Composition for use in the prophylactic treatment of hypocalcemia in ruminants

Abstract

The present application discloses compositions and principles for use before parturition in the preventive treatment of hypocalcemia in ruminants, such as cattle, particularly compositions comprising a phosphate binder for use in the preventive treatment of intrapartum hypocalcemia in ruminants, such as cattle, e.g., where the composition is in unit dosage form and one or more doses of the unit dosage form of the composition are manually administered per day to the gastrointestinal tract of the ruminant, or the composition is provided in a wet form. The present application also discloses compositions comprising one or more phosphate binders and one or more nutrients selected from minerals, vitamins, and amino acids, as well as compositions comprising an inhibitor of the small intestinal Na-phosphate transporter, for use in the preventive treatment of intrapartum hypocalcemia in ruminants, such as cattle. The phosphate binder is selected from salts of aluminum, iron, sevelamer, and lanthanum with inorganic or organic acids, their hydrates, or any mixtures thereof.

Description

[Technical Field]

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

[0002] Periparturitional hypocalcemia is a common condition in dairy cows. The incidence of clinical hypocalcemia (milk fever) is approximately 4% worldwide, with significant inter-farm variability. Subclinical clinical hypocalcemia typically occurs in 25% of first-calf cows and 50% of high-yielding cows.

[0003] Intrapartum hypocalcemia occurs when a cow's calcium demands prevent it from maintaining plasma calcium levels. Plasma calcium levels are normally tightly homeostatically regulated and typically remain fairly constant throughout the different metabolic stages of the reproductive cycle. Intrapartum hypocalcemia typically occurs during the transition from dry to lactating cows. During the dry period, calcium demands are extremely low, and calcium absorption mechanisms are not activated because calcium demands can be met through passive absorption across epithelial cells. As calving approaches, the animal begins producing colostrum and then milk, initiating a rapid increase in calcium demand. Plasma calcium levels decline, and the cow's own defense mechanisms are initiated to counteract the decline in plasma calcium. There is a time lag of several days for the initiation of active absorption mechanisms, resulting in a decline in the animal's productive capacity. The productive responses to intrapartum hypocalcemia are well described and include increased incidence of dystocia, retained placenta, metritis, ketosis, lower reproduction, and increased culling rates.

[0004] Existing methods for preventing intrapartum hypocalcemia include: Dietary cation-anion balance (DCAB) in the pre-calving diet induces a controlled metabolic subclinical acidosis; the cow counters this by releasing more calcium into the plasma, thereby initiating its own calcium absorption mechanisms; High levels of zeolite in feed; Low calcium feeding before calving activates the cow's absorption mechanism; and High calcium feeding in the perinatal diet increases passive calcium absorption, which maintains plasma calcium levels.

[0005] EP 1162890B1 discloses the use of at least one compound for reducing calcium absorption from drinking water and / or for cattle feed to prevent intrapartum hypocalcemia in cattle. Various compounds are suggested for this use, such as oxalic acid, sodium oxalate, phytic acid, phytates, clay minerals including zeolites, ethylenediaminetetraacetic acid (EDTA) and its sodium salts NaEDTA and NaEDTA, trisodium nitrilotriacetate monohydrate, trisodium nitrilotriacetate, pentasodium diethylenetriaminepentaacetate, trisodium N-hydroxyethyl-ethylenediaminetriacetate, citric acid, citrates, polyphosphates, tripolyphosphates, orthophosphates, cellulose phosphate, and calcium-free derivatives of any such compounds, as well as zinc compounds selected from zinc oxide, zinc chloride, and zinc sulfate.

[0006] WO2008 / 005217A2 discloses a pharmaceutical composition comprising a pharmaceutically acceptable ferrous compound for use in a method of treating a subject with hyperphosphatemia.

[0007] US 8,236,358 B1 discloses compositions and methods suitable for the treatment of hyperphosphatemia based on phosphate-binding magnesium salts.

[0008] US 4,931,290 discloses a method for reducing the tendency of dairy cows to develop severe milk fever at the time of calving, which comprises administering to the cow after calving a composition comprising a water-soluble calcium compound and a complexing agent for serum phosphorus.

[0009] 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, 1 February 2008, pp. 234-239, XP022491628, ISSN: 1090-0233, DOI: 10.1016 / J.TVJL.2007.01.007) disclose a study to test whether supplementing dry cow rations with phosphorus and magnesium interferes with the beneficial effects of zeolite supplementation on periparturient blood calcium concentrations in dairy cows.

[0010] There remains a need for compositions for use before parturition in the prophylactic treatment of intrapartum hypocalcemia in ruminants, such as cattle. Summary of the Invention

[0011] In a first aspect, the present invention provides a composition (see claim 1) comprising one or more phosphate binders for use before parturition in the preventive treatment of intrapartum hypocalcaemia in ruminants.

[0012] In a second aspect, the present invention provides a composition comprising one or more phosphate binders for use before parturition in the prophylactic treatment of intrapartum hypocalcaemia in ruminants, wherein the composition is in unit dosage form and one or more doses per day of the unit dosage form of the composition are administered manually into the gastrointestinal tract of the ruminant (see claim 12).

[0013] In a third aspect, the present invention provides a composition (see claim 15) for use before parturition in the preventive treatment of intrapartum hypocalcaemia in ruminants, comprising one or more phosphate binders, wherein the composition is provided in a moist form. [Brief explanation of the drawings]

[0014] For the experiment described in more detail in Example 2 below: [Figure 1] FIG. 1 shows the effect of the phosphate binder aluminum sulfate on serum inorganic phosphate levels during the perinatal period for the control and treatment groups, respectively. [Figure 2] FIG. 2 shows the effect of the phosphate binder aluminum sulfate on serum total calcium levels during the perinatal period for the control and treatment groups, respectively. [Figure 3] FIG. 3 shows the effect of the phosphate binder aluminum sulfate on milk production during the first 5 weeks postpartum for the control and treatment groups, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0015] A number of improvements and alternatives to the prophylactic treatment of intrapartum hypocalcemia are described below. The improvements and alternatives primarily utilize the use of phosphate binders.

[0016] In this specification, the term "phosphate-binder" should be understood to refer to a compound or substance that is capable of binding phosphate, for example, typically in an amount of at least 50 mg P / g, in particular at least 100 mg P / g, in particular at least 150 mg P / g.

[0017] 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 aluminum silicate, aluminum silicate, 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, ferrous ammonium citrate, sucroferric oxyhydroxide, ferric trimaltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof or any mixtures thereof. Preferably, the applicable phosphate binders are non-toxic at therapeutically effective amounts.

[0018] As used herein, the term "ruminants" typically refers to cattle, sheep and goats, especially cattle.

[0019] Phosphate binders in the prophylactic management of intrapartum hypocalcaemia Several studies have investigated the relationship between inorganic phosphorus levels in the pre-calving diet and intra-calving hypocalcemia. Phosphate may also play an important role in the pathogenesis of milk fever, and increased phosphate concentrations increase the risk of milk fever. In cattle, there is evidence that a pre-calving diet high in phosphorus can negatively affect calcium homeostasis at calving (Kichura, et al., 1982, Livestock Prod. Sci., 31:271-286; Barton, et al., 1987, J. Dairy Sci. 70:1186-1191). Therefore, it is recommended that the pre-calving diet contain a maximum of 22 g of phosphorus per animal per day (National Research Council. 2001. Nutrient Requirements of Dairy Cattle. 7 threvised edition. National Research Council. National Academic Press, Washington, DC.; Weiss, Real World Recommendations for Minerals and Vitamins. Penn State Dairy Cattle Workshop, November 12-14, 2012. pp. 107-112). Because of the natural occurrence of phosphorus in commercial feed ingredients and home-grown feeds, phosphorus levels are typically about 35-50 g per day in the diet. Therefore, they cannot be used under real-world farm conditions.

[0020] The present inventors have found that reducing phosphorus is an effective way to prevent intrapartum hypocalcemia. In normal practice, it is not possible / difficult to lower the amount of phosphorus in the diet due to the phosphorus levels in the usual feed ingredients used.

[0021] EP1162890B1 discloses the use of zeolites to prevent intrapartum hypocalcemia. This document deals only with the calcium-binding effect of zeolites.

[0022] However, the present inventors have found that phosphate binding has a significantly greater effect than calcium binding in the prophylactic treatment of intrapartum hypocalcemia.

[0023] Also, because the current use of synthetic sodium aluminosilicate zeolite type A (a calcium and phosphate binder) for the prophylactic treatment of intrapartum hypocalcemia requires that significant amounts of the material be administered (approximately 400 g / cow / day), and because phosphate binding has been found to have a significantly greater effect than calcium binding, it would be advantageous to use a specified phosphate binder alone or in combination with, for example, a zeolite, in the prophylactic treatment of intrapartum hypocalcemia.

[0024] Thus, in a first aspect, the present invention provides a composition comprising one or more phosphate binders selected from aluminium, iron, sevelamer and lanthanum salts, their hydrates or any mixtures thereof with inorganic or organic acids for use before parturition in the prophylactic treatment of intrapartum hypocalcemia in ruminants, thereby reducing or avoiding subclinical or clinical hypocalcemia in periparturient cattle.

[0025] In one variation thereof, the composition further comprises a zeolite, e.g., synthetic sodium aluminosilicate zeolite type A. In such a variation, the weight ratio of the one or more phosphate binders to the zeolite ranges from 99:1 to 10:90. The incorporation of a zeolite into the composition according to the present invention provides both phosphate-binding and calcium-binding benefits in the prophylactic treatment of intrapartum hypocalcemia.

[0026] Phosphate binders and nutrients Due to imbalances in the physiological system immediately before and after calving, cattle may suffer from deficiencies in certain minerals, vitamins, amino acids, and related substances. While it is possible to add specific supplements to normal animal feed, it is necessary to administer a specific quality feed formulation to cattle around the time of calving, especially immediately before calving. For the purpose of preventive treatment of hypocalcemia, it may be desirable to administer a composition containing a phosphate binder to cattle during the last four weeks before calving, for example, the last two to three weeks before calving, for example, the last one to two weeks before calving, for example, at least one to ten days before calving. For practical and precise dosing reasons, it may be advantageous to co-administer a phosphate binder to cattle in combination with certain nutrients such as minerals, vitamins, and amino acids.

[0027] Thus, the present invention also provides a composition further comprising one or more nutrients selected from minerals, vitamins and amino acids for use before parturition in the prophylactic treatment of intrapartum hypocalcemia in ruminants.

[0028] 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, e.g., niacin and rumen-protected methionine, respectively.

[0029] Such minerals, vitamins and amino acids are typically included in a total amount of 10 to 500 g per daily dose of the composition.

[0030] 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 aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof or any mixtures thereof, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, hydrates thereof or mixtures thereof.

[0031] In one embodiment, the composition further comprises a zeolite.

[0032] The compositions may be useful before parturition in the prophylactic treatment of intrapartum hypocalcemia in ruminants, such as cattle.

[0033] Large unit dosage form of phosphate binder The phosphate binder in granular form can be administered to ruminants such as cattle by overlaying a desired amount of granules containing the phosphate binder onto regular animal feed. However, the intake of the phosphate binder granules by the cattle depends on whether the granules remain homogeneously mixed with the feed or whether some of the granules settle in the feed and remain after the cattle ingest the feed.

[0034] The inventors have found that manual administration of a "bolus" (which may be provided as a number of unit dosage forms) to the cow ensures accurate administration of the phosphate binder to the cow.

[0035] Accordingly, in a second aspect, the present invention provides a composition comprising one or more phosphate binders for use in the prophylactic treatment of intrapartum hypocalcaemia in ruminants, such as cattle, wherein the composition is in unit dosage form each containing 100 to 800g of phosphate binder, such as 150 to 700, for example 200 to 600, such as 250 to 500, for example 300 to 400g of phosphate binder, and wherein one or more doses per day of the unit dosage form of the composition are administered manually into the gastrointestinal tract of the ruminant, such as cattle.

[0036] 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 aluminum silicate, aluminum silicate, aluminum hydroxide, aluminum bromide, aluminum iodide, aluminum nitrate, sodium aluminum phosphate, lanthanum carbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof or any mixtures thereof, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, hydrates thereof or mixtures thereof.

[0037] In one embodiment, the composition further comprises a zeolite.

[0038] In some embodiments, the composition further comprises one or more nutrients described above under the heading "Phosphate binders and nutrients."

[0039] Composition of phosphate binder in wet form With respect to the subject matter described under the heading "Large Unit Dosage Forms of Phosphate Binders," it is believed that formulation of phosphate binders in wet or water-suspended form can efficiently adhere the phosphate binder composition to conventional animal feed, such that only a small portion of the phosphate binder passes through the feed and remains after the cattle have ingested the feed.

[0040] Thus, in a third aspect, the present invention provides a composition comprising one or more phosphate binders for use before parturition in the prophylactic treatment of intrapartum hypocalcaemia in ruminants, such as cattle, wherein the composition is provided to the animal in a wet form comprising 15 to 80% by weight, such as 20 to 50% by weight, water.

[0041] Typically, 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 carbonate hydroxide, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ferrous ammonium citrate, sucroferric oxyhydroxide, thiamin mononitrate ... The ferric rimaltol is selected from ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof or any mixtures thereof, for example, selected from the group consisting of aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum carbonate hydroxide, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ferrous ammonium citrate, sevelamer hydrochloride, sevelamer carbonate, and is preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, hydrates thereof or mixtures thereof.

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

[0043] In some embodiments, the composition further comprises one or more nutrients described above under the heading "Phosphate binders and nutrients." [Example]

[0044] Example 1: Phosphorus Binding Efficacy Experiments were conducted to evaluate the phosphorus-binding efficacy of aluminum, iron, sevelamer, and lanthanum compounds compared to other compounds. The in vitro method used was described by Thilsing et al. (Thilsing T, et al. Journal of Veterinary Medicine Series A. 53(2), 57-64 (2006) (the entire contents of which are incorporated herein by reference)), which mimics the digestive tract of ruminants.

[0045] Briefly, the experiment was carried out in three successive stages. In the first stage, ruminal fluid with or without one of the test compounds was incubated at a pH typical of the rumen (pH 7-8). In the second stage, HCl was added to mimic abomasal conditions (pH 1.5-3.5) and incubation resumed. In the third stage, the pH was adjusted to 1.0 with HCl. - The incubation was continued at elevated temperature, mimicking the conditions in the small intestine (pH approximately 6.8-7.2). The amount of each compound added to the rumen fluid (0.06 g per 8 ml of rumen fluid) corresponded to the actual amount used, e.g., 600 g of compound in approximately 100 kg of intestine. The compound amounts were not adjusted for dry matter or otherwise.

[0046] The free phosphorus (P) across the three stages for each compound tested is shown in Table 1. Thus, the lower the concentration of P, the more phosphorus is absorbed by the compound of interest. Table 1 also compares the amount of free P left by each compound to the amount of free P left in a control sample for zeolite 4A without the test compound.

[0047] The results, when converted to binding capacity in milligrams P per gram of test compound, are shown in Table 2. All of these values ​​are from stage 3, which represents the small intestine of ruminants, the primary site of phosphorus absorption.

[0048] As can be seen from Tables 1 and 2, simple lanthanum, aluminum, iron, and sevelamer compounds, such as lanthanum chloride, lanthanum carbonate, aluminum chloride, aluminum sulfate, iron(II) sulfate, and sevelamer hydrochloride, are better phosphorus binders than many other compounds, including being better than using zeolite 4A alone. The compounds are generally well tolerated physiologically, making them excellent for use in feed compositions for lactating animals. [Table 1] [Table 2]

[0049] Example 2: Effect of compounds on reducing hypocalcemia in periparturient dairy cows. Thirty-four prolific cows were enrolled 21 days before calving and randomly assigned to one of two dietary treatments: the control treatment (n=17) received a corn silage-based diet typical in the industry, and the experimental cows (n=17) received the same diet plus 400g of aluminum sulfate per day.

[0050] Blood samples were taken from the cows according to the following schedule: Day of allocation to close-up group - baseline values; 10, 7, 5, 3 and 1 day before the expected delivery date; · Day of delivery (within 12 hours); · 1, 2, 3, 5, 7 and 14 days after calving.

[0051] Aluminum sulfate supplementation significantly (P<0.001) reduced inorganic phosphate concentrations from pre-partum values ​​of approximately 2 mmol / L to levels of approximately 0.84 mmol / L at parturition, compared with a control value of 1.84 mmol / L, demonstrating a significant reduction in inorganic phosphate (Tables 3a and 3b and Figure 1). After parturition, when aluminum sulfate was no longer supplemented, plasma concentrations increased to the same plasma inorganic phosphate levels as controls after 3 to 5 days, indicating that the reduction was transient. [Table 3]

[0052] The experimental group had significantly (P<0.001) higher serum total calcium concentrations 12 hours after calving and on days 1 and 2 after calving (Tables 4a and 4b and Figure 2). Blood calcium concentrations averaged 0.22, 0.18, and 0.14 mmol / L, respectively, on these days, which were higher than those of control cows. This indicates that supplementation with phosphate binders during the final 21 days leading up to calving can alleviate subclinical hypocalcemia in periparturient cows. [Table 4]

[0053] Daily milk production tended to be higher in the treatment groups (Table 5 and Figure 3). Higher milk production is often associated with a lower incidence of subclinical hypocalcemia. [Table 5]

[0054] The experimental groups 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 12 hours after parturition, which was three times higher than the level in the treatment group (22%). At 24 and 48 hours after parturition, the control group continued to show higher levels of subclinical hypocalcemia than the treatment group. [Table 6]

Claims

1. A composition comprising one or more phosphate binders selected from salts of aluminum, iron, sevelamer and lanthanum, their hydrates or any mixtures thereof with inorganic or organic acids, for use before parturition in the prophylactic treatment of intrapartum hypocalcemia in ruminants.

2. 2. The composition of 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. 3. The composition of claim 1 or 2, 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 carbonate hydroxide, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ferrous ammonium citrate, sucroferric oxyhydroxide, ferric trimaltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate, hydrates thereof, or any mixture thereof.

4. 3. The composition of claim 1 or 2, wherein the one or more phosphate binders are selected from the group consisting of aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum carbonate hydroxide, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ferrous ammonium 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 of claim 1, wherein the phosphate binder is aluminum sulfate.

6. 3. The composition according to claim 1 or 2, wherein the ruminant is selected from the group consisting of cattle, sheep and goats, preferably cattle.

7. 3. The composition of claim 1 or 2 for use in the last 4 weeks before calving, preferably the last 2 to 3 weeks before calving, such as the last 1 to 2 weeks before calving, such as at least 1 to 10 days before calving.

8. 3. The composition of claim 1 or 2, wherein the composition further comprises a zeolite, such as synthetic sodium aluminosilicate zeolite type A.

9. 9. The composition of claim 8, wherein the weight ratio of the one or more phosphate binders to the zeolite ranges from 99:1 to 10:

90.

10. 3. The composition of claim 1 or 2, further comprising one or more nutrients selected from minerals, vitamins, and amino acids.

11. 11. The composition of claim 10, wherein 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, respectively.

12. The one or more phosphate binders are 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 carbonate hydroxide, lanthanum oxycarbonate, lanthanum chloride, ferrous citrate, ferrous sulfate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferric citrate, ferric sulfate, ferric chloride, ferrous ammonium citrate, sucroferric oxyhydroxide, ferric trimaltol, ferric bicarbonate, ferric carbonate, sevelamer hydrochloride, sevelamer carbonate 11. The composition of claim 10, wherein the ferrous iron or iron-containing salt is selected from the group consisting of a salt, a hydrate thereof or any mixture thereof, such as selected from the group consisting of aluminum citrate, aluminum chloride, aluminum sulfate, lanthanum chloride, lanthanum carbonate hydroxide, lanthanum oxycarbonate, ferrous citrate, ferrous chloride, ferrous carbonate, ferrous bicarbonate, ferrous sulfate, ferric citrate, ferric sulfate, ferric chloride, ferrous ammonium citrate, sevelamer hydrochloride, sevelamer carbonate, preferably selected from the group consisting of lanthanum chloride, aluminum chloride, aluminum sulfate, ferrous sulfate, sevelamer hydrochloride, lanthanum carbonate, a hydrate thereof or a mixture thereof, optionally in combination with one or more zeolites, such as synthetic sodium aluminosilicate zeolite type A.

13. 10. The composition of claim 1, wherein the ruminant is, for example, a cow, and the composition is in unit dosage form, each comprising 100 to 800 g of phosphate binder, such as 150 to 700, for example 200 to 600, such as 250 to 500, for example 300 to 400 g of phosphate binder, and one or more doses per day of the unit dose of the composition are administered manually into the gastrointestinal tract of the ruminant.

14. The composition of claim 1, wherein the ruminant is, for example, a cow, and the composition is provided to the animal in a moist form containing 15 to 80% by weight of water.

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