Pharmaceutical composition adapted for administration to a non-human animal, its uses and associated methods

Abstract

The present invention relates to a pharmaceutical composition suitable for administration to a non-human animal, comprising at least the following three components: - one or more active ingredients; - a deliescence accelerator; - a deliescence retardant, wherein the deliescence accelerator and the deliescence retardant are incorporated into the composition so as to form a controlled-release matrix of the active ingredient(s). The invention also relates to the uses of these compositions, as well as a method for measuring their in vitro deliescence.

Description

An apparent density greater than 0.45 allows for the creation of a sufficiently dense bolus while reducing the amount of bulking agent. This has the added advantage of freeing up space in the formulation for other ingredients, including active ingredients and any other excipients. It is particularly advantageous for the compression agent to exhibit both wet granulation and compression properties, meaning the ability to form grains that are sufficiently resistant to crushing once dried.Of all possible compressing agents, the applicants prefer that those used in the invention be chosen from the group consisting of magnesia oxide, quicklime, dolomitic lime, slaked lime, magnesia hydroxide, anhydrous dicalcium phosphate, tricalcium phosphate, natural or precipitated calcium carbonate, high-density calcium carbonate, litothamnium, magnesium carbonate, basic heavy magnesium carbonate, or a mixture thereof, and preferably magnesia oxide. Even more preferably, these compressing agents are all used in powder form. According to a particularly advantageous aspect, the compression agent is present in the composition according to the invention in quantities of between 0% and 70%, preferably between 0% and 60%, more preferably between 0% and 40% by weight relative to the total weight of the composition. During the development of the compositions according to the present invention, the applicant also discovered that several parameters other than those already mentioned could influence the decay time to varying degrees. Therefore, determining these parameters enabled the applicant to develop another definition of the compositions according to the present invention based on the desired or actual in vitro or in vivo decay of the composition, which is also valid and verified by statistical modeling. One of these parameters is the solubility index, which is an absolute value obtained by adding 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 by the weight percentage 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: - either available in the official documentation of the component supplier or its technical data sheets; - either obtained from reference works, such as: - the “Nuffield 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-organic compounds: a compilation of solubility data from the periodical literature”, Linke, William, Seidell, Atherton, ACS 1958-1965; - “Perry's Chemical Engineers Handbook”, 7th Ed, Robert H. Perry, 1977; — the “Usuel de Chimie Générale et Minérale”, 1920-today, Bernard, M, and Busnot, F. - or calculated in the laboratory, with regard to 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 containing 200 g of cold water at a temperature between 18 and 25°C is placed on a magnetic stirrer. A given quantity of the substance whose solubility is to be measured is stirred in a very large excess until saturation. After one hour of stirring, the saturated solution is filtered through a funnel fitted with filter paper (the undissolved particles are retained on the filter). The filtrate is collected. This is analyzed using a Sartorius MA 150 moisture analyzer: the test sample is 2 to 3 g of filtrate, spread and evenly distributed on a metal dish, and heated to 105°C to measure the dry residue at constant weight after evaporation of the water. The value of the dry residue is given by the instrument in grams in 100 g of solution. The water content is then determined by subtraction. Then, through calculation, we deduce the solubility of the substance to be analyzed, expressed in grams in 100 g of water. Indeed, the applicants discovered that a high solubility index value leads to compositions that generally decompose quite rapidly, while a low solubility index value tends to lead to compositions that decompose very slowly. This finding was confirmed by statistical analysis and modeling performed on the different compositions prepared by the applicant during the development of the invention. Thus, according to a first aspect, a galenic composition according to the invention is proposed, which comprises: - one or more active ingredients; - a solubility index in water at room temperature between 4.5 and 38; - a lignosulfonate-based component in quantities ranging from 3% to 25% by weight relative to the total weight of the composition; - a component based on fatty substances in quantities ranging from 1% to 8% by weight relative to the total weight of the composition, which composition exhibits a degradation of between one hour and less than or equal to 30 days. According to a second aspect, a galenic composition is proposed, which includes: - one or more active ingredients; - a solubility index in water at room temperature between 2.5 and 11.5; - a lignosulfonate-based component in quantities ranging from 3% to 16% by weight relative to the total weight of the composition; - a component based on fatty substances in quantities between 2% and 10% by weight relative to the total weight of the composition; which composition exhibits a degradation of more than 30 days and less than or equal to 90 days. According to a third aspect, a galenic composition is proposed, which includes: - one or more active ingredients; a solubility index in between 2 and 4; 192296058930000170203 — a lignosulfonate-based component, in quantities between 3% and 8% by weight relative to the total weight of the composition; — a component based on fatty substances, in quantities between 3% and 12% by weight relative to the total weight of the composition; which composition exhibits an in vivo decay greater than 90 days and less than or equal to 180 days. Advantageously, the compositions thus defined may also further comprise a compression agent in quantities of between 0% and 70% by weight relative to the total weight of the composition, preferably between 0% and 60%, and more preferably between 0% and 40% by weight relative to the total weight of the composition. According to a fourth aspect, a galenic composition is proposed, which includes: — one or more active ingredients; — a solubility index in water at room temperature between 2 and 4; 15 — a lignosulfonate-based component in quantities between 3% and 8% in weight relative to the total weight of the composition; — a component based on fatty substances in quantities between 3% and 12% by weight relative to the total weight of the composition; — a compression agent, in quantities between 4% and 30% by weight per 20 relative to the total weight of the composition; which composition exhibits a degradation of more than 180 days. The applicant also observed another phenomenon when the compositions according to the invention comprise zinc oxide alone as the active ingredient, namely that it is necessary to include in the composition a compressing agent, preferably magnesia oxide, failing which the composition did not behave as expected and tended to break down, or even disintegrate, erratically, rather than disintegrate. In addition to the components listed above, the composition may of course include adjuvants and excipients, for example, binders, flavorings, sweeteners, flavor enhancers, lubricants to aid compression when the composition is presented in bolus or tablet form, and similar substances. Examples of these adjuvants are given below for illustrative purposes: - binders: water-soluble cellulose ethers, povidones, gum arabic, etc., in quantities between 3% and 7% by weight relative to the total weight of the composition; - compression aid lubricants: magnesium stearate, in quantities between 1% and 6% by weight of the total weight of the composition; - sweeteners, flavourings, flavour enhancers, in quantities between 0.05% and 2%. In general, the total quantity of adjuvants and excipients is between 1% and 10%. During the development of the compositions described above, the applicant made some surprising discoveries, as it was found that one of the active ingredients, namely calcium and / or magnesium pidolate, had remarkable effects on the animals that ingested it. In particular, calcium pidolate, as well as magnesium pidolate, possibly in combination with calcium pidolate, had a remarkable effect on non-human female animals that had recently given birth and were producing milk, as well as on their offspring that fed on the milk produced. Indeed, the applicant found, particularly in postpartum cows, for example, that they began to produce significant quantities of milk much earlier and in greater amounts than other cows in the same situation but receiving only a standard calcium supplement.A similar effect was observed in sows, specifically that piglets suckled by their mothers, whose mothers had received peripartum calcium and / or magnesium pidolate, exhibited greater weight gain than a comparable group of piglets whose mothers had not received these salts. This likely resulted in an acceleration of farrowing, allowing the sow to produce more litters per year and requiring less monitoring time. reduced birthing time. Beyond the effect of calcium supplementation, the applicant discovered that the pidolate ion, in salt form with calcium and / or magnesium, could not only provide calcium to non-human animals but also induce the mobilization of endogenous calcium ions in the animal in question. This effect had apparently never been revealed or demonstrated before. When the animal is a dairy cow, this effect results in a much earlier resumption of milk production than in a cow that has not received such supplementation, which in turn makes the cow more productive in the long term in terms of milk yield. Thus, the applicant discovered a surprising and, from a physiological and economic point of view, very interesting use of calcium and / or magnesium pidolate for the breeder of these animals.This has led to the development of other uses for calcium and / or magnesium pidolate, as described below. According to one aspect, the invention preferably relates to the use of calcium and / or magnesium pidolate as a source of calcium and / or magnesium for a non-human animal, preferably a livestock animal. Preferably, the use of calcium and / or magnesium pidolate is for stimulating 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 chosen from the group consisting of cattle, sheep, goats, deer, and camelids, and preferably is a bovine. According to another preferred use, the non-human animal is monogastric, preferably chosen from the group consisting of pigs, leporids, equines, and companion animals, preferably dogs and cats, and even more preferably is a pig. It should be noted here that calcium and / or magnesium pidolate can be used in any suitable composition or vehicle, for example, simply by adding the active ingredient or a mixture of two active ingredients to the animal's feed. However, it is preferable that calcium and / or magnesium pidolate be used in its L-pidolate form, and preferably incorporated as an active ingredient in a pharmaceutical composition according to the invention. According to another aspect of the present invention, calcium and / or magnesium pidolate is intended to be used as a source of macronutrients for non-human animals, preferably livestock. In this case, it is preferred that this supply be provided via a composition according to the invention, preferably in bolus form, and that the non-human animal is a ruminant. As before, it is preferable that the non-human animal be chosen from the group consisting of cattle, sheep, goats, deer, and camelids, and preferably a bovine, when the animal in question is a ruminant. However, this use can also be made for other animals, and in other forms of presentation, for example, in the form of tablets, such as chewable tablets. In this case, it is preferable that the non-human animal be chosen from the group consisting of pigs, leporids, equines, and companion animals, preferably cats and dogs, and preferably a pig. According to another aspect of the invention, calcium and / or magnesium pidolate is intended to be used to stimulate milk production in postpartum non-human mammals, preferably livestock. Preferably, this animal is a cow, although other non-human animals could be considered. In this case, it is preferred that the pidolate in question be incorporated into a composition according to the invention, and more preferably in tablet form, and that the animal be a sow. The calcium and / or magnesium pidolate can then be administered as is, but preferably in the form of a tablet that dissolves in the animal's feed, or a chewable tablet. According to yet another aspect of the invention, a composition according to the invention containing an active ingredient based on calcium and / or magnesium pidolate is intended to be used to stimulate, around the time of parturition, a general mobilization of calcium ions in a female non-human mammal, preferably a farm animal. Preferably, the female non-human farm animal is a cow, and the composition is administered as a bolus. According to a preferred embodiment of this use, the female non-human farm animal is a sow, and the composition is administered as a tablet. According to yet another aspect of the present invention, a composition according to the invention, containing an active ingredient based on calcium and / or magnesium pidolate, is intended to be used to increase the weight gain of a piglet raised by its 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 and / or magnesium pidolate, to accelerate the farrowing time of the animal, and preferably, the sow. According to two further aspects of the present invention, it is provided that: — the use of calcium and / or magnesium pidolate for maintaining blood calcium levels peripartum blood in cows greater than 85 mg / l by intake of at least the equivalent of 3.78g, preferably at least the equivalent of 7.56g, of calcium in the form of pidolate salt; - the use of calcium and / or magnesium pidolate for the increase of peripartum blood phosphate levels in cows beyond 55 mg / l by supplying at least the equivalent of 30.24g of calcium pidolate and / or 7.5g of magnesium pidolate. Thus, as can be seen from the above, the applicant has developed several uses for calcium and / or magnesium pidolate in the field of animal nutrition and animal health. It has been determined that, when the two pidolates are used together, a 4:1 ratio of calcium pidolate to magnesium pidolate is preferable. To support the applicant's position, it seems important to describe, from a biochemical perspective, the mechanisms regulating blood concentrations of macro-elements such as calcium, phosphorus, and magnesium, a process known as homeostasis. The body's vital functions also depend on the homeostasis of these elements. When this homeostasis is disrupted, pathological events occur. For example, 99% of organic Ca constitutes the skeleton in the form of complex salts (hydroyapatite), in ionized form, in close relation with P, Ca has multiple functions: — transmission of nerve impulses - involvement in muscle contraction (smooth or striated) - regulation of cell membrane permeability - regulation of hormonal message transduction mechanisms — participation in blood clotting — enzymatic activation - control of ATP utilization (close relationship with the 3 phosphate groups of the ATP structure). The regulation of blood calcium, without causing harm to the cow, particularly with regard to osteoporosis, depends on several factors: parathyroid hormone (PTH), calcitriol (1,25-dihydroxyvitamin D), and secondarily thyroid calcitonin. Thanks to the Transmembrane-sensitive receptors stimulate PTH secretion and calcitriol synthesis when serum calcium levels decrease. PTH promotes calcium resorption from bone and renal tubular reabsorption of calcium. It also influences calcitriol synthesis. Calcitriol, produced by the kidneys, stimulates intestinal (duodenum-jejunum) absorption of dietary calcium and regulates calcium resorption from bone. Hypocalcemia and milk fever occur when calcium from bone cannot be displaced and the diet does not compensate for the loss of calcium from milk. When serum calcium levels rise, PTH secretion decreases, leading to a reduction in bone resorption and tubular reabsorption, and consequently, calcitriol synthesis decreases due to impaired intestinal absorption. This then triggers the production of thyroid calcitonin. There are several factors affecting regulation by PTH: - Hypomagnesemia hinders the parathyroid response. Mg status decreases when K absorption increases, for example when turning out to pasture, which leads to hypocalcemia; - Diets too high in Ca (alfalfa, excess of Ca-rich CMV), during the end of gestation, inhibit PTH secretion. Conversely, diets low in Ca, for example, less than 20g of daily Ca intake, stimulate PTH secretion allowing good osteoclastization and the production of calcitriol, which improves the absorption of dietary Ca by enterocytes; - Metabolic alkalosis, which is defined by a urinary pH greater than 7.8, with a positive DABA, due to excess K and chloride deficiency, predisposes to hypocalcemia and vitular fever; — controlled ruminal acidification and negative Baca (0.15 Ca + at 0.15 Mg = Na + K) - (Cl + at 0.25 S + 0.5 P) = - 200 mEQ / kg. Sulfates are less acidifying than chlorides (of Mg, ammonium), allowing effective prevention of VF; - liver failure (steatosis) decreases the synthesis of 25-hydroxyvitamin D, which will be deficient at the renal level for the production of 1,25-dihydroxyvitamin D or calcitriol; - Corticosteroids are aggravating factors in hypocalcemia, particularly in cases of muscle disorders or inflammation of the nerve trunks. There are also factors affecting the absorption of dietary calcium - with the increase in the animal's age, there is a decrease in the number of PTH receptors, which results in a decrease in the animal's ability to maintain its homeostasis; - estrogens, which increase at the time of parturition, have an inhibitory effect on the homeostatic response; — calcitonin secreted by the thyroid decreases osteoclastase and increases urinary excretion of Ca; - if the acidosis is too high, with the blood pH decreasing, osteoclasm will be increased for a better acid-base balance of the blood, by the Ca ion. There are also factors affecting renal calcitriol production, as this is practically the same between a healthy animal and a cow with vitular neurosis, where the level is slightly higher: - a BACA+ reduces calcitriol synthesis, because alkaloses reduce its production and the sensitivity of renal tissue to PTH; - High blood concentrations of P inhibit its activity and increase hypocalcemia. Magnesium is known to participate in nucleic acid metabolism, chromatin organization, protein synthesis, and energy production in the cytoplasm and mitochondria. It is an essential cofactor for the activity of numerous enzymes present 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, nucleic acids, and cell membranes. It controls the use of ATP, which serves as a substrate or phosphate donor (TATP, which has three negatively charged phosphate groups, is stabilized by the magnesium ion). As a divalent cation, it is essential for the electrochemical stability of many charged molecules in the cell and for membrane cohesion.Magnesium reserves in the bones are significant, representing approximately 70% of body magnesium, but short-term mobilization is low. If dietary magnesium intake is insufficient, or if ruminal magnesium absorption is impaired by antagonists, the cow's blood status will be compromised. Below 18 mg / L, hypomagnesemia will lead to hypocalcemia. Hypomagnesemia also interferes with the ability of calcium target cells to stimulate additional PTH production, resulting in decreased PTH levels. However, in hypocalcemia, PTH increases magnesium reabsorption by the kidneys because renal excretion is slowed. In summary, PTH is hypercalcemic and hypophosphatemic, calcitriol is hypercalcemic and hyperphosphatemic, calcitonin is hypocalcemic and hypophosphatemic (inhibition of bone resorption) and phosphatonin is hypophosphatemic. To regulate blood calcium, phosphorus, and magnesium levels during the peripartum period, it is essential to: - to avoid any alkalosis, hepatic steatosis or renal 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, by optimizing the intake of neither too much nor too little Ca, P and Mg. As stated above, the compositions according to the invention may incorporate calcium and / or magnesium pidolate as active ingredients, which may subsequently be used in applications according to the invention. The calcium and / or magnesium pidolates used according to the invention have maximum gastrointestinal bioavailability, allowing for the delivery of 13.5% of Ca and 8.5% of Mg, for example, via two 75g boluses, directly metabolized by enterocytes, and the capture, or chelation, of Ca, Mg, and P present in the digestive tract via the pidolate protein complex. They also allow for the mobilization of bone Ca via carboxyglutamic acid and the regulation of serum calcium and phosphate levels around parturition (peripartum), as demonstrated by zootechnical trials conducted by the applicant and described below.Furthermore, the compositions of the invention containing calcium and / or magnesium pidolate in bolus form allow for controlled release in a single dose, thus avoiding the burst effect and the corresponding drop in blood levels. Secondly, they cause a significant increase in growth hormone, a precursor of IGF-1 (insulin-like growth factor) involved in the formation of bone and muscle cells. Trials on cows Trials administering a composition according to the invention in bolus form, containing calcium and magnesium L-pidolate in a 4:1 mixture, were conducted on cows around the time of calving. These trials were carried out in parallel with comparative trials of the efficacy of two products already marketed and available on the market, namely Bovicalc and Calform-phosphorus. The trials involved 5 groups of 6 high-producing, multiparous dairy cows, in the peripartum period, having calved at least once, from the same farm, and receiving no Ca or Mg-based products other than those listed below. One group among the 5 test groups received no product and is considered the control group. Each group was identified by a letter, in this case N, O, P, Q, and R. The start of the procedures was approximately 2 to 3 hours before parturition. The time of parturition was recorded, indicated as HO, and blood tests were performed around the time of parturition and up to 25 hours afterward. These blood sampling periods are indicated by reference to parturition, hence the reference H, and are therefore: - H-4 to 5: 4 to 5 hours before parturition; — HO: time of birth; - H+3 to 4: 3 to 4 hours after giving birth; - H+12 to 13: 12 to 13 hours after giving birth; - H+22 to 25: 22 to 25 hours after giving birth. The administration of the various products was carried out in the following manner: - group N: two boluses according to the invention in a single dose as soon as the first signs of parturition appear, immediately after the blood samples, the reference of the bolus according to the invention being 7040-2-13 (13003), i.e. 7.56g of Ca, and 1.19g of Mg; - group O: three boluses according to the invention in a single dose from the first signs of parturition, immediately after blood sampling, the reference of the bolus according to the invention being 7040-2-13 (13003), i.e. 11.34g of Ca, and 1.78g of Mg; - group P: control group, no product administered; — Group Q: a Bovicalc bolus, at the first signs of calving, immediately after blood sampling, then a second Bovicalc bolus 4 to 5 hours after calving, and finally a third Bovicalc bolus 12 hours after calving, immediately after the 5 blood samples, as recommended by the supplier; - Group R: one 350ml bottle of Calform, from the first signs of calving, and after blood samples, a second 350ml bottle of Calform 4 to 5 hours after calving, then a third 350ml bottle of Calform 12 hours after calving, immediately after blood samples, following the supplier's recommendations. 10. The three administrations of Bovicalc provided a total of 129 g of Ca contained in the three boluses, and the three vials of Calform-phosphorus provided 156 g of Ca. In terms of Mg intake, the 3 vials of Calform-phosphorus provided 2.4 g. The boluses according to the invention did not provide any phosphorus, compared to the 135 g of P in the 3 vials of Calform-phosphorus. The bolus according to the invention, bearing the reference 7040-2-13 (13003), had the following composition 15 next: Name Value Reference 7040-2-13 (13003) Active ingredient - Calcium / Magnesium pidolate (4:1 mixture) 50.00% Accelerator - Arbo C12 Lignosulfonate 12.00% Retarder - Hydrogenated soybean oil 8.00% Bulk - Iron particles 29.00% Excipients 1.00% TOTAL 100.00% Solubility Index 27.32 Dissolution Time 33 hours Table 1: Bolus 7040-2-13 (13003) Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 8595 May 20 85 85 86 83 83 8662 August 28 88 79 80 79 76 5282 September 2 82 82 83 84 74 9467 October 6 84 76 80 75 69 8855 October 16 83 82 89 75 80 9576 January 7 82 81 78 84 85 Lot N 84.0 80.8 82.7 80.0 77.8 Table 2: Calcium Level Results Lot N Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 8664 May 19 72 66 69 62 9559 September 12 99 90.0 93.0 101.0 88.0 9462 October 3 98 92.0 95.0 94.0 90.0 7820 October 11 92 85.0 93.0 89.0 90.0 9454 October 16 83 84.0 82.0 81.0 78.0 8849 J October 17 92 93.0 93.0 89.0 79.0 LotO 92.8 86.0 87.0 87.2 81.2 Table 3: Calcium Results Lot O Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 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: Calcium Results Lot P Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 8849 S 31-Aug 87 87 87 91 90 8846 29-Oct 93 96 85 93 86 9439 05-Nov 64 65 72 75 77 9538 20-Feb 89 93 96 86 91 8670 25 / 04 85 86 86 90 91 9406 27 / 04 75 83 85 88 92 Lot Q 82.2 85 85.2 87.2 87.8 Table 5: Calcium Results Lot Q Identity Date Part H-4 to H-1 H0 H + 3 to 4 H+ 12 to 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 of Calcium Levels in Lot R Comparison of serum calcium levels in group N versus group P. Group O. Group R The calcium levels in group N were slightly higher than those in the control group P, but although in a hypocalcemia risk zone (i.e., a blood calcium level below 85 mg / L), blood calcium levels were maintained at a good level and no morbid manifestations appeared, unlike in the control group, where one in six cows suffered from milk fever. The calcium levels in groups Q and R were slightly higher (7 to 11%) than those in group N, whose subjects received only one bolus administration according to the invention. This is surprising, given the massive calcium intake from Bovicalc (17 times higher) and Calform-phosphorus (20 times higher). 10 plus), that blood levels of Ca hardly exceed 92 mg / l for these two products. Comparison of serum calcium levels in groups N and O versus groups PO R The calcium levels in group O are higher than those in groups N and P, as the blood levels of the cows sampled at H-4 to H-1 are above 90mg / l, thus indicating a lower risk for the subjects in this group, but the values ​​show that the blood profile is 15 substantially parallel to that of group N. It is therefore certain that the bolus according to the invention based on Ca and Mg pidolates, the degradation of which takes place over approximately 30 hours, directly affects the homeostasis of Ca and P. Comparison of low blood calcium levels in each group: Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 5282 02-Sept 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 82.8 80.3 82.5 79.5 77.0 Table 7: Low Blood Calcium Levels - Lot N Identity Date Part H-4 to H-1 H0 H + 3 to 4 H+ 12 to 13 H + 22 to 25 9454 16-Oct 83 84.0 82.0 81.0 78.0 LotO 83.0 78.0 74.0 75.0 70.0 Table 8: Low Blood Calcium Levels - Lot O Identity Date Part H-4 to H-1 H0 H + 3 to 4 H + 12 to 13 H + 22 to 25 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 78.0 77.0 72.8 71.6 73.8 Table 9: Low Blood Calcium Levels - 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 Blood Calcium Levels - Lot Q Identity Date Part H-4 to H-1 H0 H + 3 to 4 H+ 12 to 13 H + 22 to 25 8851 Nov 10 83 81 74 81 73 9433 Dec 25 80 83 81 90 108 9480 Jan 25 84 85 86 82 83 Lot R 82.3 83.0 80.3 84.3 88.0 Table 11: Low Blood Calcium Levels - Lot R The 4 calcium levels in group N were 5 to 12% higher than the 5 in group P, within 4 to 12 hours after calving. Those in groups Q and R showed a significant increase, especially from the twelfth hour onward, as the calcium levels in the cows of group Q were very low before calving. Furthermore, 10 of the calcium levels in cow No. 9315 of group P were representative of the progression of milk fever, which was observed and treated approximately twelve hours after calving. Comparison of serum phosphorus levels in batches N and O versus batches PO R: Identity Date Part H-4 to H-1 HO H + 3 to 4 H + 12 to 13 H + 22 to 25 8595 May 20 41.9 38.6 57.2 55.8 48.8 8662 August 28 50.9 41.3 48.9 57.7 58.4 5282 September 2 82.1 69.3 82.2 76.8 72.4 9467 October 6 43.3 38.5 58.8 52.5 49.3 8855 October 16 42.3 42.2 51.0 57.4 51.4 9576 January 7 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 - Lot N Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 8664 May 19 67 53.5 69.9 56.6 9559 Sept 12 69.9 75.4 82.6 106.4 82.8 9462 Oct 3 65.1 60.8 69.4 97.0 53.6 7820 Oct 11 64.6 47.6 69.7 61.7 56.1 9454 Oct 16 48.5 40.2 47.3 64.2 46.1 8849 J Oct 17 71.4 53.7 84.5 76.1 54.7 LotO 64.4 55.6 67.8 79.2 58.3 Table 13: Phosphoremia - Lot O Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 9320 August 26 41.7 43.5 44.1 43.3 45.9 9413 October 28 51.2 54.3 43.8 47.6 50.6 8476 November 15 54.9 58.1 62.0 66.1 67.8 8489 November 21 58.2 55.8 61.3 79.3 68.2 9552 November 22 46.4 54.5 68.2 50.6 45.9 9315 February 8 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 - Lot P Identity Date Part H-4 to H-1 HO H + 3 to 4 H + 12 to 13 H + 22 to 25 8849 S 31-Aug 53.5 50.5 52.9 39.1 42.0 8846 29-Oct 67.2 57.4 50.3 59.1 44.6 9439 05-Nov 22.5 15.3 17.9 24.1 36.3 9538 20-Feb 36.9 43.5 42.5 47.6 43.8 8670 25 / 04 33.45 53.86 58.27 57.37 39.22 9406 27 / 04 50.6 63.4 79.58 89.97 92.57 Lot Q 44 47.3 50.1 52.94 49.7 Table 15: Phosphoremia - Lot Q Identity Date Part H-4 to H-1 HO H + 3 to 4 H+ 12 to 13 H + 22 to 25 9556 Oct 10 74.1 71.7 92.9 78.6 51.4 8851 Nov 10 39.5 43.4 50.8 45.1 41.0 8590 Nov 23 49.9 52.3 45.3 61.8 52.3 9433 Dec 25 77.6 71.9 77.3 70.7 71.7 8531 Jan 25 45.1 58.5 66.4 64.6 56.6 9480 Jan 26 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 - Lot R The serum phosphorus levels of group N, which received no phosphorus supplementation, are comparable to, or even slightly higher than, those of group R, which received three doses of 135g of phosphorus. They are significantly higher than those of the control group P and especially group Q, which, in addition to the other group, received no phosphorus supplementation. The serum phosphorus levels of group N and group O are comparable, albeit at different levels. The dose-response effect is clearly evident in group O. It is therefore clear that the pidolates mobilize endogenous organic phosphorus or induce its production. Except for group O, which had only one animal at risk, the comparison of at-risk (less than 55 mg / L) or high-risk (less than 40 mg / L) blood phosphorus levels in each group is worth examining. The values ​​in group N, after a drop in blood levels at calving (1 to 2 hours after a single administration of the two boluses), rebounded strongly and exceeded those of group R, which provided 135 g of phosphorus in three administrations. Group O, with only one animal at risk, was not included in the analysis but is nevertheless very representative. The mobilization of endogenous organic phosphorus by the pidolates is confirmed. Results of cow behavior after calving: The cows were studied in terms of their physical behavior at the time of, and after, the calving. The results of this study were expressed as a percentage relative to 100%, representing the behavior of a cow in ideal physical condition. The values ​​for groups N and O showed a clear improvement compared to the other three groups. Indeed, the physical behaviors of the cows in groups N and O were 75% and 72%, respectively, relative to ideal physical condition. 5 ideal, compared to 38.9% of group P, 33.3% of group Q, which showed mastitis metritis after calving, and 55.6% of group R. These positive results are attributable to the calcium and magnesium pidolates, which have a very good effect on calcium, phosphorus, and magnesium homeostasis. As shown by the excellent biochemical results of the serum phosphorus levels in groups N and O (Figures IA, IB), the metabolic phosphorus 10, exacerbated by the pidolates, stimulates chewing, rumination, and digestion by increasing the gut flora, and that, moreover, 5-oxo-l-proline, via glutathione, has a clear effect on the oxidative stress inherent in parturition. Comparative milk production according to the INRA method: At the instigation of the French dairy herd improvement program, a calculation method based on lactation on the 4th, 5th, 15th and 6th days after calving was developed and proposed by INRA (National Institute for Agricultural Research) Agronomic), to know "the peak of 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 14.33 31.70 30.63 26.77 24.50 30.50 Prod Milk max pot 25.04 39.63 38.73 35.48 33.58 38.62 Prod Milk pot 11.72 41.49 40.55 37.15 35.16 40.44 Actual Lactation 5609 8877 8676 7948 7522 8651 Nl Dairy Products 6827 7082 7326 7449 7895 TOTAL 8877 8676 8074 7999 8651 Table 17: Milk production, days 4, 5, 6 postpartum Thus, it was observed, firstly, that the average (of the 4th, 5th, and 6th days) of each batch at NO is almost equivalent for batches N (31.7), O, and R, compared to batch P (26.7) and batch Q (24.5), representing a daily difference of 5 to 71 liters more milk, and secondly, that the forecasts of Five lactations were favorable to group N, with +226 liters compared to group R, and 800-870 liters compared to groups P and Q. A comparison of the production of each group during the first 8 days revealed the same phenomenon. It appears that the use of pidolates according to the invention stimulates milk production in larger quantities very early after calving, particularly on days 4 and 5, which has a significant impact on the 10 overall production and profitability of the animal, as well as the quality of the milk produced. A comparison was made between the actual production of the previous year (year Nl) and the forecasts for the cows in the trial, and the results are presented below: Lot Nl in kg Forecast Difference % N 6827 8877 2050 30 0 7082 8676 1594 23 P 7326 7948 622 8 Q 7449 7522 73 1 R 7895 8651 756 10 Table 18: Comparison of Production Nl As can be seen, the administration of calcium and / or magnesium pidolates according to the present invention in the form of two or three boluses makes it possible to significantly increase the quantity of milk, compared to commercial products, which only provide calcium. Conclusions: The pidolates of the invention, when used as supplements, are just as effective, if not more effective, than existing products, notably Calform and Bovicalc, both in calcium supplementation and calcium level control, and in managing phosphate levels, particularly during calving. This is important given that milk fever, hypophosphatemia, and the "downing cow" syndrome complicate hypocalcemia in 55% of observed cases. The three zootechnical comparisons highlight a clear superiority of groups N and O compared to the control group P and group Q, as well as superior results compared to group R. Without wishing to be bound by any hypothesis, the applicant believes that this superiority is attributable not only to the induction, or mobilization, of endogenous calcium production, but also to the mobilization of endogenous organic phosphorus.It is also possible that, via the same pathway, the bone resorption of calcium by hydroxyproline and the anti-stress action of 5-oxo-l-proline allow for a rapid revitalization of the animal. Furthermore, in addition to their undeniable effects on the dairy behavior of cows, the pidolates according to the invention, when administered as a bolus, are easily, safely, and administered in a single dose, at a time when the animal is most receptive, unlike the three or four recommended or usual administrations of commercial products. Trials on sows / piglets Trials of a composition according to the invention were also conducted on sows entering the farrowing house, approximately seven days before the piglets gave birth. The piglets were then fed by the sow. The composition was administered in tablet form, which was either dissolved in the animals' feed or chewed directly by them. Sow 1001 Trial Trial 1001 consisted of recording the productivity and farrowing behavior of a group of 24 treated sows, designated group A, compared to that of 23 control sows, designated group B. Piglets in group A showed an average weaning weight per piglet more than 5% higher than that of the untreated group. Sow Trial 1003 Two piglets were selected to form two test populations, with two groups per population. For the first test population, 12 sows were chosen, divided into two distinct groups of six sows, each sow being clearly identified. The first group, called group IA, consisted of six sows. Group 1A received the tablets according to the invention orally for 14 days, added to the drinking water or feed pellets, at a rate of one tablet per day, starting seven days before farrowing (i.e., upon the animals' entry into the farrowing house) and ending seven days after farrowing. The individual identification and weighing of the piglets were carried out on the first day and at weaning, at approximately 28 days. The second group, called group IB, also consisted of six sows.Group IB received a placebo tablet, administered orally for 14 days, added to the drinking water or feed pellets, at a rate of 1 tablet per day starting 7 days before farrowing and ending 7 days after farrowing. Individual identification and weighing of the piglets were carried out 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 to the drinking water or feed pellets, at a rate of 1 tablet per day, starting 7 days before farrowing and ending 7 days after farrowing. The piglets were not identified, but each group was weighed on the first day and at weaning 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 the drinking water or on feed pellets, at a dose of 1 tablet per day starting 7 days before farrowing and ending 7 days after farrowing. The piglets were not identified, but each group of piglets per sow was weighed on the first day and at weaning at 28 days. The sows were studied and judged at farrowing according to the following criteria: - Date of birth — Duration of labor - Ease of reading - Recording of treatments performed or obstetric interventions - Return of appetite — Condition of the udder — Rectal temperature check following parturition and 12 hours later - Treatment of sows with a temperature above 39.3°C - Cannibalism Subsequently, the following evaluations were carried out: - During the last birth — Total number of piglets born - Stillborn piglets - Weaned piglets - At birth - Range - Number of births - Number of stillbirths - Identification of each piglet in LOT N° 1 — Weighing of each piglet in batch No. 1 - Weighing of the litter of Lot No. 2 - Homogeneity - at 3 days and 7 days: morbid manifestations (diarrhea, omphalitis, arthritis) - at 28 days: 5 - Weaning date - number of piglets present - Weighing of each piglet in batch No. 1 — Weighing of the litter from lot No. 2 — homogeneity 10 - at slaughter: where possible, the carcass weight of the individuals in batch No. 1, A and B, identified on the first day, were checked The composition according to the invention that was administered was as follows: Name Value Reference VST 212 Active ingredient - Calcium pidolate (12.5% ​​Ca) 60.00% Accelerator - Arbo C12 lignosulfonate 4.00% Retarder - Hydrogenated soybean oil 4.50% Compressing agent - Anhydrous dicalcium phosphate 12.13% Excipients 19.37% TOTAL 100.00% Solubility Index 27.32 Table 19: VST 212 Formulation 15 The results of this trial are presented below: Population 1, Group A (entered the farrowing house on 21 / 10) - 72 weaned piglets Sow No. Days before Farrowing Weight on Day 1 Weaning Weight Average Daily Gain 7362 6 1.18 8.48 7.23 0.249 8600 8 1.2 7.66 6.59 0.244 9756 6 1.76 7.91 6.15 0.212 9841 8 1.98 9.29 7.33 0.272 8595 7 1.24 8.62 7.31 0.261 9942 4 1.34 7.68 6.31 0.204 Average 6.5 1.45 8.67 6.82 0.240 Table 20: Population 1 - Group A - Weight Population 1, Group B (entered the farrowing house on 21 / 10) - 66 weaned piglets Sow No. Days before Farrowing Weight on Day 1 Weaning Weight Average Daily Gain 9943 7390 8 1.59 8.15 6.49 0.241 8690 10 1.41 6.03 4.59 0.184 9758 8 1.23 7.63 6.39 0.237 9837 8 1.34 7.33 5.97 0.221 9836 8 1.24 7.68 6.41 0.237 Average 8.4 1.36 7.36 5.97 0.224 Table 21: Population 1 - Group B - Weight Comparison of Group IA and Group IB Total Population: 138 Number of Days Before Parturition Weight on Day 1 Weaning Weight Weight Gain Weight Average Daily Gain Difference in Days -1.900 0.087 0.912 0.852 0.016 Difference % -22.62% 6.42% 12.39% 14.27% 7.37% Table 22: Summary Comparison - Population 1 As can be seen, the sows in group 1A, having received a composition based on calcium and / or magnesium pidolate according to the invention, had a shorter farrowing time than 5 those that received only the placebo. In addition, the weight gain in piglets fed under sows that received calcium and / or magnesium pidolate was significantly greater, on the order of 14% more weight, compared to their counterparts whose nurse sows had received only the placebo. Population 2, Groups A and B (entered the farrowing house on 21 / 10) - 144 piglets weaned in total Number of Weaned Piglets Number of Days Before Farrowing Weight on Day 1 Weaning Weight Average Daily Gain Group A: 74 7.000 1.270 7.230 5.960 0.213 Group B: 70 8.000 1.440 6.910 5.470 0.201 Difference in Days -0.830 -0.173 0.315 0.489 0.012 Difference % -10.640 -12.030 4.560 8.940 5.970 Table 23: Population 2 - Comparison Group A - Weight As can be seen, in group 2A, whose sows received the calcium and / or magnesium pidolates according to the invention, farrowing was shorter than in the placebo group. Furthermore, the piglets in group A also showed greater weight gain. 15 important than their counterparts in group 2B. These results clearly demonstrate that calcium and / or magnesium pidolates, as used according to the invention, have a significant impact on piglet growth, specifically on achieving a higher finished carcass weight for the same fattening period, or a shorter fattening period for the same carcass weight. This also has a positive impact on the sow's overall health, as shorter farrowing times indicate better recovery from the stress of entering the farrowing house and giving birth. This improved health has significant implications for the farmer, both in terms of investment in animal monitoring and in terms of the overall productivity of their farm. Finally, during the development of the compositions according to the present invention, the applicant also discovered a way to measure the in vitro decay of the composition reproducibly and thus be able to predict with a fairly high degree of certainty the duration of decay in vivo, once the composition has been ingested by the animal. To the applicant's knowledge, this is the first time such a feat has been achieved. Indeed, it would appear that the prior art in this area is limited to reproducing a synthetic salivary buffer proposed in an article published in 1948 by McDougall, E.I., entitled "Studies on ruminant saliva. The composition and output of sheep saliva," published in Biochem. J., 43: 99-109. This article describes a set of components representing a synthetic "salivary" buffer, which is assumed to constitute the sheep's dissolution medium and has a pH of around 8.Paradoxically, the model proposed therein, which has been used for years for dissolution testing and in vitro studies of active ingredients for ruminant animals, is essentially a salivary buffer. Since then, this buffer has been used as a starting point by others, who have modified it to a pH closer to that of the rumen. However, the applicant has observed that the buffer initially proposed by McDougall, and subsequently modified by others through the addition of acetic acid, exhibits a significant pH shift over time, such that it no longer fulfills its function as a buffer. Indeed, the primary role of a buffer is to exhibit relatively constant behavior over a fairly narrow and well-defined pH range. In ruminant animals, the temperature and pH of the rumen are generally between approximately 38 degrees Celsius and approximately 41 degrees Celsius, with a pH between 5.8 and 6.4. Thus, another object of the present invention is a method for measuring the in vitro delitude of a composition according to the invention, comprising the steps of: - prepare an aqueous buffer solution; - introduce a composition according to the invention into the buffer solution; - maintain the buffer and composition at constant temperature and agitation; - determine the degradation of the composition at regular intervals until its complete degradation. Several complementary and preferred steps can 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 an equivalent volume of buffer solution every hour after the initial introduction of the composition into the buffer solution. According to another preferred variant, the method further includes a step of replacing the buffer solution with an equivalent volume 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 includes a step of replacing the buffer solution with an equivalent volume 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 includes a step of replacing the buffer solution with an equivalent volume of buffer solution every seventy-two hours after initial introduction of the composition into the buffer solution. Regardless of the variants used, it is also preferred that the method further include a step of removing the remaining solid material from the composition when replacing the buffer solution, rubbing said remaining solid material to remove a surface film, and reintroducing said remaining material into the buffer solution. In the rumen, bolus-type compositions are subject to significant friction phenomena, in addition to perpetual mixing and agitation movements. The method is advantageously and preferably carried out by maintaining the temperature of the solution at 39 degrees Celsius. Furthermore, the agitation in this method is preferentially carried out using a magnetic bar. rotary rotating between 200 and 300 revolutions per minute. According to other advantageous and preferred features, the determination of deliquescence is carried out by weighing the composition before its introduction into the buffer solution, and then again at each replacement of the buffer solution, the composition is presented as a bolus, and the composition is introduced in a mesh bag 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 Na2HPO4·2H2O, 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 disodium 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 adding distilled or deionized water. Then, mix with stirring until complete dissolution and a translucent solution is obtained. The pH value obtained is 5.80 / 5.85; - By adjustment: prepare a base solution and an acid solution separately. The acid solution contains 0.1M citric acid (NaCl) 0.5 g / L in distilled or deionized water to make 1 L, giving a solution with a pH of approximately 2.30. The base solution contains 0.2M sodium hydrogen phosphate dihydrate (NaCl) 0.5 g / L in distilled or deionized water to make 1 L, giving a solution with a pH of approximately 8.88. After preparing the solutions, gradually pour the acidic solution into the basic solution while stirring. Monitor the pH until the desired value of 5.80 / 5.85 is reached, as the pH will decrease with each addition of acid. Approximately 1.2 liters of acidic solution are required for every 2 liters of basic solution. For the purposes of the measurement method, the composition is presented as a bolus. Preferably, the bolus is enclosed and suspended in a net, for example, an orange net. It is stirred in Erlenmeyer flasks with the buffer described above, for a total volume of 3 liters. The system is stirred, for example, with a magnetic stir bar, preferably with rotation on a hot / stirring plate, so as to obtain a relatively low vortex. The stirring speed is preferably 200 to 300 rpm, and the measurement temperature is maintained at 39°C ± 0.1 degrees Celsius. Preferably, for boluses with a short dissolution time, the dissolving / buffering solution is changed hourly with fresh New buffer. According to another preferred embodiment of the invention for medium-duration boluses, the buffer solution is changed every 24 hours with new buffer. According to another preferred embodiment of the invention, for long-duration boluses, the buffer solution is changed every 48 hours with new solvent. The boluses are generally weighed at T=0 to determine their dry weight. At each emptying: T+1, T+2, ..., T+n, etc., they are removed from the solution, rinsed lightly under running water and / or gently rubbed between the fingers to remove a surface film, and then weighed "wet," including the water of constitution that has penetrated the matrix. Dissolution profiles are established and expressed as: % weight loss of boluses over time / versus initial dry weight of boluses. Furthermore, in order to demonstrate the inability of the buffer proposed by McDougall to fulfill its buffering role, tests were conducted with compositions according to the invention, in bolus form, and with the buffer and method according to the present invention. Details of these tests are given below: Preparation of 10L of McDougall buffer solution modified by adjusting the pH to 6.5 by adding acetic acid 1. Take 10L of deionized water 2. Weigh the ingredients: - NaHCO3: 98g - Na2HPO4,12H2O: 93g - NaCl: 4.7g - KC1: 5.7g - Anhydrous CaCl2: 0.4g - Anhydrous MgCl2: 0.6g 3. Dissolve the ingredients 4. pH measurement: 8.24 at 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 conforms to that according to the invention: references RI2208 and RI 2210. N° du bolus Durée de délitescence Tampon Mc Dougall pH mesuré Tampon Mc Dougall T° mesurée Tampon Vétalis pH mesuré Tampon Vétalis T° mesurée RI 2208 T0 (13h40) 6,75 39,0°C 5,84 39,0°C R12210 6,75 39,0°C 5,84 39,0°C R12208 T+30min (14hl0) 6,76 39,0°C 5,85 39,0°C R12210 6,78 39,0°C 5,85 39,0°C RI 2208 T+lh (15h40) 6,79 39,0°C 5,86 39,0°C R12210 6,81 39,0°C 5,87 39,0°C R12208 T+2h (16h40) 6,82 39,0°C 5,86 39,0°C R12210 6,82 39,0°C 5,85 39,0°C R12208 T+3h (16h40) 6,90 39,1°C 5,87 39,1°C R12210 6,93 38,9°C 5,86 38,9°C RI 2208 T+4h (17h40) 6,98 38,9°C 5,90 38,9°C R12210 6,98 38,9°C 5,89 39,1°C RI 2208 T+8h (21h40) 7,34 (22h08) 38,9°C 5,97 (22hl2) 39,0°C R12210 7,36 (22h05) 39,0°C 6,02 (21h50) 39,0°C RI 2208 T+ljour (13h40) 7,86 38,9°C 6,10 38,9°C R12210 8,17 39,1°C 6,03 38,9°C R12208 T+2jours (13h40) 8,32 39,1°C 6,23 39,1°C R12210 8,50 39,0°C 6,11 38,9°C R12208 T+3jours (13h40) 8,60 (14hl8) 39,0°C 6,39 (14hl0) 38,9°C R12210 8,72 (14h30) 39,1°C 6,20 (14hl5) 38,9°C Table 24: Tampon Comparison As can be seen, the modified "buffer" solution initially proposed by McDougall and adjusted by the addition of acetic acid exhibits a very significant pH shift over time, changing from 6.75 at T0 to 8.72 at T+3J, which completely negates the value of this buffer as a representative buffer for studying the in vitro delitude of compositions according to the invention. 10 such as boluses, intended for ruminant animals. Furthermore, it should be noted that the McDougall buffer shows a pH shift even after heating, changing from pH 6.5 after adjustment with acetic acid to pH 6.75 after being heated to 39 degrees Celsius. In contrast, the buffer prepared by the depositor, whose pH at T0 was 5.84, shows little change. throughout the entire period of the delimination of the tested compositions, the pH measurement after three days of delimination indicated a pH value of 6.20. Thus, the buffer developed by the applicant is perfectly suited to an in vitro delimination measurement protocol mimicking that of ruminant animals for compositions according to the invention which are presented in the form of boluses. Examples of boluses corresponding to the composition according to the invention have been produced, and their details are given below. These examples have been divided into bolus categories according to the duration of decay, that is, according to the following classification: - bolus with a disintegration period of between 1 hour and 30 days, called a short-term bolus; - bolus with a disintegration period of between 31 and 90 days, called medium-duration bolus; - bolus with a decay period of between 91 and 180 days, called a long-term bolus; - bolus with a decay period exceeding 180 days, called an ultra-long-term bolus. All the compositions described can be obtained using a general preparation process which will be detailed below: 1. Powder mixture comprising: the active ingredient(s), the possible compression agent, possibly the degradation accelerator, and a binder, in a mixer / granulator type apparatus. 2. Granulation of the mixture thus obtained with water (or possibly low-strength water alcohol), then drying in an oven set at approximately 50°C. 3. Crushing and / or calibrating the aggregate if necessary, to obtain a grain that passes through a sieve with a dimension less than or equal to 4 mm. 4. Final mixing: from the grain obtained at the end of step 3, add compression aid lubricant, degradation retardant and possibly ballast agent in case the latter is introduced during the final mixing. 5. Optionally, in the case of tablets and boluses, compression of the mixture prepared in step 4 in a suitable matrix. Other alternatives to the process described above can be considered: • Introduction of the ballast agent at the time of step 1 before wet granulation; • Introduction of the binder and / or the degradation accelerator after dissolving, then spraying of an aqueous (or hydro-alcoholic) solution onto the 5. Granulating mixture, at the time of step 2; • Introduction of the retardant according to the "hotmelt" technique (in the form of melted fat), during step 4, i.e. during the final mixing. Short-term bolus (1 hour to 30 days) 10 Some examples of short-term formulations according to the invention, in bolus form, are given below. Product Active Ingredient Accelerator Retarder Bulk RI-01-02 Copper Glycinate ArboC12 (Na / NH4) Camuba Wax Iron Powder RI-01-03 Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Palm Oil Iron Powder RI-01-06 Copper Glycinate ArboC12 (Na / NH4) Micronized C16 / C18 Stearine Iron Powder RI-01-07 Copper Glycinate Arbo C12 (Na / NH4) Paraffin Iron Powder RI-01-04 Copper Glycinate ArboC12 (Na / NH4) Cetyl Palmitate Iron Powder RI-01-05 Copper Glycinate Arbo C12 (Na / NH4) Glyceryl Trihydroxystearate Iron Powder RI-07-03 Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Castor Oil Iron Powder RI-07-04 Copper Glycinate Arbo C12 (Na / NH4) Stearic Acid 92% Iron Powder Product Active Ingredient Accelerator Retarder Bulk RI-07-01 Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder 7040-2-13 (13003) Ca / Mg Pidolate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder 7040-2-13-6 (13003) Ca / Mg Pidolate Arbo C12 (Na / NH4) Hydrogenated Cottonseed Oil Iron Powder RI-47-02 bis (A) Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder R1-47-02-B (3-2) Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-06-06 (b) Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-06-01 Ultrazine Copper Glycinate (Na) Hydrogenated Soybean Oil Iron Powder RI-06-02 Ultrazine Copper Glycinate (Ca) Hydrogenated Soybean Oil Iron Powder RI-06-03 Lignobond DD Copper Glycinate (Ca) Hydrogenated Soybean Oil Iron Powder RI-06-04 Borresperse Copper Glycinate (Na) Hydrogenated Soybean Oil Iron Powder RI-06-05 Borresperse AM320 Copper Glycinate (NH4) Hydrogenated Soybean Oil IronRI-07-05 Copper Glycinate Arbo Tll N5 (NH4) Hydrogenated Soybean Oil Iron Powder RI-07-06 Copper Glycinate Arbo NI 8 Na Hydrogenated Soybean Oil Iron Powder RI-07-07 Copper Glycinate Arbo Kl 8 K Hydrogenated Soybean Oil Iron Powder Product Active Ingredient Accelerator Retarder Bulk RI-07-08 Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Zinc Powder RI-02-01 Copper Glycinate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-09-10 Anhydrous Magnesium Sulfate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-47-01 (bis) Vitamin C Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-47-03 A (3-2) Copper Sulfate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-42-02 Copper Carbonate Arbo C12 (Na / NH4) Hydrogenated Soybean Oil Iron Powder RI-37-10(A) Cobalt Carbonate Arbo C12 (Na / NH4) Soybean Oil Hydrogenated Iron Powder Table 25: Components of Short-Term Bolus The percentages of the different components, their solubility index, and their degradation times are given below: Product PA% Ag. Accel. % Ag. Delay. % Ag. Comp. % Weight % Excip. % Ground Index. Duration (hour) 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 Rl-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 Product PA% Ag. Accelerate. % Ag. Delay. % Ag. Comp. % Eastern % Excip. % Sol Index. Duration (high) RI-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 07-03 4.28 28.560 63.5h 7040-2-13 (13003) 50 12 8 0 29 1 27.315 33h 7040-2-13-6 (13003) 50 12 8 0 29 1 27.315 30-30-25 bis 12 5 0 28.2 4.8 28.560 72h R1-47-02-B (3-2) 50 12 8 0 25.2 4.8 28.560 93h RI-06-06 (b) 50 12 8 0 25.24.28.560 h 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 RI-06-03 50 12 8 0 25.28.28.28.60 h RI-06-04 50 12 8 0 25.2 4.8 28.560 48h RI-06-05 50 12 8 0 25.2 4.8 28.560 48h RI-07-05 50 12 8 0 25.28.28.28.60 h RI-07-06 50 12 8 0 25.2 4.8 28.560 39h RI-07-07 50 12 8 0 25.2 4.8 28.560 48h RI-07-08 50 12 8 0 25.28.28.28.54 h RI-02-01 50 12 8 0 25.2 4.8 28.560 57h RI-09-10 57 5 8 0 25.2 4.8 26.718 36.75h RI-47-01 (bis) 50 12 12 024 llh 204.38 Product PA% Ag. Accel. % Ag. Delay. % Ag. Comp. % Weight % Excip. % Ground Index. Duration (hourd) RI-47-03 A (3-2) 50 12 8 0 25.2 4.8 21.095 llh RI-42-02 50 12 8 0 25.2 4.8 6.845 17d Rl-37-10(A) 50 8 8 0 29.2 4.8 4,703 hrs Table 26: Quantities Components Short Duration Bolus Average duration bolus (31 to 90 days) Some examples of medium-duration formulations according to the invention, in bolus form, are given below. Product Active Ingredient Accelerator Delay Ag. Compression Weight Rl-37-09 (A) Cobalt Carbonate Arbo C12 Hydrogenated Soybean Oil Iron Powder RI-42-01 Copper Oxide Arbo C12 Hydrogenated Soybean Oil Iron Powder R2-47-02 - A(1.5) PA Mixture: Glycinates / Vitamins / Carbonates / Oxides ArboC12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder R2-47-01 - A (2.4) Trace Element / Macroelement Mixture Arbo C12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder Mg / Cu / Se Bolus (Test 3) Trace Element / Macroelement Mixture Arbo C12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder Product Active Ingredient Accelerator Retarder Ag. Compression Weight R2-47-03 A(3.1) Mixture Trace Elements / Macroelements / Vitamins Arbo C12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder Rl-18-01 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Tricalcium Phosphate Iron Powder RI-16-09 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Slaked Lime Iron Powder RI-32-04 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Quicklime Iron Powder RI-22-02 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil CaCO3 production Iron Powder RI-22-08 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Heavy Magnesium Carbonate Iron Powder RI-22-01 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Anhydrous Dicalcium Phosphate No. 1 Iron powder RI-16-05 Copper Carbonate Arbo C12 Hydrogenated soybean oil Anhydrous dicalcium phosphate No. 2 Iron powder RI-16-06 Copper Carbonate Arbo C12 Hydrogenated soybean oil Lithothamnium powder Iron powder RI-16-07 Copper Carbonate Arbo C12 OilHydrogenated soybean oil, Heavy Calcium Carbonate, High Density Iron Powder RI-22-07, Arbo C12 Copper Carbonate, Hydrogenated soybean oil, Magnesium Hydroxide, Iron Powder Product Active Ingredient Accelerator Retarder Ag. Compression Weight RI-12-02 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder RI-51-04 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder RI-12-01 Copper Carbonate Arbo C12 Hydrogenated Soybean Oil Magnesium Oxide Iron Powder Table 27: Components Bolus Average Duration The percentages of the different components, their solubility index, and their degradation times are given below: Product PA% Ag. Accel. % Ag. Delayed. % Ag. Comp. % Read % Excip. % Sol Index. Duration (days) Rl-37-09 (A) 50 4 8 0 33.2 4.8 2.562 32 RI-42-01 50 12 8 0 25.2 4.8 2.562 70 R2-47-02 - 835 1 (1-53) 5.44 11.107 40 R2-47-01 - A (2.4) 19.5 7 2 61 7 3.5 11.455 44 Mg / Cu / Se bolus (Assay 3) 19.13 A- 7 1 62.37 140 7-3.5 R (3-1) 64.55 7 5 8.65 10 4.8 4.734 61 Rl-18-01 50 4 8 15 18.2 4.8 2.562 68 RI-16-09 50 4 8 RI 47 15-3 182 4.2 50 4 8 15 18.2 4.8 2.580 81 Product PA% Ag. Accel. % Ag. Delayed. % Ag. Comp. % Read % Excip. % Sol Index. Duration (days) 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 I-16-05 50 4 8 15 18.2 4.8 2.565 58 I-16-06 50 4 8 15 18.2 4.8 2.562 56 I-16-07 50 4 8 17-8 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 16.2 125 4.8 74 -3.63 18.2 4.8 2.562 77 Table 28: Quantities Components Bolus Average Duration Long-Term Bolus (91 to 180 days) Some examples of long-term formulations according to the invention, in bolus form, are given below. Product P. A % Ag. Accel. % Ag. Retard. % Ag. Comp. % Lest. % Excip. % Soil Index Duration (days) RI-51-03 50 Copper oxide 6 Arbo C12 8 Hydrogenated soybean oil 15 Magnesium oxide 16.2 Iron powder 4.8 3.633 98 Product P. A % Ag. Accel. % Ag. Delay .% Ag. Comp. % Weight % Excip. % Ground Index. Duration (days) R2-07-01 66.5 Mixture of Co, Mn carbonates, Cu and Zn oxides, vitamins A and E, sodium selenite, and calcium iodate 3 Arbo C12 5 Hydrogenated soybean oil 10.7 Magnesium oxide 10 Iron powder 4.8 2.592 100 Rl-16-14 62.57 Mixture of Co, Mn carbonates, Cu and Zn oxides, vitamins A and E, sodium selenite, and calcium iodate 4 Arbo C12 5 Hydrogenated soybean oil 13.63 Magnesium oxide 10 Iron powder 4.8 3.128 101 RI-22-09 Copper oxide: 41.6 Zinc oxide: 25, Sodium selenite: 0.445 4 Arbo C12 5 Hydrogenated soybean oil 6.8 Magnesium oxide 12.3 Iron powder 4.875 3.009 160 Product P. A % Ag. Accel. % Ag. Delay .% Ag. Comp. % Weight % Excip. % Ground Index. Duration (days) RI-13-01 50 Manganese Carbonate 6 Arbo C12 8 Hydrogenated Soybean Oil 15 Magnesium Oxide 16.2 Iron Powder 4.8 3.633 131 RI-16-15 61.8 Zinc Oxide, Copper, Cobalt, and Manganese Carbonates, CaIO3, Sodium Selenite 4 Arbo C12 5 Hydrogenated Soybean Oil 15 Magnesium Oxide 9.285 Iron Powder 4.875 2.797 176 RI-22-12 Copper Oxide: 11.6 Zinc Oxide: 55, Sodium Selenite: 0.445 4 Arbo C12 5 Hydrogenated Soybean Oil 6.78 Magnesium Oxide 12.3 Iron Powder 4.875 3,009,138 Table 29: Long-Term Bolus Compositions Ultra-long duration bolus (greater than 180 days) Some examples of ultra-long-duration formulations according to the invention, in bolus form, are given below. Product P. A % Ag. Accel. % Ag. Delay .% Ag. Comp. % Weight % Excip. % Ground Index. Duration (days) RI-26-04 50 Zinc Oxide 4 Arbo C12 8 Hydrogenated Soybean Oil 15 Slaked Lime 18.2 Powdered Iron 4.8 2.583 215 RI-22-10 Copper Oxide: 31.6 Zinc Oxide: 35 Sodium Selenite: 0.445 4 Arbo C12 5 Hydrogenated Soybean Oil 6.78 Magnesium Oxide 12.3 Powdered Iron 4.875 3.009 200 RI-22-11 Copper Oxide: 21.6 Zinc Oxide: 45 Sodium Selenite: 0.445 4 Arbo C12 5 Hydrogenated Soybean Oil 6.78 Magnesium Oxide 12.3 Powdered Iron 4.875 3.009 200 RI-12-05 Zinc Oxide: 50 6 Arbo C12 8 Hydrogenated Soybean Oil 15 Magnesium Oxide 16.2 Powdered Iron 4.8 3.633 265 Table 30: Ultra-Long Duration Bolus Compositions

Claims

DEMANDS 1) Calcium and magnesium pidolate as a macro-element supplement for a non-human animal, preferably a farm animal, for use in stimulating milk production in a female non-human animal, preferably postpartum. 2) Calcium and magnesium pidolate according to claim 1, the non-human animal being a ruminant, selected from the group consisting of cattle, sheep, goats, cervids, camelids, and preferably is a bovine. 3) Calcium and magnesium pidolate according to claim 1, the non-human animal being monogastric, selected from the group consisting of pigs, leporids, equids, companion animals, and preferably is a pig. 4) Calcium and magnesium pidolate according to any one of claims 1 to 3, calcium and magnesium L-pidolate being incorporated as an active ingredient in a pharmaceutical composition. 5) Calcium and magnesium pidolate according to claim 4, the non-human animal being a ruminant and the composition being in the form of a bolus, or the non-human animal is monogastric and the composition is in the form of a chewable tablet. 6) Calcium and magnesium pidolate according to claim 4, the non-human animal being chosen from the group consisting of cattle, sheep, goats, cervids, camelids, pigs, leporids, equids, and companion animals. 7) Galenic composition, containing an active principle based on calcium and magnesium pidolate, for its use to stimulate, around parturition, a general mobilization of endogenous calcium ions in a female non-human mammalian animal, preferably from breeding. 8) Composition according to claim 7, which is in the form of a bolus or in the form of a tablet. 9) Pharmaceutical composition, containing an active ingredient based on calcium and magnesium pidolate, for use in increasing the weight gain of a raised piglet under the mother. 10) Galenic composition, containing an active principle based on calcium and magnesium pidolate, for its use to accelerate the time of farrowing, preferably in sows. 11) Calcium and magnesium pidolate for its use in maintaining peripartum blood calcium levels in cows above 85 mg / l by providing at least the equivalent of 3.78g, preferably at least the equivalent of 7.56g, of calcium in the form of pidolate salt. 12) Calcium and magnesium pidolate for its use in increasing peripartum blood phosphate levels in cows above 55 mg / l by providing at least the equivalent of 30.24g of calcium pidolate and / or 7.5g of magnesium.