 to

Identity Date Part H-4 to H-1 HO H + 3 to 4 13 H + 22 to 25

9556 10-Oct 74, 71, 7 92.9 78.6 51, 4

8851 10-nov 39.5 43.4 50.8 45, 1 41, 0

8590 23-Nov 49.9 52.3 45.3 61, 8 52.3

9433 25-dec 77.6 71, 9 77.3 70.7 71, 7

8531 25-Jan 45, 1 58.5 66.4 64.6 56.6

9480 26-Jan 25.2 25.3 37.7 38.6 28.2 Lot R 51, 9 53.8 61, 7 59.9 50.2

Table 16: Phosphoremia -

Phosphoremias of batch N, which received no phosphorus supply, are comparable to, or even somewhat superior to those of batch R, which have nevertheless received a three-fold administration of 135 g of phosphorus. They are clearly superior to the control batch P and especially to lot Q which, in addition, did not receive any phosphorus input. Phosphoremias of Lot N and Lot O are comparable at different levels. The dose effect appears clearly in lot O. It is obvious that pidolates mobilize endogenous organic phosphorus or induce its production.

Except for lot O, which has only one animal at risk, comparisons of phosphorus at risk, ie less than 55 mg / l, or at high risk, that is to say below 40mg / l, of each lot is interesting to consider. The values of lot N, after a drop in blood status at the time of calving, that is to say 1 to 2 hours after a single administration of the two boli, stands up proudly and exceeds that of batch R which brings 135g of phosphorus in three

administrations. Lot O with only one subject was not taken into account, but is nevertheless very representative. The mobilization of endogenous organic phosphorus by pidolates is confirmed.

Results of cow behavior after calving:

Cows were studied in terms of their physical behavior at the time of, and after, the farrowing. The results of this study were expressed in percent compared to 100% representing the behavior of a cow in ideal physical shape. The values of lots N and O showed a clear positivity compared to the other three lots. In fact, the physical behaviors of cows in lots N and O were 75% and 72% compared to an ideal physical form, compared to 38.9% of lot P, 33.3% of lot Q, showing mastitis after calving, and 55.6% of batch R.

These good results are due to pidolates of Ca and Mg, whose action on homeostasis of Ca, P and Mg is very good. As shown by the excellent biochemical results of the N and O batch phosphoremias, the metabolic phosphorus exacerbated by pidolates, stimulates chewing, rumination and digestion by multiplying the digestive flora and that on the other hand the 5-oxo-1 -proline has, through glutathione, an obvious action on the oxy dative stress inherent to the farrowing.

Dairy production compared according to INRA method:

At the instigation of the French dairy control, a method of calculation based on the lactation of the 4th, 5th, and 6th days after calving was developed and proposed by the INRA (National Institute of Agronomic Research), to know "the peak lactation "and better understand future milk production.

Lot N Lot O Lot P Lot Q Lot R

Prod J4 12 30.4 29.4 26.1 23 29.1

Prod J5 15 31.1 29.6 25.5 24.8 29.4

Prod J6 16 33.6 32.9 28.7 25.7 33

Average 14.33 31.70 30.63 26.77 24.50 30.50

Prod Max milk

 potential 25.04 39.63 38.73 35.48 33.58 38.62

Prod Milk

 potential 11.72 41.49 40.55 37.15 35.16 40.44

Lactation

 Real 5609 8877 8676 7948 7522 8651

Prod N-1 milk 6827 7082 7326 7449 7895

TOTAL 8877 8676 8074 7999 8651

Table 17: Milk production, days 4,5,6 postpartum

Thus, it has been found, on the one hand, that the average (days 4, 5, and 6 days) of each lot at N0 is almost equivalent for lots N (31.7), O and R, compared to lot P ( 26.7), and lot Q (24.5), which is a daily difference of 5 to 71 extra milk, and that, on the other hand, the lactation forecasts are favorable for lot N, with +226 liters compared to in batch R, and 800-870 liters compared to batch P and Q. A comparison of the productions of each batch during the first 8 days made it possible to note the same phenomenon. It follows that the use of the pidolates according to the invention makes it possible to stimulate the production of milk in larger quantities very soon after calving, on days 4 and 5 in particular, which has a non-negligible impact on the production. and the profitability of the animal, as well as the quality of the milk produced.

A comparison between the actual production of the previous year (year N-1) and the forecasts cows from the trial was done and the results presented below

 Table 18: Production Comparison N-1

As can be seen, the administration of calcium and / or magnesium pidolates according to the present invention in the form of two or three boli makes it possible to significantly increase the quantity of milk, relative to the products of commerce, which do not lead to only calcium.

Conclusions:

The pidolates of the invention used in supply are just as powerful, if not more efficient than existing products, in particular Calform and Bovicalc, both in terms of calcium intake and the control of calcium levels, and for the management of phosphorus levels, in particular during the birth. This is important when we know that milk fever or fever, as well as hypophosphoremias, and the "cow-cow" syndrome, complicate hypocalcemia in 55% of cases. The 3 zootechnical comparisons show a clear superiority of lots N and O compared to control group P and Lot Q, but also superior results compared to batch R. Without being bound by any hypothesis, the applicant believes that this superiority is due not only to the induction or mobilization of endogenous calcium production, but also to the mobilization of endogenous organic phosphorus. It can not be excluded that, by the same route, bone resorption of calcium by hydroxyproline, and the anti-stress action of 5-oxo-1-proline, allow a rapid revitalization of the animal. Furthermore, apart from their undeniable effects on the dairy behavior of cows, the pidolates according to the invention, when they are administered in the form of boli, are easily, safely, and at one time, at a time when the is the most available animal, unlike the three or four recommended or usual products of commerce. Tests on sows / piglets

Tests of a composition according to the invention were also conducted on sows at the entrance to maternity, about seven days before the farrowing of the piglets which were then fed by the sow. The composition was administered in tablet form, which either melted in animal feed or was chewed directly therefrom.

1001 Sow Test

Test 1001 was to record the productivity and calving behavior of a group of 24 treated sows, designated group A, compared to that of 23 control sows, designated group B. Piglets of group A showed an average weight per piglet at weaning higher than that of the untreated group by more than 5%.

1003 Sow Test

Two pigments (lots of piglets) were chosen to constitute 2 test populations, with 2 groups per population. For the first test population, 12 sows were selected, separated into 2 distinct groups of 6 sows, each sow being well identified. The first group, called lot 1 A, consisted of 6 sows. The group 1A received the tablets according to the invention orally for 14 days, added in the drinking water or on the feed granules, at a rate of 1 tablet per day starting 7 days before the farrowing. either at the entry into maternity of animals, and ending 7 days after farrowing. Identification and individual weighing of piglets was done on the first day and at weaning, at about 28 days. The second group, called Lot 1B, also consisted of 6 sows. Group 1B received a placebo tablet, administered orally for 14 days, added to drinking water or feed pellets, at a rate of 1 tablet per day starting 7 days before giving birth and finishing 7 days days after farrowing. Identification and individual weighing of piglets were done on the first day and at weaning at 28 days.

For the second population, the first group, called Lot 2A, consisted of 6 sows. This group 2A received the tablets according to the invention administered orally for 14 days, added in the drinking water or on the feed granules, at a rate of 1 tablet per day starting 7 days before the birth and ending 7 days after farrowing. Piglets were not identified, but each batch was weighed on the first day and weaned at 28 days. The second group, called Lot 2B, consisted of 6 sows. This group 2B received a placebo tablet, administered orally for 14 days, added to drinking water or feed pellets at a rate of 1 tablet per day starting 7 days before giving birth and ending 7 days after farrowing. Piglets were not identified, but each batch of piglets per sow was weighed on the first day and at weaning at 28 days.

Sows were studied and judged at birth according to the following criteria:

- Date of birth

- Duration of the farrowing

- Easy to read

- Recording of treatments performed or obstetric interventions

- Restore the appetite

- State of the udder

- Rectal temperature control after farrowing and 12 hours later

- Treatment of sows with a temperature greater than 39.3 ° C

- Cannibalism

And subsequently, the following assessments were made:

- At the last farrowing

- Total born piglets

- Dead piglets born

- Weaned piglets

- At birth

- Range of reach

- Number of born

- Number of deaths born

- Identification of each piglet of LOT N ° 1 - Weighing of each piglet of batch N ° 1

- Weighing the scope of Lot N ° 2

- Homogeneity

- at 3 days and 7 days: morbid manifestations (diarrhea, omphalitis, arthritis)

- 28 days:

- weaning date

- number of piglets present

- Weighing of each piglet of batch N ° 1

- Weighing the scope of the lot N ° 2

- homogeneity

- on slaughter: where possible, the carcass weight of the individuals in lot No 1, A and B, identified on the first day, were checked

The composition according to the invention that was administered was as follows:

Table 19: VST Formulation 212 The results of this test are presented below:

Population 1, Group A (entry into maternity on 21/10) - 72 weaned pigs

 Table 20: Population 1 - Group A - Weight

Population 1, Group B (entered maternity on 21/10) - 66 weaned piglets

Table 21: Population 1 - Group B - Weight Comparison Group 1 A and Group 1B

 Table 22: Summary Comparison - Population 1

As can be seen, the sows of group 1 A, having received a composition based on calcium pidolate and / or magnesium according to the invention had a farrowing time shorter than those having had only the placebo. In addition, weight gain in piglets fed sows fed calcium and / or magnesium pidolate was significantly higher, by about 14% more weight compared to their counterparts, including sow feeders. had received only the placebo.

Population 2, Groups A and B (entry into maternity on 21/10) - 144 pigs weaned in total

 Table 23: Population 2 - Comparison Group A - Weight

As can be seen, in group 2A, whose sows had received the calcium and / or magnesium pidolates according to the invention, the farrowing period was shorter than the placebo group. In addition, Group A piglets also showed increased weight gain. important than their counterparts in Group 2B.

These results clearly show that the calcium and / or magnesium pidolates as used according to the invention have a non-negligible impact on the growth of piglets, in particular on the higher carcass weight of the finished pig for the same purpose. fattening time, or shorter fattening time for the same carcass weight. This also has a positive effect on the general health of the sow, as the shorter farrowing times indicate a better recovery of the animal following the stress induced by entry into maternity and parturition. This health recovery has important consequences for the farmer, both in terms of the animal's surveillance investment, but also in terms of

overall productivity of its operation.

Finally, during the preparation of the compositions according to the present invention, the applicant has also found the possibility of measuring the in vitro disintegration of the composition in a reproducible manner and thus be able to predict with a fairly high degree of certainty the duration of disintegration in vivo, once the composition is ingested by the animal. To the knowledge of the applicant, this is the first time that such an exploit could be realized. Indeed, it would seem that the prior art in this field is limited to reproducing a synthetic salivary buffer proposed in an article published in 1948 by McDougall, E.I., entitled "Studies on ruminant saliva. Tea

composition and output of sheeps saliva "published in Biochem. J., 43: 99-1 09. This article describes a set of components representing a "salivary" synthesis buffer which is supposed to constitute the medium of dissolution of the sheep and which has a pH around 8. Paradoxically, the model which contains is proposed and has been used for years for dissolution tests and studies of active ingredients for ruminant animals in vitro is, basically, a salivary buffer. Since then, this buffer has been taken as a starting point, by others, to modify it, by bringing it back to a pH closer to the pH of the rumen. However, the Applicant has noticed that the buffer initially proposed by McDougall, and since modified by others by addition of acetic acid, has a significant pH shift or shift with time, so that it does not even fill up. buffer role. Indeed, the main role of a buffer is to exhibit a substantially constant behavior over a relatively small and well defined pH range. For ruminant animals, the temperature and pH of the rumen is generally between about 38 degrees Celsius and about 41 degrees Celsius, for a pH of between 5.8 and 6.4.

Thus, another object of the present invention is a method for measuring the in vitro disintegration of a composition according to the invention, comprising the steps of: - Prepare an aqueous buffer solution;

introducing a composition according to the invention into the buffer solution;

- Keep the buffer and composition at constant temperature and stirring;

- Determine the disintegration of the composition at regular intervals until complete disintegration thereof.

Several complementary and preferred steps may be added to the method described above. According to a first preferred alternative, the method according to the invention further comprises a step of replacing the buffer solution with a quantity of equivalent volume buffer solution every hour after initial introduction of the composition into the buffer solution.

In another preferred embodiment, the method further comprises a step of replacing the buffer solution with a volume equivalent amount of buffer solution every twelve hours after initial introduction of the composition into the buffer solution.

According to yet another preferred variant, the method further comprises a step of replacing the buffer solution with a volume equivalent amount of buffer solution every forty-eight hours after initial introduction of the composition into the buffer solution.

According to yet another preferred variant, the method further comprises a step of replacing the buffer solution with a volume equivalent amount of buffer solution every seventy-two hours after initial introduction of the composition into the buffer solution. Whatever the variants used, it is also preferred that the method further comprises a step of removing the remaining solid material from the composition upon replacement of the buffer solution, scrubbing said remaining solid material to remove a surface film, and re-introducing said remaining material into the buffer solution.

In the rumen, in fact, bolus-type compositions are subject to significant friction phenomena, apart from constant movements of stirring and stirring.

The method is advantageously and preferably carried out by maintaining the temperature of the solution at 39 degrees Celsius. In addition, the agitation of the method is preferably carried out by a rotating magnetic bar rotating between 200 to 300 rpm.

According to other advantageous and preferred characteristics, the determination of the disintegration is carried out by weighing the composition before its introduction into the buffer solution, then again during each replacement of the buffer solution, the composition is in the form of a bolus, and the composition is introduced into a net before introduction into the buffer solution. Advantageously, the composition is suspended in the buffer solution.

Preferably, the buffer solution used in the method according to the invention is composed of 0.2M Na ₂ HPO ₄ .2H ₂ 0, 0.1M citric acid and 0.5 g / L NaCl. This buffer can be prepared in two ways as described below:

- by direct mixing: to prepare 1 liter of buffer, weigh 22.25 g of di-sodium

 hydrogen phosphate dihydrate (Na2HPO4.2H2O), 7.2 g of anhydrous citric acid, 0.5 g of anhydrous NaCl, and make up to 1 liter by addition of distilled or deionized water. Then mix with stirring until complete dissolution and obtaining a translucent solution. The pH value obtained is 5.80 / 5.85;

- by adjustment: prepare separately a basic solution and an acid solution. The acid solution contains 0.1 M citric acid NaCl 0.5 g / liter in distilled or deionized water qs 1 liter, giving a solution of pH = 2.30 approximately. The basic solution contains 0.2 M sodium dihydrogen phosphate dihydrate NaCl 0.5 g / liter in distilled or deionized water qs 1 liter, giving a solution of pH = 8.88 approximately.

After preparing the solutions, pour gradually and with stirring the acid solution on the basic solution. Progressively follow the evolution of the pH until the desired value is reached: 5.80 / 5.85, the pH falling as the acid is added. About 1.2 liters of acid solution is required for 2 liters of basic solution. For the purposes of the measurement method, the composition is presented as a bolus. Preferably, the bolus is trapped and suspended in a net, for example orange fillet. It is stirred in Erlenmeyer flasks with the buffer described above, for a volume of 3 liters. The system is agitated, for example with a magnet bar, preferably with stirring plate / heating plate rotation, so as to have a relatively low vortex agitation. The stirring speed is preferably 200 to 300 rpm, and the measurement temperature is maintained at 39 ° C +/- 0.1 degree Celsius. Preferably for boli In short-term disintegration, the dissolution / buffer solution is changed every hour by new buffer. According to another preferred variant of the invention for medium-duration boli, the buffer solution is changed once every 24 hours with new buffer. According to another preferred variant of the invention, for long-term boluses, the buffer solution is changed every 48 hours by new solvent. The boli are generally weighed at T = 0 for evaluation of their dry weight. At each emptying: T + 1, T + 2, T + n, etc., they are removed from the solution, passed slightly under the tap and / or rubbed gently between the fingers, to eliminate a surface film, and then weighed in a " wet, with the constitution water that has penetrated inside the matrix. The dissolution profiles are established and expressed in:% of weight losses of boli as a function of time / versus initial dry weight of boli.

In addition, and in order to demonstrate the inability of the buffer proposed by McDougall to fulfill its role of buffer, tests were conducted with compositions according to the invention, in the form of a bolus and the buffer and the method according to the present invention. invention. The details of these tests are given below: Preparation of 10L of Me Dougall buffer solution modified by adjusting the pH to 6.5 by addition of acetic acid

1. Take 10L of deionized water

2. Weigh the ingredients: - NaHCO ₃ : 98g

Na ₂ HPO ₄ , 12H ₂ O

- NaCl: 4.7g

- KC1: 5.7g

CaCk anhydrous

- Anhydrous MgCl ₂ : 0.6g

3. Dissolve the ingredients

4. pH measurement: 8.24 to 20.8 ° C

5. Adjust the pH to 6.50 with acetic acid

6. Homogenize 7. Heat the buffer to 39 ° C: (temperature reached in lh): pH 6.75

8. Disintegration of 2 boli whose composition is in accordance with that according to the invention: references R12208 and R12210.

 Table 24: Comparative Buffers

As can be seen, the "buffer" solution, modified initially proposed by

McDougall, adjusted by the addition of acetic acid, shows a very important pH shift with time, passing from 6.75 to T0, to 8.72 at T + 3J, which removes the interest of this buffer as a buffer representative for the study of in vitro disintegration of compositions according to the invention, such as boli, for ruminant animals. In addition, it should be noted that the McDougall buffer shows a pH shift already after heating, from pH 6.5 after adjustment with acetic acid to pH 6.75 after being brought to 39 degrees Celsius . AT on the other hand, the buffer prepared by the applicant, whose pH at T0 was 5.84, hardly changed during the entire duration of the disintegration of the compositions tested, the measurement of the pH after three days of disintegration indicating a pH value of 6, 20. Thus, the buffer developed by the applicant is entirely suitable for an in vitro disintegration measurement protocol mimicking that of ruminant animals for compositions according to the invention which are in the form of a bolus.

Examples of boli corresponding to the composition according to the invention were made and their details given below. These examples were divided into bolus categories, according to the duration of disintegration, ie, according to the following classification:

- disintegrating bolus between 1 hour and 30 days, called short-term bolus;

- disintegration bolus between 31 days and 90 days, called medium-duration bolus;

- disintegrating bolus between 91 days and 180 days, called long-term bolus;

- 180-day disintegration bolus, referred to as an ultra-long-life bolus.

All the compositions described can be obtained according to a general method of preparation which will be detailed below:

1. Mixture of powders comprising: the active principle (s), the compressing agent

 optionally, optionally the disintegration accelerator, optionally the weighting agent and the retarding agent, and any binder, in a mixer type apparatus, or in a mixer / granulator.

2. Potential granulation of the mixture thus obtained with water (or possibly low-titre alcohol), then drying in an oven set at about 50 ° C, or alternatively drying in a fluidized air bed (LAF) type apparatus .

3. Grinding and / or sizing of the dry or wet granulate, to obtain a grain passing on a sieve of size less than or equal to 4 mm, followed by a possible drying, according to one of the two methods above.

4. Final mixing: starting from the grain obtained at the end of step 3, addition of a lubricating aid for compression, a disintegrating agent and possibly a weighting agent in the event that they are introduced during the final mixing. 5. Optionally, for the case of tablets: compression of the mixture prepared in step 1; and for the boli: compression of the mixture from step 4, into a suitable matrix.

Other alternatives to the process described above can be envisaged:

• Introduction of the weighting agent and / or the retarding agent, at the time of step 1;

• Introduction of the binder and / or the accelerating agent of disintegration after dissolution and then spraying an aqueous solution (or hydro-alcoholic) on the mixture to be granulated, at the time of step 2;

• Introduction of the retarding agent according to the technique of "hotmelt" (in the form of melted fat), during step 4, that is to say during the final mixing.

Short Term Bolus (1 hour to 30 days)

Some examples of short-term formulations according to the invention, in the form of a bolus, are given below.

Product Principle Active Accelerator Delay Self

Rl-07-03 Arbo Glycinate C12 castor oil Iron hydrogenated copper (Na / NH ₄ ) powder

RI -07-04 Arbo Glycinate C12 Stearic Acid 92% Iron Powder Copper (Na / NH ₄ )

RI -07-01 Arbo Glycinate C12 Soybean Iron Iron Copper Powder (Na / NH ₄ ) Hydrogenated

7040-2-13 Arbo Pidolate C12 Soybean Iron Powder (13003) Hydrogenated Ca / Mg (Na / NH ₄ )

7040-2-13-6 Arbo Pidolate C12 Cottonseed Iron Oil Powder (13003) Hydrogenated Ca / Mg (Na / NH ₄ )

RI -47-02 bis Arbo Glycinate C12 Soybean Iron Iron Powder (A) Copper (Na / NH ₄ ) Hydrogenated

R1-47-02-B Arbo Glycinate C12 Soybean Iron Powder (3.2) Copper (Na / NH ₄ ) Hydrogenated

RI -06-06 (b) Arbo Glycinate C12 Soybean Iron Iron Copper Powder (Na / NH ₄ ) Hydrogenated

RI -06-01 Ultrazine Glycinate (Na) Soybean Oil Iron Hydrogen Copper Powder

RI -06-02 Ultrazine Glycinate (Ca) Soybean Iron Hydrogenated Copper Powder

Rl-06-03 Lignobond Glycinate DD Soybean Iron Hydrogenated Copper Powder (Ca)

RI -06-04 Borresperse Glycinate (Na) Soybean Oil Iron Hydrogenated Copper Powder

Rl-06-05 Borresperse Glycinate Soybean Iron Iron Copper Powder AM320 (NH ₄ ) Hydrogenated

Rl-07-05 Arbo Glycinate Tl l N5 Soybean Iron Hydrogenated Copper (NH ₄ ) Powder Product Principle Active Accelerator Delay Self

Rl-07-06 Arbo Glycinate N18 Na Soybean Iron Hydrogenated Copper Powder

Rl-07-07 Arbo Glycinate Kl 8 K Soybean Iron Hydrogenated Copper Powder

Rl-07-08 Arbo Glycinate C12 Soybean Oil Zinc Copper Powder (Na / NH ₄ ) Hydrogenated

Rl -02-01 Arbo Glycinate C12 Soybean Iron Iron Copper Powder (Na / NH ₄ ) Hydrogenated

Rl -09-10 Mg Arbo Sulphate C12 Hydrogenated Soybean Iron (Na / NH ₄ ) Hydrogenated Soybean Oil

Rl -47-01 Vitamin C Arbo C12 Soybean Iron Hydrogenated Powder (bis) (Na / NH ₄ )

Rl -47-03 A Arbo Sulphate C12 Soybean Iron Powder (3.2) Copper (Na / NH ₄ ) Hydrogenated

Rl -42-02 Arbo Carbonate C12 Soybean Iron Powder

Hydrogenated copper (Na / NH ₄ )

Rl-37-10 (A) Arbo Carbonate C12 Soybean Iron Powder

Hydrogenated cobalt (Na / NH ₄ )

VST 224 Pidolates of Ca Arbo C12 Rapeseed Oil Iron Powder

 40% 1 and hydrogenated Mg

 10%

 Table 25: Short Term Bolus Components

The percentages of the various components, their solubility index, and their periods of disintegration are given below: Product RA% Ag Ag Ag Ag Leste% Excip. % Index Duration

 Accel. Delay. % Comp. % Ground. (h ouj)

%

 RI -01 -02 50 12 8 0 25.2 4.8 28.560 36h

RI -01-03 50 12 8 0 25.2 4.8 28.560 57h

RI -01-06 50 12 8 0 25.2 4.8 28.560 57h

RI -01-07 50 12 8 0 25.2 4.8 28.560 38h

RI -01 -04 50 12 8 0 25.2 4.8 28.560 48h

RI -01-05 50 12 8 0 25.2 4.8 28.560 48h

Rl-07-03 50 12 8 0 25.2 4.8 28.560 35h

RI -07-04 50 12 8 0 25.2 4.8 28.560 33h

RI -07-01 50 12 12 0 21.2 4.8 28.560 63.5h

7040-2-13 50 12 8 0 29 1 27.315 33h (13003)

7040-2-13-6 50 12 8 0 29 1 27.315 30h (13003)

RI -47-02 bis 50 12 5 0 28.2 4.8 28.560 72h (A)

 R1-47-02-B 50 12 8 0 25.2 4.8 28.560 93h (3.2)

RI -06-06 (b) 50 12 8 0 25.2 4.8 28.560 48h

RI -06-01 50 12 8 0 25.2 4.8 28.560 39h

RI -06-02 50 12 8 0 25.2 4.8 28.560 48h

Rl-06-03 50 12 8 0 25.2 4.8 28.560 48h

RI -06-04 50 12 8 0 25.2 4.8 28.560 48h

Rl-06-05 50 12 8 0 25.2 4.8 28.560 48h

Rl-07-05 50 12 8 0 25.2 4.8 28.560 40h Product RA% Ag Ag Ag Ag Leste% Excip. %> Index Duration

 Accel. Delay. % Comp. % Ground. (h ouj)

%

Rl-07-06 50 12 8 0 25.2 4.8 28.560 39h

Rl-07-07 50 12 8 0 25.2 4.8 28.560 48h

Rl-07-08 50 12 8 0 25.2 4.8 28.560 54h

Rl -02-01 50 12 8 0 25.2 4.8 28.560 57h

Rl -09-10 57 5 8 0 25.2 4.8 26.718 36.75h

Rl -47-01 (bis) 50 12 12 0 22 4 38,040 l lh

Rl -47-03 To 50 12 8 0 25.2 4.8 21.095 l lh (3.2)

Rl -42-02 50 12 8 0 25.2 4.8 6.845 17j

Rl-37-10 (A) 50 8 8 0 29.2 4.8 4.703 Hj

VST 224 50% 3% 8% 0 35% 4% 22,946 28 to

 30H

Table 26: Quantities Bolus Components Short Duration

Bolus Medium Duration (31 days to 90 days ^)

Some examples of medium-duration formulations according to the invention, in the form of a bolus, are given below.

Product Principle Active Accelerator Delay Ag.

 Compression

R2-47-02 - PA Blend: Arbo C12 Soybean Iron Oxide Powder

 Magnesia Hydrogen Glycinates

A (1.5)

 copper 6,12%, of

 zinc 2.05%, and of

 manganese 6.06%,

 Carbonates

 2.67% copper and

 manganese 6.00%,

 Zinc oxide

 7,10%, Iodate of

 calcium 1.56%,

 Sodium selenite

 0.22%, beta-carotene 2.00%,

 lives. At 0.54%, lives.

 D3 0.05% and lives E

 3.8%

Bolus Mg / Blend of Macro Arbo C12 Soybean Iron Oxide Powder and Oligofluoromagnesium Magnesia

Cu / Se

 items

(Trial 3)

R2-47-03 Mixture of PA: Arbo C12 Soybean Iron Oxide Hydrogenated Powder Magnesia

A (3.1) Copper oxides

 7.47%>, zinc

 23.60%

 Carbonates

 manganese

 13.27% and

 cobalt 0.846%,

 Calcium iodate

 3.34%, Selenite of

 sodium 0.551%

 lives. At 0.713%, vit.

E 14, 75% Product Principle Active Accelerator Delay Ag.

 Compression

Rl-18-01 Arbo Carbonate C12 Soybean Phosphate Iron Powder

 Tricalcium hydrogenated copper

Rl-16-09 Carbonate Arbo C12 Soybean Oil Lime Flame Iron Powder

 Hydrogenated copper

Rl-32-04 Arbo Carbonate C12 Soybean Oil Quicklime Iron Powder

 Hydrogenated copper

RI -22-02 Arbo Carbonate C12 Soybean CaC03 Iron Powder

 Hydrogenated copper production

RI -22-08 Arbo Carbonate C12 Soybean Carbonate Iron Powder

 Hydrogenated copper heavy Mg

RI -22-01 Arbo Carbonate C12 Soybean Phosphate Iron Powder

 Hydrogenated Copper Bicalcium

 anhydrous N ° l

Rl-16-05 Arbo Carbonate C12 Soybean Phosphate Iron Powder

 Hydrogenated dicalcium copper

 anhydrous N ° 2

Rl-16-06 Arbo Carbonate C12 Soybean Oil Lithotam Iron Powder

 Hydrogenated Copper Powder

Rl-16-07 Carbonate Arbo C12 Soybean Carbonate Iron Powder

 Hydrogenated Copper Heavy Calcium

 High density

RI -22-07 Arbo Carbonate C12 Soybean Iron Hydroxide Powder

 Hydrogenated Copper Magnesia

Rl-12-02 Arbo Carbonate C12 Soybean Iron Oxide Powder

 Hydrogenated Copper Magnesia

RI -51-04 Arbo Carbonate C12 Soybean Iron Oxide Powder

Hydrogenated Copper Magnesia Product Principle Active Accelerator Delay Ag.

 Compression

Rl-12-01 Arbo Carbonate C12 Soybean Iron Oxide Powder

 Hydrogenated Copper Magnesia

Bolus Blend of Arbo C12 Iron Oxide Oil Powder Plant Plant Powder Rapeseed Magnesia

Hydrogenated Officinal Test 11 Carbonate

4.7 (wormwood, squash, calcium

 goosefoot,

 male fern,

 tanaisie, boldo, garlic,

 elk, artichoke,

 thyme) +

 lithothamne

 Bolus Blend of Arbo C12 Iron Oxide Oil Powder Plant Plant Powder Rapeseed Magnesia

Hydrogenated Officinal 12 Test Carbonate

2.4 (wormwood, squash, calcium

 goosefoot,

 male fern,

 tanaisie, boldo, garlic,

 elk, artichoke,

 thyme) +

 lithothamne

 Table 27: Medium Duration Bolus Components

The percentages of the various components, their solubility index, as well as their duration of disintegration are given below:

Product PA% Ag Ag Ag Ag + Leste% Excip. % Index Duration

 Accel. Delay. % Comp. % Ground. (days)

%

Mg Bolus / 19,13 7 1 62.37 7 3.5 10.974 45 Cu / Se (Test

3)

 R2-47-03 To 64.55 5 5 8.65 10 4.8 4.734 61 (3.1)

Rl-18-01 50 4 8 15 18.2 4.8 2.562 68

Rl-16-09 50 4 8 15 18.2 4.8 2.583 79

Rl-32-04 50 4 8 15 18.2 4.8 2.580 81

RI -22-02 50 4 8 15 18.2 4.8 2.562 47

RI -22-08 50 4 8 15 18.2 4.8 2.568 46

RI -22-01 50 4 8 15 18.2 4.8 2.565 60

Rl-16-05 50 4 8 15 18.2 4.8 2.565 58

Rl-16-06 50 4 8 15 18.2 4.8 2.562 56

Rl-16-07 50 4 8 15 18.2 4.8 2.562 56

RI -22-07 50 4 8 15 18.2 4.8 2.562 72

Rl-12-02 50 8 8 15 14.2 4.8 4.703 70

RI -51-04 50 6 8 15 16.2 4.8 3.633 74

Rl-12-01 50 4 8 15 18.2 4.8 2.562 77

Bolus Plant 35.7 3 5 9.0 35 4.5 85 Test 11 4.7 (MgO)

 7.8

 (CaC03)

 Bolus Plant 35.7 3 5 11.8 35 4.5 70 Test 12 2.4 (MgO)

 5

 (CaC03)

Table 28: Quantities Components Bolus Average Duration Long Term Bolus (91 days to 180 days)

Some examples of long-term formulations according to the invention, in the form of a bolus, are given below.

Product PA Ag Ag Ag Ag Leste Excip. Index Duration

 Accel Delay Comp. % % % Ground. (days)

. %. %

Rl-16-14 62.57 4 5 13.63 10 4.8 3.128 101

 Arbo Oil Iron Oxide Blend

 Carbonates of C12 C12 Soy Magnesia Powder

 0.860%, Mn hydrogen

 13.5%, ene oxides

 of Cu 7.6% and

 Zn 20%,

 vitamins A

 0, 772% and E

 15.88%, Selenite

 Sodium

 0.560%, and

 iodate of Ca

 3.4%

RI -22-09 Oxide of 4 5 6.8 12.3 4.875 3.009 160

 Copper: 41.6 Arbo Oil Iron Oxide

 Zinc Oxide: C12 Soy Magnesia Powder

 25, Hyd Selenite

 sodium: 0.445

Rl-13-01 50 6 8 15 16.2 4.8 3.633 131

 Arbo Carbonate Iron Oxide Oil

 Manganese C12 Soy Magnesia Powder

 hydrogenated

Aeneas Product PA Ag Ag Ag Ag Leste Excip. Index Duration

 Accel Delay Comp. % % % Ground. (days)

. %. %

Rl-16-15 61.8 4 5 15 9.285 4.875 2.797 176

 Zinc Oxide, Arbo Iron Oxide Oil

 31; C12 carbonates of soybean Magnesia powder

 copper, 12.5; hydrogenated

 cobalt, 1.52; Aeneas

 and manganese,

 15; CaI03, 1.6;

 Selenite of

 sodium, 0.22

Rl-22-12 Oxide of 4 5 6,78 12,3 4,875 3,009 138 Copper: 11,6 Arbo Oil Iron Oxide

 Zinc Oxide: C12 Soy Magnesia Powder

 55, Hyd Selenite

 sodium: 0.445

VST228-1 62.88 3 7 11.32 12.3 3.5 3.229 145 bis Test 2 Copper Oxide Arbo Oil Iron Oxide

3.4 Black 57.83%, C12 Magnesia Powder

 Rapeseed Iodate

 Calcium 3.95%, hydrog

 Selenite of enée

 sodium l, l% o

 VST228-4 61.67 3 6 12.53 12.3 4.5 3,373 125 bis Test 3 Copper Oxide Arbo Oil Iron Oxide

3.4 Black 57.83%, C12 Magnesia Powder

 Rapeseed Iodate

 Calcium 2, 74%, hydrogen

 Selenite of enée

 sodium 1.1%

 VST 228-6 61.07%: 3% 5% 13.76% 12.68 4.5% 125 4.2 Copper Oxide Arbo Oil Oxide%

 black 52.05%, C12 of Magnesia Iron

 Rapeseed Iodate Powder

 7% calcium, hydrog

 Selenite of enée

sodium 2.02% Product PA Ag Ag Ag Ag Leste Excip. Index Duration

 Accel Delay Comp. % % % Ground. (days)

. %. %

VST 215 66.13%: 3% 3% 11.04% 12% 4.83% 2,766 180 D12 H1 Arbo Mix Iron Oxide Oil

 Vitamin E 20% C12 Magnesia Powder

 and Vitamin A Rapeseed

 2%, Hydrogen oxides

 Manganese

 8.684%, of

 copper 7.6% o and

 zinc, 21.725%>,

 Carbonate

 cobalt 0.86%,

 Iodate of

 calcium 4.53%,

 Selenite of

 sodium 0.732%

 Table 29: Long Term Bolus Compositions

Ultra-long Bolus Duration ί Greater than 180 days ^)

Some examples of ultra-long term formulations according to the invention, in the form of a bolus, are given below.

Product P.A.% Ag. Ag. Ag. Excip. Index Duration

 Accel. Comp. Delay % % % Ground. (days)

%. %

 RI -26-04 50 4 8 15 18.2 4.8 2.583 215

 Zinc Oxide Arbo Oil Lime Iron

 C12 soybean extinct powder

 hydrogenated

 Aeneas

RI -22- 10 Oxide of 4 5 6.78 12.3 4.875 3.009 200

 Copper: 31.6 Arbo Oil Iron Oxide

 Soya C12 Oxide Magnesia Powder

 Zinc: 35, hydrog

 Selenite of enée

 sodium: 0.445

RI -22- 11 Oxide of 4 5 6.78 12.3 4.875 3.009 200

 Copper: 21.6 Arbo Oil Iron Oxide

 Soya C12 Oxide Magnesia Powder

 Zinc: 45, hydrog

 Selenite of enée

 sodium: 0.445

Rl-12-05 Oxide of 6 8 15 16.2 4.8 3.633 265

 Zinc: 50 Arbo Oil Iron Oxide

 C12 Soy Magnesia Powder

 hydrogenated

Aeneas

Product P.A.% Ag. Ag. Ag. Excip. Index Duration

 Accel. Comp. Delay % % % Ground. (days)

%. %

VST 226-6 68.12%: 3% 5% 6.78% 12.6% 4.5% 3.317 300

2R Arbo Oil Iron Oxide Blend

 C12 oxide magnesia powder

 Copper 21.99% Rapeseed

 and Hydrogen Zinc

 38.61%, ene

 Carbonate

 cobalt 1.28%,

 Selenite of

 sodium 1.03%,

 Iodate of

 calcium 5.21%

 VST 227-4 64.65%: 3% 6% 9.55% 12.3% 4.5% 3.339 275

Test 3 4.2 Arbo Mix Iron Oxide Oil

 C12 oxide magnesia powder

 Copper 23.05% Rapeseed

 and zinc hydrogen

 40.5%, en

 Selenite of

 sodium 1.1%

 Table 30: Ultra-Long-Lasted Bolus Compositions

Claims

Galenic composition adapted for administration to an animal, preferably rearing, comprising at least the following three components:

One or more active ingredients;

An accelerating agent of disintegration;

A disintegrating agent,

And in which the disintegration accelerating agent and the retarding agent of

 Delitescence are integrated into the composition so as to form a controlled release matrix of the active ingredient (s).

The pharmaceutical composition of claim 1, wherein the controlled release matrix is formed by homogenously mixing the active ingredient (s) with the disintegrating agent and the disintegration accelerating agent.

A pharmaceutical composition according to any one of the preceding claims which further comprises a weighting agent.

A composition according to any one of the preceding claims which comprises a weighting agent which is a metal or metal alloy in particulate form.

The composition of claim 3, wherein the weighting agent is selected from the group consisting of iron, steel, cast iron, bronze, copper, brass, nickel, tungsten, zinc, constantan , chromium, manganese, ferro-nickel, and preferably is iron.

A composition according to any one of the preceding claims, wherein the composition is in the form of a bolus.

Composition according to any one of the preceding claims, in which the composition is in the form of a bolus which has a density greater than 1.5 g / cm ³ , preferably greater than 1.8 g / cm ³ , and even more preferably greater than 2.0 g / cm ³ .

8) Composition according to any one of claims 1 to 5, wherein the

 The composition is in the form of a chewable tablet.

9) Composition according to any one of the preceding claims, wherein the agent for accelerating disintegration is a lignosulphonate in the form of hydrosulfide powder, with a molecular weight of between 10,000 Daltons and 200,000 Daltons.

10) Composition according to any one of the preceding claims, wherein the accelerating agent of the disintegration is a lignosulphonate in the form of water-soluble powder, selected from the group consisting of lignosulphonates based on calcium, lignosulphonates based on ammonium , sodium lignosulphonates, potassium lignosulphonates, or a mixture thereof.

11) A composition according to any one of the preceding claims, wherein the disintegration accelerating agent is a lignosulphonate selected from the group consisting of mixed acid lignosulphonates, simple acid lignosulphonates, simple basic lignosulphonates and simple neutral lignosulphonates and mixtures thereof.

12) Composition according to any one of the preceding claims, wherein the accelerating agent of the disintegration is present in amounts of between 3% to 25% by weight relative to the total weight of the composition, preferably between 3% to 16%, or even between 3% and 8%, by weight relative to the total weight of the composition.

A composition according to any one of the preceding claims, wherein the retarding agent is a room temperature solid fatty substance selected from the group consisting of hydrogenated rapeseed oil, hydrogenated soybean oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated castor oil, vegetable waxes, alcohol and fatty acid esters, cerides, cetyl palmitate, carnauba wax, white beeswax, and candelilla wax, stearin, stearic acid, glycerol trihydroxystearate, microcrystalline wax, solid paraffin, and white melamine wax, and mixtures thereof . 14) Composition according to any one of the preceding claims, wherein the retarding agent is present in amounts of between 1% and 12%, preferably 1% to 8%, more preferably between 2% and 10%, and even more preferably between 3% to 12% by weight relative to the total weight of the composition.

15) Composition according to claim 1, having a total disintegration of between one hour and less than or equal to 30 days.

16) Composition according to claim 1, having a total disintegration greater than 30 days and less than or equal to 90 days.

17) Composition according to claim 1, having a total disintegration greater than 90 days and less than or equal to 180 days.

18) Composition according to any one of the preceding claims, having a total disintegration greater than 180 days.

19) Composition according to any one of the preceding claims, which

 further comprises a calcium, magnesium or phosphorus based mineral agent in the form of an inorganic salt of inorganic nature, or a mixture thereof.

20) A composition according to any one of the preceding claims, wherein the compressing agent is in powder form and is selected from the list consisting of one or more calcium, magnesium, or phosphorus-based salts having a solubility in water at room temperature of less than 0.25 g in 100 g of water, preferably less than 0.15 g in 100 g of water.

A composition according to any one of the preceding claims, wherein the powdery compressing agent is selected from the group consisting of magnesia, quicklime, dolomitic lime, slaked lime, magnesium hydroxide, anhydrous dicalcium phosphate, tricalcium phosphate, natural or precipitated calcium carbonate, high density calcium carbonate, litothamne, magnesium carbonate, basic heavy magnesium carbonate, or a mixture thereof and preferably is magnesia oxide. 22. A composition according to claim 20 or claim 21, wherein the compressing agent is present in the composition at values between 0% to 70%, preferably 0% to 60%, and more preferably 0% to 60%. %> to 40%> by weight relative to the total weight of the composition.

23) Composition according to any one of the preceding claims, wherein the active ingredient (s) is a trace element or a mixture of trace elements selected from the group consisting of ferrous carbonate, ferrous chloride tetrahydrate, ferric chloride hexahydrate, citrate ferrous hexahydrate, ferrous fumarate, ferrous lactate tetrahydrate, ferric oxide, ferrous sulfate monohydrate, ferrous sulfate heptahydrate, ferric acid amino chelate, hydrated, glycine iron chelate, hydrated, iron pidolate , calcium iodate hexahydrate, anhydrous calcium iodate, sodium iodide, potassium iodide, cobalt acetate tetrahydrate, basic cobalt carbonate monohydrate, cobalt carbonate hexahydrate, sodium chloride cobalt hexahydrate, cobalt sulfate heptahydrate, cobalt sulfate monohydrate, cobalt nitrate hexahydrate, cobalt pidolate, cupric acetate monohydrate alkaline carbonate of copper monohydrate, cupric chloride dihydrate, copper methionate, cupric oxide, cupric sulfate pentahydrate, cuprous chelate of amino acids, hydrated, cuprous glycine chelate, hydrated, chelate of copper hydroxyl analogue

methionine, copper pidolate, manganous carbonate, manganous chloride tetrahydrate, manganese acid phosphate trihydrate, manganous oxide, manganic oxide, manganous sulfate tetrahydrate, manganous sulfate monohydrate, manganese acid chelate amino, hydrated, glycine manganese chelate, hydrated, manganese chelate of hydroxy-methionine analogue, manganese pidolate, zinc lactate trihydrate, zinc acetate dihydrate, zinc carbonate, zinc chloride monohydrate, zinc oxide, zinc sulfate heptahydrate, zinc sulfate monohydrate, zinc amino acid chelate, hydrated, glycine zinc chelate, hydrated, zinc chelate hydroxy-methionine analogue, zinc pidolate, ammonium molybdate, sodium molybdate, sodium selenite, sodium selenate, organic selenium form produced by Saccharomyces cerevisiae, the selenium nomethionine obtained from inactivated selenium yeast, and selenomethionine produced by Saccharomyces cerevisiae. 24) Composition according to any one of the preceding claims, wherein the active ingredient is a vitamin or a mixture of vitamins selected from the group consisting of vitamin A, vitamin D2, 25-hydroxycalciferol, vitamin D3, beta -carotene, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, pantothenic acid, vitamin PP, vitamin B9, vitamin H2, B7 or BW, choline, inositol, carnitine, betaine, and taurine.

25) Composition according to any one of the preceding claims, wherein the active ingredient is a macroelement or a mixture of macroelements based on calcium, magnesium, phosphorus, potassium, sodium or sulfur having a solubility in water greater than 0, 25 g in 100 g of water, and preferably selected from the group consisting of L-pidolates of calcium and magnesium, calcium and magnesium amino acid chelates, calcium or magnesium glycinates, lactates calcium and magnesium, calcium and magnesium gluconates, calcium and magnesium formates, calcium and magnesium citrates, calcium sulphate, magnesium sulphate, or a mixture thereof.

26) A composition according to any one of the preceding claims, wherein the active ingredient is a prebiotic or a mixture of prebiotics, preferably selected from the group consisting of fructooligosaccharides (FOS), inulin and / or derivatives thereof. inulin, manno-oligosaccharides (MOS), and a combination of manno- oligosaccharides with β-glucans.

27) A composition according to any one of the preceding claims, wherein the active ingredient is a probiotic or a mixture of probiotics, preferably selected from the group consisting of Saccharomyces cerevisiae, YEnterococcus faecium, Bacillus cereus var. toyo, Bacillus subtilis, Bacillus lichreniformis, Bacillus amyloliquefaciens, Clostridium butyricum, Pediococcus acidilacti,

 Lactobacillus rhamnosus, Lactobacillus farciminis, and Kluyveromyces marxianus- fragilis.

28. Composition according to any one of the preceding claims, in which the active principle is an amino acid, a peptide, a protein, an enzyme or a mixture thereof, preferably chosen from the group consisting of proteins or concentrates. water-soluble powdered milk proteins, lyophilized or atomized powder colostrum, powdered whey, purified or enriched fractions of IgG, lactoferrin, lactoperoxidase, animal or plant enzymes, promutase, 3-phytase, 6-phytase, endo-1,4-betaglucanases, endo-1,4-betaxylanases, enzymes improving or promoting the digestion of the animal, free amino acids or in the form of salts or peptides, L- carnitine, more particularly in its dipeptide form, or any other water-soluble peptide of molecular weight greater than a dipeptide.

29) Composition according to any one of the preceding claims, wherein the active ingredient is in powder form and is obtained from a plant extract, a fraction or a molecule purified thereof, an essential oil, a molecule purified aromatic, or a mixture thereof.

30) Composition according to any one of the preceding claims, wherein the active ingredient is a therapeutic molecule or a mixture thereof selected from the list consisting of antibiotics, antibacterials,

 anti-parasitic drugs, antihelminthics, anti-coccidials, anti-cryptosporidials, antiparamphistomas, anti-protozoa, anti-mycotic agents, anti-inflammatories, antiallergics, immunomodulators, anti-ulcer and anti-emetics, anti-diarrheal drugs, antispasmodics, laxatives, purgatives, meteorifers, ruminal motor stimulants, liver function modifiers and regulators, ruminal digestive regulators, vascular active substances, active principles used in immunotherapy, immunoglobulin, interferon, anabolic agents, anti-anemic agents, anti-ketosics, oral rehydrators, lipotropic factors, the active ingredients used in hormonology and reproductive endocrinology, fertility hormones, anti- hyperthyrroid, antigalactogens, abortives, hormone inhibitors, anti-rheumatic, anti-osteoarthritis, muscle and musculoskeletal stimulants, anti-myopathics, respiratory analgesics, bronchodilators,

 mucoregulators, expectorants, antitussives, anti-infectives, diuretics, urinary acidifiers, urinary antispasmodics, general anesthetics, analgesics, anticonvulsants, sedatives, and tranquilizers.

31) Composition according to any one of the preceding claims, which comprises

One or more active ingredients;

An index of solubility in water at room temperature of between 4.5 and 38;

A lignosulfonate-based component in amounts of between 3% and 25% by weight relative to the total weight of the composition;

A component based on fatty substances in amounts of between 1% and 8% by weight relative to the total weight of the composition,

- Which composition has a disintegration of between one hour and

 less than or equal to 30 days.

32) Composition according to any one of the preceding claims 1 to 30, which comprises:

One or more active ingredients;

An index of solubility in water at ambient temperature of between 2.5 and 11.5;

A lignosulphonate-based component in amounts of between 3% and 16% by weight relative to the total weight of the composition;

A component based on fatty substances in amounts of between 2% and 10% by weight relative to the total weight of the composition;

- Which composition has a disintegration greater than 30 days and less than or equal to 90 days.

33) Composition according to any one of the preceding claims 1 to 30, which comprises:

One or more active ingredients;

A solubility index in the range of from 2 to 4; A lignosulphonate-based component, in amounts of between 3% and 8% by weight relative to the total weight of the composition;

A fat-based component, in amounts of between 3% and 12% by weight relative to the total weight of the composition;

- Which composition has an in vivo disintegration greater than 90 days and less than or equal to 180 days.

34) Composition according to any one of the preceding claims 1 to 30, which comprises:

One or more active ingredients;

An index of solubility in water at ambient temperature of between 2 and 4;

A lignosulphonate-based component in amounts of between 3% and 8% by weight relative to the total weight of the composition;

A fat-based component in amounts of between 3% and 12% by weight relative to the total weight of the composition;

A compression agent, in amounts of between 4% and 30% by weight relative to the total weight of the composition;

- Which composition has a disintegration greater than 180 days.

35) A composition according to any one of the preceding claims, which

 further comprises a weighting agent in the form of particulate iron in amounts of from 0% to 50%, preferably from 7% to 30%, more preferably from 9% to 25%, by weight relative to the total weight of the composition.

36. Composition according to any one of the preceding claims, wherein when zinc oxide is present as the sole active ingredient, the composition also comprises a compression agent which is magnesium oxide.

37) Use of calcium and / or magnesium pidolate as macro-elements for a non-human animal, preferably breeding.

38. The use of claim 37, wherein the calcium and / or magnesium pidolate stimulates milk production in a female non-human animal, preferably, postpartum.

39. The use of claim 37, wherein the animal is a ruminant.

40. The use of claim 37, wherein the non-human animal is selected from the group consisting of cattle, sheep, goats, deer, camelids, and preferably is a cow.

41. The use according to claim 37, wherein the non-human animal is

 monogastric.

42. The use of claim 37, wherein the non-human animal is selected from the group consisting of porcine, leporidae, equine, pet, and preferably is a pig.

43) Use according to any one of claims 37 to 42, wherein the calcium L-pidolate and / or magnesium is integrated as active ingredient in a pharmaceutical composition according to any one of claims 1 to 36.

44) Use of a composition according to any one of claims 1 to 36 above in providing micronutrients for non-human animals, preferably farmed.

45) Use according to claim 44, wherein the non-human animal is a ruminant and the composition is in the form of a bolus.

46. The use according to claim 44, wherein the non-human animal is selected from the group consisting of cattle, sheep, goats, deer, camelids, and preferably is a cow.

47. The use according to claim 44, wherein the non-human animal is

monogastric and the composition is in the form of a chewable tablet. 48. The use according to claim 44, wherein the non-human animal is selected from the group consisting of pigs, leporids, equines, pets, and preferably is a porcine animal.

49) Use of calcium and / or magnesium pidolate to stimulate milk production in postpartum nonhuman mammalian animals, preferably cultured.

50) Use according to claim 49, wherein the non-human post-partum mammalian animal is a cow.

51) Use according to claim 49, wherein the calcium and / or magnesium pidolate is incorporated into a composition according to any one of claims 1 to 36 and is in the form of a bolus.

52. The use of claim 49, wherein the farmed non-human mammalian animal is a sow.

53) Use according to claim 49, wherein the composition is in the form of chewable tablet.

54) Use of a composition according to any one of the preceding claims 1 to 36, containing an active ingredient based on calcium pidolate and / or magnesium, to stimulate, around a farrowing, a general mobilization of calcium ions in a female mammalian non-human animal, preferably cultured.

55. The use of claim 54, wherein the farmed non-human mammalian animal is a cow.

The use of claim 54, wherein the composition is in the form of a bolus.

57. The use of claim 54, wherein the farmed mammalian non-human animal is a sow.

58) Use according to claim 54, wherein the composition is in tablet form. 59) Use of a composition according to any one of the preceding claims 1 to 36, containing an active ingredient based on calcium pidolate and / or magnesium, to increase the weight gain of a piglet raised under the mother.

60) Use of a composition according to any one of the preceding claims 1 to 36, containing an active ingredient based on calcium pidolate and / or magnesium, to accelerate the time of farrowing, preferably the sow.

61) Use of calcium pidolate and / or magnesium for the maintenance of a

 peri-partum blood calcium levels in the cow greater than 85 mg / l by adding at least the equivalent of 3.78 g, preferably at least the equivalent of 7.56 g, of calcium in the form of pidolate salt.

62) Use of calcium and / or magnesium pidolate for increasing blood peri-partum phosphorus levels in cows above 55 mg / l by providing at least the equivalent of 30.24 g of pidolate calcium and / or 7.5g magnesium.

63) Method for measuring in vitro disintegration of a composition according to any one of claims 1 to 36, comprising the steps of:

- Prepare an aqueous buffer solution;

- introducing a composition according to any one of claims 1 to 36 into the buffer solution;

- Keep the buffer and composition at constant temperature and stirring;

to determine the disintegration of the composition at regular intervals up to

 complete disintegration of this one.

The method of claim 63, further comprising the step of replacing the buffer solution with a volume equivalent amount of buffer solution every hour after initial introduction of the composition into the buffer solution.

The method of claim 63, further comprising the step of replacing the buffer solution with a volume equivalent amount of buffer solution every twelve hours after initial introduction of the composition into the buffer solution. The method of claim 63, further comprising the step of replacing the buffer solution with a volume equivalent amount of buffer solution every forty-eight hours after initial introduction of the composition into the buffer solution.

The method of claim 63, further comprising the step of replacing the buffer solution with a volume equivalent amount of buffer solution every seventy-two hours after initial introduction of the composition into the buffer solution.

The method of any one of claims 63 to 67, further comprising the step of removing the remaining solid material from the composition upon replacement of the buffer solution, scrubbing said remaining solid material to remove a surface film and re-introducing said remaining material into the buffer solution.

The method of any of claims 63 to 68, wherein the

 solution temperature is maintained at 39 degrees Celsius.

70) Method according to any one of claims 63 to 69, wherein the agitation is performed by a rotating magnet bar rotating between 200 to 300 rpm.

71) A method according to any one of claims 63 to 70, wherein the buffer solution is composed of 0.2M Na ₂ HPO ₄ .2H ₂ 0, 0.1M citric acid and NaCl

0.5 g / L.

The method of any one of claims 63 to 71, wherein the

 Determination of the disintegration is carried out by weighing the composition before it is introduced into the buffer solution, and then again each time the buffer solution is replaced.

73. The method of any one of claims 63 to 72, wherein the

 composition is in the form of a bolus.

The method of any one of claims 63 to 73, wherein the

composition is introduced into a net before introduction into the buffer solution. The method of any one of claims 63 to 74, wherein the composition is suspended in the buffer solution.