US20170246206A1 - Calcium Formate for Use as a Dietary Supplement - Google Patents

Calcium Formate for Use as a Dietary Supplement Download PDF

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US20170246206A1
US20170246206A1 US15/596,587 US201715596587A US2017246206A1 US 20170246206 A1 US20170246206 A1 US 20170246206A1 US 201715596587 A US201715596587 A US 201715596587A US 2017246206 A1 US2017246206 A1 US 2017246206A1
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calcium
calcium formate
phosphorus
formate
dose
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US15/596,587
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Hector F. DeLuca
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Wisconsin Alumni Research Foundation
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Wisconsin Alumni Research Foundation
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Priority claimed from US09/469,513 external-priority patent/US6160016A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Antacids are often used to bind dietary phosphorus to prevent phosphorus retention and prevent its absorption. This process is referred to as phosphorus binding and appears to be a chemical reaction between dietary phosphorus and the cation present in the binder compound, which is usually albumin or calcium. The binding results in the formation of insoluble and unabsorbable phosphate compounds, adsorption of phosphorus ions on the surface of binder particles, or a combination of both.
  • Antacids are used widely, often in large quantities, for indigestion, heartburn or peptic ulcer disease. Despite their consumption in large amounts and often over long periods of time, phosphorus depletion is uncommon in these settings. This fact is additional evidence of the inefficiency of antacids as phosphorus binding agents.
  • the inefficiency of commonly used phosphorus binders creates a clinical dilemma.
  • the dose of the binder must be increased to control hyperphosphatemia, but increased risk of toxicity of the binder results from the increased dose.
  • This toxicity includes bone disease and aluminum dementia from aluminum-containing antacids and hypercalcemia and soft tissue calcification from calcium-containing antacids. These risks are particularly problematic in patients with chronic renal disease.
  • a phosphorus binder available which does not have the risks associated with ingestion of presently available binders.
  • the binder should be more efficient in binding phosphorus and, thus, would not have to be consumed in the large quantities necessary, for example, when calcium carbonate-containing compositions are used.
  • Such a phosphorus binder would be particularly valuable for administration to individuals with chronic renal failure, in whom phosphorus retention is a serious concern and the risk of toxicity from consumption of presently-available binders is greater than in individuals in whom kidney function is normal.
  • Calcium is an abundant element in the human body and plays an important role in many physiological processes. Nutritional and metabolic deficiencies of calcium can have adverse effects, typically manifested through deficiencies in the structure, function and integrity of the skeletal system. The most common calcium-modulated metabolic bone disorder is osteoporosis.
  • Calcium supplements may be the preferred way to obtain supplemental calcium.
  • Calcium carbonate is usually recommended for economic reasons. However, calcium carbonate usage requires sufficient gastric acids for its utilization. Some individuals, especially the elderly, may have limited amounts of gastric acid, and achlorhydric patients have little gastric acid. For such cases, calcium carbonate is poorly utilized. Using large amounts of calcium carbonate may also lead to constipation and abdominal distention. Calcium lactate or calcium citrate may then be used.
  • the present invention relates to a method of binding phosphorus in the gastrointestinal tract and, thus, reducing phosphorus absorption from the intestine. It also relates to a method of reducing serum phosphate levels because phosphorus bound in the gastrointestinal tract results in lower phosphorus absorption than would otherwise occur. It is particularly useful in the treatment and prevention of hyperphosphatemia in individuals with renal disease or other disease in which the ability to excrete phosphorus from the body (e.g., in the urine) is impaired.
  • the method of the present invention comprises orally administering to an individual a composition which includes calcium formate in sufficient quantity to effectively bind phosphorus, preferably present in food and beverages consumed by the individual, and prevent its absorption in the intestine.
  • the calcium formate is administered at a dose of between 0.5 and 10.0 grams.
  • the present invention is also a method of using calcium formate as a dietary calcium supplement.
  • the method comprises orally administrating to an individual a composition comprising calcium formate in sufficient quantities to improve calcium balance or retention.
  • calcium formate may be supplied orally to an individual in order to supplement the individual's calcium intake.
  • the present invention relates to a calcium formate composition for oral administration to an individual.
  • the composition is useful in reducing phosphorus absorption in the gastrointestinal tract.
  • Calcium formate is shown below to be effective in inhibiting phosphorus absorption when administered orally in in vivo tests and has been shown to prevent the absorption of ingested phosphorus at a lower dose than other calcium-containing binders.
  • calcium formate alone or in combination with other materials, can be used to bind phosphorus in the gastrointestinal tract, thus reducing the percentage of an amount of phosphorus consumed (i.e., of a given “dose” of phosphorus) which is absorbed.
  • this dose would be 0.5-10.0 grams when adjusted to doses intended for human patients.
  • the present invention also relates to a method of inhibiting gastrointestinal phosphorus absorption.
  • the method of the present invention is based on the demonstration that calcium formate is an effective binder of phosphorus when administered orally to an individual.
  • the method comprises orally administering a quantity of calcium formate sufficient to bind with phosphorus in the gastrointestinal tract.
  • this dose is between 10-200 milliequivalents of calcium and is preferably present in either tablet or gelatin capsule form.
  • the oral dose is ingested at mealtimes.
  • phosphorus includes phosphorus and phosphate in its various forms (e.g. HPO 4 ⁇ , PO 4 ⁇ 3 , etc.).
  • calcium formate is administered, alone or in combination with other substances (e.g., in a hard gelatin capsule; along with materials necessary to form a tablet or caplet as a delivery vehicle for the calcium formate; or along with a second phosphorus binder or other pharmaceutically useful substance) in sufficient quantities to reduce phosphorus absorption in the gastrointestinal tract.
  • the calcium formate is administered orally, preferably close in time to food and beverage consumption.
  • at mealtimes we mean within 30 minutes of a meal.
  • anhydrous calcium formate (10-200 milliequivalents calcium) is taken prior to food consumption (e.g., meal time) and a second dose of 0.5-10.0 grams of anhydrous calcium formate is taken after food consumption.
  • the dose or quantity to be taken at a given time varies on an individual-by-individual basis and can be adjusted as needed (e.g., by monitoring serum concentration of phosphorus and calcium).
  • calcium formate is administered, alone or in combination with other substances, in sufficient quantities to supplement an individual's calcium intake.
  • the Examples below indicate that calcium formate in quantities between 0.5 and 3.0 g/day are sufficient to improve calcium balance, bone density and calcium retention.
  • the present invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising calcium formate in a pharmaceutically acceptable carrier, wherein the calcium formate is present in an amount between 0.5-1.0 grams.
  • the pharmaceutical composition comprises calcium formate in amount suitable to inhibit gastrointestinal absorption of phosphorus, provides between 11 and 44 milliequivalents of calcium, and is 10% lighter than the corresponding calcium acetate dose and is the richest form of calcium available.
  • corresponding or “therapeutically equivalent,” we mean a dose that is equally effective.
  • the pharmaceutical composition essentially comprises only calcium formate and at least one pharmaceutically carrier, wherein the calcium formate is present in an amount sufficient to produce between 11 and 44 milliequivalents of calcium.
  • essentially comprises we mean that calcium formate is the only active ingredient in the pharmaceutical composition.
  • the present invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising calcium formate in a pharmaceutically acceptable carrier combined with other therapeutic agents, preferably a vitamin D compound.
  • the calcium formate is combined with vitamin D is cholecalciferol in a range of 125 IU to 400 IU in a tablet or capsule.
  • the animals were then placed on a basal diet that contains 0.02% calcium, i.e. an extremely low calcium diet. These animals served as controls. Another group were placed on the same diet containing calcium formate, providing calcium at 0.25% of the diet. Another group was supplied calcium formate at 0.47% calcium in the diet, and another group was provided 0.47% calcium in the form of calcium carbonate. Growth of the animals reflects the ability of the animals to utilize calcium. Using a growth assay of this type to illustrate the effectiveness of the calcium salt is supported by Steenbock et al. J. Nutr. 57:449-468 (1955).

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Abstract

A calcium formate composition for oral administration to an individual for the purpose of supplementary dietary calcium is disclosed.

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • This application is a continuation of U.S. patent application Ser. No. 15/342,908 filed Nov. 3, 2016; which is a continuation of U.S. patent application Ser. No. 14/172,423 filed Feb. 4, 2014, currently abandoned; which is a continuation of U.S. patent application Ser. No. 13/281,754 filed Oct. 26, 2011, currently abandoned; which is a continuation of U.S. patent application Ser. No. 12/943,660 filed Nov. 10, 2010, currently abandoned; which is a continuation of U.S. patent application Ser. No. 11/021,533, filed Dec. 23, 2004, issued as U.S. Pat. No. 7,850,991; which is a continuation of U.S. patent application Ser. No. 10/636,157, filed Aug. 7, 2003, currently abandoned; which is a continuation of U.S. patent application Ser. No. 10/326,789, filed Dec. 19, 2002, currently abandoned; which is a continuation-in-part of U.S. patent application Ser. No. 09/961,729, filed Sep. 24, 2001 and issued as U.S. Pat. No. 6,528,542; which is a continuation of U.S. patent application Ser. No. 09/649,710, filed Aug. 25, 2000, issued as U.S. Pat. No. 6,489,361 and U.S. patent application Ser. No. 09/469,513, filed Dec. 22, 1999, issued as U.S. Pat. No. 6,160,016. Each of these documents are incorporated by reference as if set forth fully herein.
    • STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • Not Applicable.
    • BACKGROUND OF THE INVENTION A. Calcium Formate as a Phosphate Binder.
  • Phosphorus retention plays a major role in chronic renal failure in the development of both secondary hyperparathyroidism and osteodystrophy. Bricker et al., Archives of Internal Medicine 123:543-553 (1969); Rubini et al., Archives of Internal Medicine 124:663-669 (1969); Slatopolsky et al., J. Clinical Investigation 50:492-499 (1971); Bricker, N. S., New England Journal of Medicine 286:1093-1099 (1972); Slatopolsky et al., Kidney Int. 2:147-151 (1972).
  • Antacids are often used to bind dietary phosphorus to prevent phosphorus retention and prevent its absorption. This process is referred to as phosphorus binding and appears to be a chemical reaction between dietary phosphorus and the cation present in the binder compound, which is usually albumin or calcium. The binding results in the formation of insoluble and unabsorbable phosphate compounds, adsorption of phosphorus ions on the surface of binder particles, or a combination of both.
  • Presently-used antacids are inefficient at binding phosphorus in vivo. For example, a recent study by Ramirez et al., noted that even though aluminum-containing or calcium-containing antacids were administered in large excess, they bound only 19-35 percent of dietary phosphorus. Ramirez et al., Kidney Int. 30:753-759 (1986). Similar conclusions can be derived from data presented in earlier studies. Kirsner, J. B., J. Clinical Investigation, 22:47-52 (1943); Clarkson et al., Clinical Science 43:519-531 (1972); Cam et al., Clinical Science and Molecular Medicine 51:407-414 (1976); Man et al., Proceedings of the European Dialysis and Transplantation Association 12:245-55 (1975).
  • Antacids are used widely, often in large quantities, for indigestion, heartburn or peptic ulcer disease. Despite their consumption in large amounts and often over long periods of time, phosphorus depletion is uncommon in these settings. This fact is additional evidence of the inefficiency of antacids as phosphorus binding agents.
  • The inefficiency of commonly used phosphorus binders creates a clinical dilemma. The dose of the binder must be increased to control hyperphosphatemia, but increased risk of toxicity of the binder results from the increased dose. This toxicity includes bone disease and aluminum dementia from aluminum-containing antacids and hypercalcemia and soft tissue calcification from calcium-containing antacids. These risks are particularly problematic in patients with chronic renal disease.
  • It would be very useful to have a phosphorus binder available which does not have the risks associated with ingestion of presently available binders. The binder should be more efficient in binding phosphorus and, thus, would not have to be consumed in the large quantities necessary, for example, when calcium carbonate-containing compositions are used. Such a phosphorus binder would be particularly valuable for administration to individuals with chronic renal failure, in whom phosphorus retention is a serious concern and the risk of toxicity from consumption of presently-available binders is greater than in individuals in whom kidney function is normal.
  • U.S. Pat. No. 4,870,105 addresses these concerns by disclosing a calcium acetate phosphorus binder. However, it would be advantageous to find a binder with a smaller anion and, hence, a smaller effective dose.
    • B. Calcium Formate as a Dietary Supplement.
  • Calcium is an abundant element in the human body and plays an important role in many physiological processes. Nutritional and metabolic deficiencies of calcium can have adverse effects, typically manifested through deficiencies in the structure, function and integrity of the skeletal system. The most common calcium-modulated metabolic bone disorder is osteoporosis.
  • A preferred approach to calcium supplementation is through dietary sources. Dairy products are the major contributors of dietary calcium, as are green vegetables (e.g. broccoli, kale, turnip greens, Chinese cabbage), calcium-set tofu, some legumes, canned fish, seeds and nuts. Breads and cereals can contribute significantly to calcium intake.
  • Calcium supplements may be the preferred way to obtain supplemental calcium. Calcium carbonate is usually recommended for economic reasons. However, calcium carbonate usage requires sufficient gastric acids for its utilization. Some individuals, especially the elderly, may have limited amounts of gastric acid, and achlorhydric patients have little gastric acid. For such cases, calcium carbonate is poorly utilized. Using large amounts of calcium carbonate may also lead to constipation and abdominal distention. Calcium lactate or calcium citrate may then be used.
  • Needed in the art of calcium supplementation is a very soluble calcium supplement with smaller anion and, hence, a smaller effective dose. Other objects, features and advantages of the present invention will become apparent to one of skill in the art after review of the specification and claims.
    • SUMMARY OF THE INVENTION
  • In one embodiment, the present invention relates to a method of binding phosphorus in the gastrointestinal tract and, thus, reducing phosphorus absorption from the intestine. It also relates to a method of reducing serum phosphate levels because phosphorus bound in the gastrointestinal tract results in lower phosphorus absorption than would otherwise occur. It is particularly useful in the treatment and prevention of hyperphosphatemia in individuals with renal disease or other disease in which the ability to excrete phosphorus from the body (e.g., in the urine) is impaired.
  • The method of the present invention comprises orally administering to an individual a composition which includes calcium formate in sufficient quantity to effectively bind phosphorus, preferably present in food and beverages consumed by the individual, and prevent its absorption in the intestine. In an advantageous form of the invention, the calcium formate is administered at a dose of between 0.5 and 10.0 grams.
  • The present invention is also a method of using calcium formate as a dietary calcium supplement. The method comprises orally administrating to an individual a composition comprising calcium formate in sufficient quantities to improve calcium balance or retention.
  • In an advantageous form of the invention, the calcium formate is administered in a dose between 0.5 and 3.0 g/day as a supplement. The present invention is also a pharmaceutical composition comprising calcium formate in combination with a pharmaceutically acceptable carrier. In a preferred embodiment, the composition comprises 0.5 grams of calcium formate per capsule or tablet. In another preferred embodiment, the composition comprises calcium formate and at least one additional therapeutic ingredient. In a most preferred embodiment, this therapeutic ingredient is a vitamin D compound, typically cholecalciferol.
  • It is a feature of the present invention that the amount of calcium-containing compound sufficient to inhibit gastrointestinal phosphorus absorption is 10% lighter than therapeutically equivalent amounts of previously known calcium acetate compounds.
  • It is another feature of the present invention that calcium formate may be supplied orally to an individual in order to supplement the individual's calcium intake.
  • While the present invention is susceptible to various modifications and alternative forms, exemplary embodiments thereof are shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description of exemplary embodiments is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention relates to a calcium formate composition for oral administration to an individual. The composition is useful in reducing phosphorus absorption in the gastrointestinal tract. Calcium formate is shown below to be effective in inhibiting phosphorus absorption when administered orally in in vivo tests and has been shown to prevent the absorption of ingested phosphorus at a lower dose than other calcium-containing binders. As a result of these discoveries, calcium formate, alone or in combination with other materials, can be used to bind phosphorus in the gastrointestinal tract, thus reducing the percentage of an amount of phosphorus consumed (i.e., of a given “dose” of phosphorus) which is absorbed. Preferably, this dose would be 0.5-10.0 grams when adjusted to doses intended for human patients.
  • The present invention also relates to a method of inhibiting gastrointestinal phosphorus absorption. The method of the present invention is based on the demonstration that calcium formate is an effective binder of phosphorus when administered orally to an individual. The method comprises orally administering a quantity of calcium formate sufficient to bind with phosphorus in the gastrointestinal tract. Preferably, this dose is between 10-200 milliequivalents of calcium and is preferably present in either tablet or gelatin capsule form. In a most preferable form of the present invention, the oral dose is ingested at mealtimes.
  • As a result of the present invention it is possible to administer calcium formate to reduce absorption of dietary phosphorus, which has the net effect of reducing the risks of adverse effects (e.g., bone disease and secondary hyperparathyroidism) observed in individuals (e.g., chronic renal patients) in whom the ability to excrete phosphorus in the urine is impaired.
  • As used herein, the term “phosphorus” includes phosphorus and phosphate in its various forms (e.g. HPO4−, PO4 −3, etc.).
  • According to the method of the present invention, calcium formate is administered, alone or in combination with other substances (e.g., in a hard gelatin capsule; along with materials necessary to form a tablet or caplet as a delivery vehicle for the calcium formate; or along with a second phosphorus binder or other pharmaceutically useful substance) in sufficient quantities to reduce phosphorus absorption in the gastrointestinal tract. The calcium formate is administered orally, preferably close in time to food and beverage consumption. By “at mealtimes” we mean within 30 minutes of a meal.
  • In one embodiment, 0.5-10.0 grams of anhydrous calcium formate (10-200 milliequivalents calcium) is taken prior to food consumption (e.g., meal time) and a second dose of 0.5-10.0 grams of anhydrous calcium formate is taken after food consumption. The dose or quantity to be taken at a given time varies on an individual-by-individual basis and can be adjusted as needed (e.g., by monitoring serum concentration of phosphorus and calcium).
  • In another embodiment of the present invention, calcium formate is administered, alone or in combination with other substances, in sufficient quantities to supplement an individual's calcium intake. The Examples below indicate that calcium formate in quantities between 0.5 and 3.0 g/day are sufficient to improve calcium balance, bone density and calcium retention.
  • The present invention is also a pharmaceutical composition comprising calcium formate in a pharmaceutically acceptable carrier, wherein the calcium formate is present in an amount between 0.5-1.0 grams. In another embodiment, the pharmaceutical composition comprises calcium formate in amount suitable to inhibit gastrointestinal absorption of phosphorus, provides between 11 and 44 milliequivalents of calcium, and is 10% lighter than the corresponding calcium acetate dose and is the richest form of calcium available. By “corresponding” or “therapeutically equivalent,” we mean a dose that is equally effective.
  • In another embodiment of the present invention, the pharmaceutical composition essentially comprises only calcium formate and at least one pharmaceutically carrier, wherein the calcium formate is present in an amount sufficient to produce between 11 and 44 milliequivalents of calcium. By “essentially comprises” we mean that calcium formate is the only active ingredient in the pharmaceutical composition.
  • The present invention is also a pharmaceutical composition comprising calcium formate in a pharmaceutically acceptable carrier combined with other therapeutic agents, preferably a vitamin D compound. Most preferably, the calcium formate is combined with vitamin D is cholecalciferol in a range of 125 IU to 400 IU in a tablet or capsule.
    • EXAMPLE 1
  • Calcium Formate as a Phosphate Binder in Normal Rats.
  • TABLE 1
    Serum (mg %) Serum Ca (mg %)
    Group % Ca Formate (mean ± SEM) Weight (mean ± SEM)
    1 Week on Diet
    1 0 4.96 ± .48 209 ± 5.5 ND
    2 1 3.25 ± .31 229 ± 5.5 ND
    3 2 2.50 ± .32 211 ± 6.3 ND
    4 3  2.5 ± .20 194 ± 6.5 ND
    2 Weeks on Diet
    1 0 5.98 ± .39 295 ± 4.8 11.4 ± .20
    2 1 4,70 ± .62 211 ± 3.8 14.0 ± .51
    3 2  2.7 ± .24 198 ± 5.2 12.8 ± .94
    4 3  2.9 ± 0.8 150 ± 8.0 12.9 ± 1.3
    ND = not determined. There were at least 6 rats per group.
  • Five-week-old Sprague Dawley rats were given a synthetic diet containing 0.47% Ca and 0.2% phosphorus for two weeks prior to the addition of calcium formate to the diet. Body weights were measured and blood serum was collected after one or two weeks on calcium formate.
  • The results of this experiment are tabulated in Table 1. All rats supplied with calcium formate had less serum phosphorus than control rats. There seemed to be little difference in serum phosphorus between rats on 2% or 3% calcium formate, thus indicating that a saturation binding point had been reached.
    • EXAMPLE 2
  • Twenty 15-day-old weanling rats from Holzmann Company were placed on a an adequate synthetic diet called “Diet 11” (Suda, T., et al., J. Nutr. 100:1049-1052, 1970). This diet is supplemented with vitamins A, D, E and K as described in that paper. Therefore, these are vitamin D-sufficient animals.
  • The animals were then placed on a basal diet that contains 0.02% calcium, i.e. an extremely low calcium diet. These animals served as controls. Another group were placed on the same diet containing calcium formate, providing calcium at 0.25% of the diet. Another group was supplied calcium formate at 0.47% calcium in the diet, and another group was provided 0.47% calcium in the form of calcium carbonate. Growth of the animals reflects the ability of the animals to utilize calcium. Using a growth assay of this type to illustrate the effectiveness of the calcium salt is supported by Steenbock et al. J. Nutr. 57:449-468 (1955).
  • Table 2, below, tabulates the results. Referring to Table 2, we conclude that calcium formate is at least equal to calcium carbonate in ability to supply calcium to experimental rats. In fact, there is a slightly better growth obtain with 0.25% calcium as the formate in comparison to other treatment groups. Calcium formate can therefore be used as a dietary supplement to provide dietary calcium.
  • TABLE 2
    Average Body Weight in Grams ± S.E.M for 5 Rats
    Control Diet Calcium Formate Calcium Carbonate
    Day (0.02% Ca) (0.25% Ca) (0.47% Ca) (0.47% Ca)
    7 47.6 ± 10.8 54.3 ± 4.0 51.0 ± 10.6 48.6 ± 4.9
    14  74 ± 10.7 84.6 ± 5.5 78.0 ± 19   80.4 ± 10.4
    21 85.6 ± 10  131.0 ± 5.7* 127 ± 11* 126.2 ± 11* 
    *Significantly different from control by Students ‘t’ test.
    P < 0.001.
  • Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration from the specification and practice of the invention disclosed herein. All references cited herein for any reason, including all journal citations and U.S./foreign patents and patent applications, are specifically and entirely incorporated herein by reference. It is understood that the invention is not confined to the specific reagents, formulations, reaction conditions, etc., herein illustrated and described, but embraces such modified forms thereof as come within the scope of the following claims.

Claims (13)

We claim:
1. A method for increasing dietary calcium in an individual, comprising: orally ingesting a quantity of calcium formate sufficient to improve calcium balance or retention.
2. The method according to claim 1 wherein the quantity of calcium formate is present in an amount sufficient to provide between 10-60 milliequivalents of calcium.
3. The method according to claim 1 wherein the calcium formate is in tablet form.
4. The method according to claim 1 wherein the calcium formate is in gelatin capsule form.
5. The method of claim 1 wherein the calcium formate is orally ingested in a first and second dose, wherein the first dose is before a mealtime and the second dose is after a mealtime.
6. The method of claim 1 wherein the quantity is a dose of between 0.5 g and 3.0 g per day.
7. The method of claim 6 wherein the quantity is administered once a day.
8. The method of claim 1 wherein the calcium formate is combined in a dose with a second, biologically active compound.
9. The method of claim 8 wherein the second compound is a vitamin D compound.
10. The method of claim 9 wherein the vitamin D is cholecalciferol.
11. The method of claim 10 wherein the cholecalciferol is in between 125 IU and 400 IU.
12. The method of claim 6, wherein the quantity is between 1.0 g and 2.0 g per day.
13. The method of claim 1 wherein the calcium formate is at least 0.47% calcium in the diet of the individual.
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US09/469,513 US6160016A (en) 1999-12-22 1999-12-22 Phosphorus binder
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US09/961,729 US6528542B2 (en) 1999-12-22 2001-09-24 Calcium formate for use as a dietary supplement
US10/326,789 US20030100609A1 (en) 1999-12-22 2002-12-19 Calcium formate for use as a dietary supplement
US10/636,157 US20040029964A1 (en) 1999-12-22 2003-08-07 Calcium formate for use as a dietary supplement
US11/021,533 US7850991B2 (en) 1999-12-22 2004-12-23 Calcium formate for use as a dietary supplement
US12/943,660 US20110059927A1 (en) 1999-12-22 2010-11-10 Calcium Formate For Use As A Dietary Supplement
US13/281,754 US20120046252A1 (en) 1999-12-22 2011-10-26 Calcium Formate for Use as a Dietary Supplement
US14/172,423 US20140155360A1 (en) 1999-12-22 2014-02-04 Calcium Formate for Use as a Dietary Supplement
US15/342,908 US20170049808A1 (en) 1999-12-22 2016-11-03 Calcium Formate for Use as a Dietary Supplement
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