Composition for prophylactic treatment of hypocalcemia in ruminants

Abstract

The present application discloses compositions and principles for the prophylactic treatment of hypocalcemia in ruminants (e.g., cattle) prior to childbirth, i.e. Compositions comprising one or more phosphate binding agents for the prophylactic treatment of parturient hypocalcemia in ruminants (e.g., cattle), e.g., where the compositions are in one or more unit dosage forms, e.g., in one or more unit dosage forms. And wherein one or more unit dosage forms of the composition are manually administered per day to the gastrointestinal tract of the ruminant, or wherein the composition is provided in wet form. The present application also discloses compositions comprising one or more phosphate binding agents and one or more nutrients selected from the group consisting of minerals, vitamins and amino acids, and compositions comprising inhibitors of the small intestine Na-phosphate transporter for use in the prophylactic treatment of parturient hypocalcemia in ruminants, such as cattle. The phosphate binder is selected from aluminum salts, ferric salts, sevelamer salts and lanthanum salts formed with inorganic or organic acids, hydrates thereof or any mixture thereof.

Description

Field of the Invention

[0001] The present invention relates to compositions and principles for the prophylactic treatment of hypocalcemia in ruminants prior to parturition. Background of the Invention

[0003] Parturient hypocalcemia is a common disease in dairy cows. The global incidence of clinical hypocalcemia (milk fever) totals approximately 4%, and varies widely between farms. Subclinical hypocalcemia typically occurs in 25% of first-calving heifers and 50% of multiparous cows.

[0004] Parturient hypocalcemia occurs when the cow is unable to maintain plasma calcium levels due to calcium demand. Calcium levels in plasma are usually tightly regulated by homeostasis and are generally very constant during different metabolic stages of the reproductive cycle. Parturient hypocalcemia typically occurs during the transition from dry cow to lactating cow. During the dry period, calcium demand is very low, and the calcium absorption mechanism is not activated because passive absorption between epithelial cells can meet the calcium demand. Near parturition, the animal begins to produce colostrum and subsequent milk, resulting in a sudden increase in calcium demand. The decrease in plasma calcium levels activates the animal's own defense mechanism to counteract the plasma calcium decline. The time lag in activating the active absorption mechanism is several days, which impairs the animal's productive capacity. The production responses to parturient hypocalcemia are well described, including increased frequency of dystocia, retained placenta, metritis, ketosis, reduced fertility, and increased culling rate.

[0005] Existing methods for preventing parturient hypocalcemia include:

[0006] Dietary cation-anion balance (DCAB) in the prepartum diet induces controlled metabolic subclinical acidosis; the cow counteracts this by releasing more calcium into the plasma, thereby activating the animal's own calcium absorption mechanism;

[0007] High zeolite levels in the feed;

[0008] Low calcium feeding in the prepartum diet activates the cow's absorption mechanism; and

[0009] High calcium feeding in the peripartum diet - increases passive calcium absorption and maintains plasma calcium levels.

[0010] EP 1162 890 B1 discloses the use of at least one compound for the prophylaxis of parturient hypocalcemia in cattle, said compound reducing the calcium absorption of cattle from drinking water and / or from the diet. Various compounds are proposed for this use, such as oxalic acid, sodium oxalate, phytic acid, phytates, clay minerals including zeolites, ethylenediaminetetraacetic acid (EDTA) and its sodium salts Na2EDTA and Na4EDTA, trisodium nitrilotriacetate monohydrate, trisodium nitrilotriacetate, pentasodium diethylenetriaminepentaacetate, trisodium N-hydroxyethyl-ethylenediaminetriacetate, citric acid, citrates, polyphosphates, tripolyphosphates, orthophosphates and cellulose phosphates and calcium-free derivatives of any such compounds, and zinc compounds selected from zinc oxide, zinc chloride and zinc sulfate.

[0011] WO 2008 / 005217 A2 discloses a pharmaceutical composition comprising a pharmaceutically acceptable ferrous ion compound for use in a method of treating a subject suffering from hyperphosphatemia.

[0012] US 8,236,358 B1 discloses compositions and methods suitable for the treatment of hyperphosphatemia with magnesium salts that bind phosphate.

[0013] US 4,931,290 discloses a method for reducing the tendency of dairy cows to develop severe milk fever after calving, said method comprising administering to the cow after calving a composition comprising a water-soluble calcium compound and a serum phosphorus complexing agent.

[0014] Pallesen et al.: “Effect of pre-calving zeolite, magnesium and phosphorus supplementation on periparturient serum mineral concentrations”, VETERINARY JOURNAL, BAILLIERE TINDALL, LONDON, GB, Vol. 175, No. 2, February 1, 2008, pp. 234-239, XP022491628, ISSN: 1090-0233, DOI: 10.1016 / J.TVJL.2007.01.007, discloses a study testing whether supplementing the diet of dry dairy cows with phosphorus and magnesium would interfere with the beneficial effect of zeolite supplementation on the periparturient blood calcium concentration in dairy cows.

[0015] There is still a need for compositions for the prophylactic treatment of parturient hypocalcemia in ruminants (such as cattle) before parturition. SUMMARY OF THE INVENTION

[0016] In a first aspect, the present invention provides a composition for prophylactically treating parturient hypocalcemia in ruminants before parturition, the composition comprising one or more phosphate-binders, see claim 1.

[0017] In a second aspect, the present invention provides a composition for prophylactically treating parturient hypocalcemia in ruminants before parturition, the composition comprising one or more phosphate-binders, wherein the composition is in one or more unit dosage forms, and wherein one or more doses of the unit dosage forms of the composition are manually administered to the gastrointestinal tract of the ruminant per day, see claim 12.

[0018] In a third aspect, the present invention provides a composition for prophylactically treating parturient hypocalcemia in ruminants before parturition, the composition comprising one or more phosphate-binders, wherein the composition is provided in a wet form, see claim 15. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Shows the effects of the phosphate-binder aluminum sulfate on the periparturient serum inorganic phosphate levels in the control group and the treatment group respectively;

[0020] Figure 2 Shows the effects of the phosphate-binder aluminum sulfate on the periparturient serum total calcium levels in the control group and the treatment group respectively; and

[0021] Figure 3 Shows the effects of the phosphate-binder aluminum sulfate on the milk production in the first 5 weeks after parturition in the control group and the treatment group respectively;

[0022] This experiment is described in more detail in Example 2 below. DETAILED DESCRIPTION OF THE INVENTION

[0024] Many improvements and alternatives for prophylactically treating parturient hypocalcemia are described below. The improvements and alternatives mainly utilize the use of phosphate-binders.

[0025] As used herein, the term "phosphate-binder" should be understood to mean a compound or substance capable of binding phosphate, for example, usually in an amount of at least 50 mg P / g, particularly at least 100 mg P / g, particularly at least 150 mg P / g.

[0026] Examples of phosphate binders are aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminosilicate, aluminosilicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum carbonate hydroxide, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sucroferric oxyhydroxide, ferric trimaltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof, or any mixture thereof. Preferably, the applicable phosphate binder is non-toxic at therapeutically effective amounts.

[0027] As used herein, the term "ruminant" generally refers to cattle, sheep, and goats, particularly cattle.

[0028] Phosphate Binders in the Prophylactic Treatment of Parturient Hypocalcemia

[0029] A number of studies have investigated the relationship between inorganic phosphorus levels in the prenatal diet and parturient hypocalcemia. Phosphate may also play an important role in the pathogenesis of milk fever, with increased phosphate concentrations being associated with an increased risk of milk fever. In cattle, there is evidence that a high-phosphate prenatal diet can have a negative impact on calcium homeostasis at calving (Kichura et al., 1982, Livestock Prod. Sci., 31:271-286.; Barton et al., 1987, J. Dairy Sci. 70:1186-1191). Thus, it is recommended that the prenatal diet for each animal include a maximum of 22 g of phosphorus per day (National Research Council. 2001. Nutrient Requirements of Dairy Cattle. 7th revised ed. National Research Council. National Academy Press, Washington, D.C.). thRevised edition. National Research Council. National Academic Press, Washington, DC.); Weiss, "Practical Application Recommendations for Minerals and Vitamins". Penn State Dairy Cattle Workshop, November 12 - 14, 2012, pp. 107 - 112 (Weiss, Real World Recommendations for Minerals and Vitamins. Penn State Dairy Cattle Workshop November 12 - 14 November 2012. 107 - 112). Since phosphorus is naturally present in commercial feed ingredients and home - produced feeds, the phosphorus level in the diet is typically about 35 to 50 grams per day. Therefore, it cannot be used under actual farm conditions.

[0030] The inventors have found that reducing phosphorus is an effective method for preventing parturient hypocalcemia. However, in normal practice, due to the phosphorus level in the normal feed ingredients used, it is impossible / difficult to achieve a low amount of phosphorus in the diet.

[0031] EP 1162890 B1 discloses the use of zeolite for preventing parturient hypocalcemia. This reference specifically discusses the calcium - binding effect of zeolite.

[0032] However, the inventors have found that in the preventive treatment of parturient hypocalcemia, phosphate binding has a more significant effect than calcium binding.

[0033] Moreover, the current use of synthetic sodium aluminosilicate zeolite (a calcium - binding agent and a phosphate - binding agent) for the preventive treatment of parturient hypocalcemia requires the administration of a large amount of this substance (about 400 g / cow / day), and since it has been found that phosphate binding has a more significant effect than calcium binding, it is considered advantageous to use a specified phosphate - binding agent alone or alternatively in combination with, for example, zeolite in the preventive treatment of parturient hypocalcemia.

[0034] Accordingly, in a first aspect, the present invention provides a composition for prophylactically treating parturient hypocalcemia in ruminants before parturition, the composition comprising one or more phosphate - binding agents selected from aluminum salts, iron salts, sevelamer salts, and lanthanum salts of inorganic or organic acids, hydrates thereof, or any mixture thereof. Thereby, subclinical or clinical hypocalcemia in periparturient cows can be reduced or avoided.

[0035] In a variant of the present invention, the composition further comprises zeolite, such as synthetic sodium aluminosilicate zeolite type A. In such a variant, the weight ratio of one or more phosphate binders to zeolite is in the range of 99:1 to 10:90. By also introducing zeolite in the composition according to the present invention, the effects of both phosphate binding and calcium binding are obtained in the prophylactic treatment of parturient hypocalcemia.

[0036] Phosphate binders and nutrients

[0037] Due to the physiological system imbalance shortly before and shortly after calving, cows may suffer from deficiencies in certain minerals, vitamins, amino acids and related substances. Although certain supplements can be added to conventional animal feed, it will be necessary to formulate feed of a specific quality to administer to cows in the vicinity of calving, especially shortly before calving. Since for the purpose of prophylactic treatment of hypocalcemia, it is desirable to administer a composition comprising a phosphate binder to cows during the last 4 weeks before calving, such as the last 2 - 3 weeks before calving, such as the last 1 - 2 weeks before calving, for example at least during the 1 - 10 days before parturition, for practical reasons and reasons of accurate administration, it is considered advantageous to co - administer a combination of a phosphate binder with certain nutrients (such as minerals, vitamins and amino acids) to cows.

[0038] Accordingly, the present invention also provides a composition for prophylactically treating parturient hypocalcemia in ruminants before parturition, the composition further comprising one or more nutrients selected from minerals, vitamins and amino acids.

[0039] In one embodiment, the minerals, vitamins and amino acids are selected from choline, magnesium oxide, magnesium chloride, magnesium sulfate, sodium chloride, sodium bicarbonate, sodium sulfate, selenium chloride, sodium selenite, cobalt chloride, cobalt sulfate, iodine chloride, copper chloride, copper sulfate, manganese chloride, manganese sulfate, manganese oxide, zinc chloride, zinc sulfate, zinc oxide, vitamin A, vitamin D, vitamin E, vitamin B12, pantothenic acid, folic acid, thiamine, biotin, niacin and lysine, isoleucine, threonine, lysine and rumen protected methionine, such as niacin and rumen protected methionine respectively.

[0040] Such minerals, vitamins and amino acids are generally included in a total amount of 10 to 500 grams per daily dose of the composition.

[0041] Typically, one or more phosphate binders are selected from aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminosilicate, aluminosilicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum chloride, iron citrate, iron sulfate, sevelamer hydrochloride, sevelamer carbonate, their hydrates or any mixture thereof, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, their hydrates or mixtures thereof.

[0042] In one embodiment, the composition further comprises zeolite.

[0043] The composition can be used for prophylactic treatment of parturient hypocalcemia in ruminants (such as cattle) before parturition.

[0044] Large unit dosage form of phosphate binder

[0045] By administering the phosphate binder in particulate form to ruminants (such as cattle), a desired amount of the particles containing the phosphate binder can be scattered on conventional animal feed. However, the intake of the phosphate binder particles by cattle will depend on whether the particles remain uniformly mixed with the feed or whether a portion of the particles sink into the feed and are left behind after the cattle consume the feed.

[0046] The inventors have found that manual administration of a "bolus" (which can be presented as multiple unit dosage forms) to cattle will ensure accurate administration of the phosphate binder to the cattle.

[0047] Accordingly, in a second aspect, the present invention provides a composition for prophylactic treatment of parturient hypocalcemia in ruminants (such as cattle), the composition comprising one or more phosphate binders, wherein the composition is in unit dosage form, each containing 100 - 800 g of phosphate binder, such as 150 - 700, such as 200 - 600, such as 250 - 500, such as 300 - 400 g of phosphate binder, and wherein one or more unit dosage forms of the composition are manually administered to the gastrointestinal tract of the ruminant (such as cattle) one or more times per day.

[0048] Typically, the one or more phosphate binders are selected from aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminosilicate, aluminosilicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum chloride, iron citrate, iron sulfate, sevelamer hydrochloride, sevelamer carbonate, their hydrates or any mixture thereof, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, their hydrates or mixtures thereof.

[0049] In one embodiment, the composition further comprises zeolite.

[0050] In some embodiments, the composition further comprises one or more nutrients as described in the content under the above title "Phosphate binders and nutrients".

[0051] Composition of the phosphate binder in wet form

[0052] Regarding the challenges described under the title "Large unit dosage forms of phosphate binders", it is believed that a formulation of the phosphate binder in a moist or water-suspended form will enable the composition of the phosphate binder to effectively adhere to conventional animal feed, such that only a minimal portion of the phosphate binder will pass through the feed and be left after the cattle ingest the feed.

[0053] Accordingly, in a third aspect, the present invention provides a composition for prophylactically treating parturient hypocalcemia in ruminants (such as cattle) before parturition, the composition comprising one or more phosphate binders, wherein the composition is provided to the animal in a wet form comprising 15 - 80% by weight (such as 20 - 50% by weight) of water.

[0054] Generally, the one or more phosphate binders are selected from aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum basic carbonate, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sucrose hydroxyiron oxide, trimaltolatoiron, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof or any mixture thereof, such as selected from the group consisting of: aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum basic carbonate, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sevelamer hydrochloride, sevelamer carbonate, preferably selected from the group consisting of: lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, hydrates thereof or mixtures thereof.

[0055] In one embodiment, the composition further comprises zeolite.

[0056] In some embodiments, the composition further comprises one or more nutrients as described in the content under the above title "Phosphate binders and nutrients". Examples

[0057] Example 1: Phosphorus binding efficacy

[0058] Experiments were conducted to evaluate the phosphorus-binding efficacy of aluminum, iron, sevelamer, and lanthanum compounds compared to other compounds. Thilsing et al. described the in vitro method used (Thilsing T et al., Journal of Veterinary Medicine Series A. 53(2), 57 - 64(2006), the entire content of which is incorporated herein by reference), which simulates the digestive tract of ruminants.

[0059] Briefly, the experiment was carried out in three consecutive stages. In stage 1, rumen fluid with or without one of the test compounds was incubated at the typical pH in the rumen (pH about 7 - 8). In stage 2, HCl was added to simulate abomasum conditions (pH about 1.5 - 3.5) and incubation was continued. In stage 3, HCO3 - was added to increase the pH to simulate small intestine conditions (pH about 6.8 - 7.2) and incubation was continued. The amount of each compound added to the rumen fluid (0.06 g / 8 ml rumen fluid) corresponded to the amount that would actually be used, for example, adding 600 g of the compound to about 100 kg of diet). The amount of the compound was not adjusted according to dry matter or others.

[0060] The free phosphorus (P) of each test compound in the three stages is shown in Table 1. Thus, the lower the concentration of P, the more phosphorus the compound in question has absorbed. Table 1 also compares the amount of free P remaining in each compound with the amount of free P in the control sample without the use of the test compound and the amount of free P remaining in 4A zeolite.

[0061] When converted to the binding capacity in milligrams of P per gram of test compound, the results are listed in Table 2. These values are all from stage 3, representing the small intestine of ruminants, which is the main site of phosphorus absorption.

[0062] As shown in Tables 1 and 2, simple lanthanum, aluminum, iron, and sevelamer compounds, such as lanthanum chloride, lanthanum carbonate, aluminum chloride, aluminum sulfate, ferrous sulfate, and sevelamer hydrochloride, are superior phosphate binders to many other compounds, including superior to 4A zeolite alone. Since these compounds are generally well physiologically tolerated, they are very suitable for use in feed compositions for lactating animals.

[0063] Table 1. Phosphate concentration in the supernatant of rumen fluid rich in Ca and / or P in samples without adding various compounds (control) and adding various compounds after adding HCl and HCO3 - was added.

[0064] The phosphate content was compared with synthetic 4A zeolite and the control.

[0065]

[0066] Table 2. Binding capacity of various compounds for inorganic phosphate in stage 3 (post - addition of HCl and HCO - - simulated small intestine). The binding capacity of the compounds under discussion was compared with that of synthetic 4A and the control.

[0067]

[0068]

[0069] Example 2: Effect of compounds on alleviating hypocalcemia in periparturient dairy cows.

[0070] Thirty - four multiparous cows were selected on day 21 before calving and randomly assigned to one of two dietary treatments. Control treatment (n = 17); a corn silage - based diet typical in the industry. Experimental cows (n = 17) received the same diet + 400 g of aluminum sulfate per day.

[0071] Blood samples were collected from the cows according to the following schedule:

[0072] · On the day of assignment to the periparturient group - baseline value;

[0073] · Days 10, 7, 5, 3, and 1 before expected calving;

[0074] · On the day of calving (within 12 hours);

[0075] · Days 1, 2, 3, 5, 7, and 14 after calving.

[0076] Supplementation with aluminum sulfate significantly (P < 0.001) reduced the inorganic phosphate concentration from a pre - initiation value of approximately 2 mmol / L at parturition to a level of approximately 0.84 mmol / L, while the control value was 1.84 mmol / L. This demonstrates the high potency of reducing inorganic phosphate (Table 3a and 3b and Figure 1 ). After parturition, in the absence of further aluminum sulfate supplementation, the plasma concentration increased to the same plasma inorganic phosphate level as the control group 3 - 5 days later, indicating that the reduction was only transient.

[0077] Table 3a and 3b. Plasma inorganic phosphate concentrations during the peripartum period. The standard error of the mean (SEM) for the entire control group was 0.1, and for the entire treatment group was 0.1. The SEM difference between the entire control group and the entire treatment group was 0.14. p - values showing the contrast test between control and treatment are presented.

[0078]

[0079]

[0080] Table 3a.

[0081]

[0082] Table 3b (continued from Table 3a).

[0083] The experimental group had significantly (P<0.001) higher serum total calcium concentrations at 12 hours after parturition and on the first and second days after calving (Tables 4a and 4b and Figure 2 ). The calcium concentrations in the blood were on average 0.22, 0.18, and 0.14 mmol / L higher than those of the control cows on these days. This demonstrated that the supplementation of phosphate binders during the last 21 days before calving successfully reduced subclinical hypocalcemia in periparturient cows.

[0084] Tables 4a and 4b. Periparturient serum total calcium concentrations (mmol / L) in the control and treatment groups. The standard error of the mean (SEM) for the entire control group was 0.05 and for the entire treatment group was 0.05. The difference in SEM between the entire control group and the entire treatment group was 0.06. The p-values showing the contrast test between control and treatment are presented.

[0085]

[0086]

[0087] Table 4a

[0088]

[0089] Table 4b (continued from Table 4a).

[0090] The daily milk yield of the treatment group tended to be higher (Tables 5 and Figure 3 ). Higher milk yields are generally associated with a lower incidence of subclinical hypocalcemia.

[0091] Table 5. Milk yields (kg / day) and standard error of the mean (SEM) in the control and treatment groups during the first 5 weeks after parturition. The p-values showing the contrast test between control and treatment are presented.

[0092]

[0093] The experimental group had a lower incidence of subclinical hypocalcemia (Ca<2.1 mmol / L) (Table 6). In the control group, 63% of the animals were diagnosed with subclinical hypocalcemia at 12 hours after calving, which was three times the level of the treatment group (22%). At 24 and 48 hours after calving, the control group continued to have a higher level of subclinical hypocalcemia than the treatment group.

[0094] Table 6. Percentages of subclinical hypocalcemia (defined as plasma calcium concentration below 2.1 mmol / L) in the control and treatment groups at 12, 24, and 48 hours after calving.

[0095]

Claims

1. A composition for prophylactically treating parturient hypocalcemia in ruminants before parturition, said composition comprising one or more phosphate binders selected from aluminum salts, iron salts, sevelamer salts, and lanthanum salts formed with inorganic or organic acids, hydrates thereof, or any mixture thereof.

2. The composition according to claim 1, wherein the inorganic or organic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, acetic acid, carbonic acid, and citric acid.

3. The composition for said use according to any one of the preceding claims, wherein the one or more phosphate binders are selected from the group consisting of aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, basic lanthanum carbonate, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sucrose hydroxyoxide iron, trimaltolatoiron, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof, or any mixture thereof.

4. The composition for said use according to any one of the preceding claims, wherein the one or more phosphate binders are selected from the group consisting of aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, basic lanthanum carbonate, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sevelamer hydrochloride, sevelamer carbonate, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, hydrates thereof, or mixtures thereof.

5. The composition for said use according to any one of the preceding claims, wherein the ruminants are selected from the group consisting of cattle, sheep, and goats, preferably cattle.

6. The composition for said use according to any one of the preceding claims, which is used during the last 4 weeks before parturition, preferably during the last 2 - 3 weeks before parturition, such as during the last 1 - 2 weeks before parturition, such as during at least 1 - 10 days before parturition.

7. The composition for said use according to any one of the preceding claims, wherein the composition further comprises zeolite, such as synthetic sodium aluminosilicate zeolite type A.

8. The composition for said use according to claim 7, wherein the weight ratio of the one or more phosphate binders to the zeolite is in the range of 99:1 to 10:

90.

9. The composition for said use according to any one of the preceding claims, further comprising one or more nutrients selected from minerals, vitamins, and amino acids.

10. The composition according to claim 9, wherein the minerals, vitamins and amino acids are respectively selected from choline, magnesium oxide, magnesium chloride, magnesium sulfate, sodium chloride, sodium bicarbonate, sodium sulfate, selenium chloride, sodium selenite, cobalt chloride, cobalt sulfate, iodine chloride, copper chloride, copper sulfate, manganese chloride, manganese sulfate, manganese oxide, zinc chloride, zinc sulfate, zinc oxide, vitamin A, vitamin D, vitamin E, vitamin B12, pantothenic acid, folic acid, thiamine, biotin, niacin, and lysine, isoleucine, threonine, lysine and rumen-protected methionine.

11. The composition according to any one of claims 9-10, wherein the one or more phosphate binders are selected from the group consisting of aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum basic carbonate, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sucrose hydroxyferric oxide, ferric maltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof or any mixture thereof, such as selected from the group consisting of aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum basic carbonate, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sevelamer hydrochloride, sevelamer carbonate, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, hydrates thereof or mixtures thereof, optionally in combination with one or more zeolites, such as synthetic sodium aluminosilicate zeolite type A.

12. A composition for prophylactically treating parturient hypocalcemia in ruminants, such as cows, before parturition, the composition comprising one or more phosphate binders selected from aluminum salts, iron salts, sevelamer salts and lanthanum salts formed with inorganic or organic acids, hydrates thereof or any mixture thereof, wherein the composition is in one or more unit dosage forms, each containing 100-800 g of phosphate binder, such as 150-700, such as 200-600, such as 250-500, such as 300-400 g of phosphate binder, and wherein one or more doses of the unit dosage form of the composition are manually administered to the gastrointestinal tract of the ruminant per day.

13. The composition according to claim 12, wherein the composition further comprises one or more nutrients selected from minerals, vitamins and amino acids.

14. The composition according to any one of claims 12 - 13, wherein one or more phosphate binders are selected from the group consisting of: aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum basic carbonate, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sucrose hydroxyiron oxide, ferric maltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, their hydrates or any mixture thereof, such as selected from the group consisting of: aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum basic carbonate, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sevelamer hydrochloride, sevelamer carbonate, preferably selected from the group consisting of: lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, their hydrates or mixtures thereof, optionally in combination with one or more zeolites, such as synthetic sodium aluminosilicate zeolite A.

15. A composition for prophylactic treatment of parturient hypocalcemia in ruminants, such as cattle, the composition comprising one or more phosphate binders selected from aluminum salts, iron salts, sevelamer salts and lanthanum salts formed with inorganic or organic acids, their hydrates or any mixture thereof, wherein the composition is provided to the animal in a wet form containing 15 - 80% by weight of water.

16. The composition according to claim 15, wherein one or more phosphate binders are selected from the group consisting of: aluminum citrate, aluminum chloride, aluminum carbonate, aluminum sulfate, aluminum oxide, ammonium aluminum sulfate, sodium aluminum sulfate, potassium aluminum sulfate, calcium aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum basic carbonate, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sucrose hydroxyiron oxide, ferric maltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, their hydrates or any mixture thereof, such as selected from the group consisting of: aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum basic carbonate, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ammonium ferric citrate, sevelamer hydrochloride, sevelamer carbonate, preferably selected from the group consisting of: lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, their hydrates or mixtures thereof, optionally in combination with one or more zeolites, such as synthetic sodium aluminosilicate zeolite A.

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