A highly water soluble ferric pyrophosphate citrate chelate useful for treating iron deficiency contains 2% or less phosphate by weight. These chelate compositions are easily milled and/or processed into dosage forms using conventional techniques, and are expected to exhibit advantageous biocompatibility as compared to conventional soluble ferric pyrophosphates, ferric salts, ferric polysaccharide complexes and ferrous salts.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides water-soluble iron chelate compositions comprising ferric pyrophosphate citrate chelate compositions. A chelate composition of the invention comprises pyrophosphate and citrate chelated to ferric iron. Chelate compositions of the invention are water-soluble iron fortificants and are useful for the treatment of iron deficiency anemia, particularly the anemia of chronic disease.

These and other features, advantages and objects of the present invention will be further understood and appreciated by those skilled in the art by reference to the following specification and claims.

DETAILED DESCRIPTION OF THE INVENTION

Compositions in accordance with certain aspects of the invention comprise stable, water-soluble ferric pyrophosphate citrate chelate compositions, having, by weight, from about 7% to about 11% iron, from about 14% to about 30% citrate, from about 10% to about 20% pyrophosphate and about 2% or less phosphate. The chelate compositions may have, by weight, about 1.5% phosphate or less, or about 1% phosphate or less. In an aspect of the invention, the chelate compositions have, by weight, about 0.1% phosphate or less. Sulfate ion content is typically from about 20% to about 35% by weight.

Methods in accordance with certain aspects of the invention comprise steps for the preparation of stable, water-soluble ferric pyrophosphate citrate chelate compositions, having, by weight, from about 7% to about 11% iron, from about 14% to about 30% citrate, from about 10% to about 20% pyrophosphate and about 2% or less phosphate. The chelate compositions may have, by weight, about 1.5% phosphate or less, or about 1% phosphate or less. In an aspect of the invention, the chelae compositions have, by weight, about 0.1% phosphate or less. Sulfate ion content is typically from about 20% to about 35% by weight.

In certain aspects of the invention, water-soluble ferric pyrophosphate citrate chelate compositions are used as a food additive, nutritional supplement, dietary supplement, medical food, nutrient, iron fortificant, and source of iron in the fields of nutrition for humans, animals, fish, and birds and diagnostics. Soluble ferric pyrophosphate citrate chelate compositions are used as a pharmaceutical and pharmacologically active ingredient for human clinical and veterinary applications in certain aspects of the invention.

A method of administering a water-soluble ferric pyrophosphate citrate chelate composition to a subject in need of such administration for the prevention or treatment of iron deficiency or anemia is provided in certain aspects of the invention.

According to a method of the present invention, a water-soluble ferric pyrophosphate citrate chelate composition is administered, alone or in combination with other substances (e.g., along with materials necessary to form a tablet, caplet, pill, capsule, troche, lozenge, powder, granulate, or solution that is suitable for ingestion) in sufficient quantities to prevent the onset or reverse the course of deleterious effects brought about by iron deficiency. Further, according to a method of the present invention, a water-soluble ferric pyrophosphate citrate chelate composition of the invention is administered, alone or in combination with other substances, in sufficient quantities in a formulation for parenteral administration to prevent the onset or reverse the course of deleterious effects brought about by iron deficiency.

A method of the present invention employs a composition as described hereinabove, which is administered to a mammal by oral ingestion or injection. The composition, so administered, may be regarded either as a food additive, a substance that is generally regarded as safe (i.e., a GRAS substance), or a drug within the meaning of Title 21 of the Code of Federal Regulations (CFR).

In a method of the present invention, a chelate composition as described hereinabove may be ingested as a food supplement, dietary supplement, nutritive supplement, or medical food. The terms "food supplement, dietary supplement, and nutritive supplement" encompass or include a composition of the present invention that augments the iron that is present in food, components of the diet, and compositions intended to provide nutrition. The term "medical food" encompasses or includes a chelate composition of the present invention that is prescribed by a clinician or physician for the purpose of augmenting iron in ingesta.

In a method of the invention, a chelate composition as described herein may be administered as a drug either orally or by injection.

Included within the scope of this invention is a method of treating iron deficits in a warm-blooded animal, including a human, using pharmaceutical compositions comprising a soluble ferric pyrophosphate citrate chelate composition of the invention and a suitable pharmaceutical carrier. For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom which includes but is not limited to mammals and birds.

The term "chelate" as used herein generally means a metal cation and anions that surround the metal cation and are joined to it by electrostatic bonds. A water-soluble ferric pyrophosphate citrate chelate composition of the invention comprises a ferric iron cation surrounded by and joined by electrostatic bonds to both citrate and pyrophosphate anions.

The term "excipient material" means any compound forming a part of the formulation which is not intended to have biological activity itself and which is added to a formulation to provide specific characteristics to the dosage form, including by way of example, providing protection to the active ingredient from chemical degradation, facilitating release of a tablet or caplet from equipment in which it is formed, and so forth.

The terms "treating" and "treatment" and the like are used herein to generally mean obtaining a desired pharmacological and physiological effect. The effect may be palliative, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease. The term "treatment" as used herein encompasses any treatment of a disease in a mammal, particularly a human and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease or arresting its development; (c) relieving the disease, causing regression of the disease and/or its symptoms or conditions; or (d) returning a clinical value to the concentration range normally found in a subject.

The phrase "therapeutically effective" is intended to qualify the amount of an active agent needed in an orally or parenterally administered therapy which will achieve the goal of abating, mitigating, reducing or preventing, for example, an iron deficiency disorder, or of restoring physiologically adequate concentrations of iron while avoiding adverse side effects typically associated with conventional iron compositions.

The term "suitable for intravenous injection" as used herein has its conventional meaning as understood by skilled artisans when referring to a composition that meets the general requirements for solutions for injection as presented in the General Chapter of the U.S. Pharmacopoeia entitled "Injections." (U.S. Pharmacopoeia, U.S. Pharmacopoeial Convention, Inc., Rockville, Md., 2006.)

The term "parenteral nutrition composition" means a composition for parenteral administration.

The term "dialysis therapy" means the clinical treatment of chronic kidney disease comprising the osmotic exchange of metabolites, toxins and water across a membrane from a renal disease patient's blood to a dialysate solution. Conventional dialysis therapy is described by S. Pastan and J. Bailey in the article entitled "Dialysis therapy" published in The New England Journal of Medicine, volume 338, number 20, pages 1428-1437 (1998).

The term "dialysate" means a composition for intravenous administration as part of a dialysis procedure for the treatment of chronic kidney disease. Dialysate is conventionally provided for use in either peritoneal dialysis (in which the peritoneal membrane constitutes the dialysis membrane) or hemodialysis (in which a synthetic membrane constitutes the dialysis membrane). Hemodialysate is generally prepared from two dry powder concentrates, including acid ("A") and base ("B") concentrates, which are reconstituted in treated water before use, or from two aqueous concentrates. The A concentrate, containing an organic acid and electrolytes and osmotic agents other than bicarbonate, is mixed with B concentrate containing bicarbonate and treated water in a dialysis machine to make the final hemodialysate. Peritoneal dialysate is a premixed solution of osmotic agents, electrolytes, and water that is used in dialysis without further constitution.

After diligent and lengthy experimentation, the inventor has discovered water-soluble ferric pyrophosphate citrate chelate compositions comprising about 2% or less phosphate. The chelate compositions may have, by weight, about 1.5% phosphate or less, or about 1% phosphate or less. In certain aspects, the chelate compositions have, by weight, about 0.1% phosphate or less.

The methods for the preparation of the water-soluble ferric pyrophosphate citrate chelate compositions of the present invention comprise combining citrate and pyrophosphate ions in water, adding ferric ion, and isolating water-soluble ferric pyrophosphate citrate chelate compositions there from. The following parameters may affect product yield, quality and/or composition: (a) the ratio of iron to citrate to pyrophosphate; (b) the purity of each raw material; (c) the volume of water that is employed; (d) the reaction temperature; (e) the organic solvent that is used to cause precipitation of the desired product, a ferric pyrophosphate citrate chelate composition of the invention; (f) the volume of organic solvent that is used to cause precipitation; and (g) the drying temperature.

A molar ratio of Fe.sup.3+ to citrate to pyrophosphate of about 1:1:0.5 may be used for obtaining a composition of the present invention. Variations in this ratio of about .+-.10% are tolerable, i.e., the molar ratio of Fe.sup.3+ to citrate to pyrophosphate may be 0.9 to 1.1 moles Fe.sup.3+:0.9 to 1.1 moles citrate:0.45 to 0.55 moles pyrophosphate. Larger changes in the molar ratio result in compositions that are different from those of the present invention. For example, use of a molar ratio of 1:0.5:1 (Fe.sup.3+ to citrate to pyrophosphate) fails to provide a chelate composition.

Each raw material exhibits high purity. The ferric salt, citrate, and pyrophosphate starting materials each contain less than 250 micrograms of the metals aluminum, antimony, arsenic, bismuth, cadmium, copper, lead, mercury, molybdenum, thallium, and tin per gram of the starting material, since these metals exhibit known toxicities in humans. The pyrophosphate preferably contains less than about 0.1% phosphate, and more preferably less than about 0.01% phosphate.

A volume of water equal to 2 milliliters (.+-.10%) of water for each gram of ferric salt starting material is adequate for dissolution of all the starting materials and the resulting chelate composition product and enables precipitation of the desired chelate composition by the addition of an organic solvent. If substantially smaller volumes of water are used, the starting materials may not dissolve completely. If substantially larger volumes of water are used, the desired chelate composition may not precipitate or may precipitate in low yield after addition of an organic solvent. Typically, a volume of water of from about 1.5 milliliters to about 10 milliliters for each gram of ferric salt can be used for dissolution of the starting materials.

Before addition of the ferric salt starting material, the reaction temperature may be increased to a temperature in the range from about 70.degree. C. to about 85.degree. C. in order to achieve complete dissolution of the starting materials. Once dissolution is complete, the reaction temperature may be lowered to a temperature in the range from about 15.degree. C. to about 75.degree. C. to prevent hydrolysis of pyrophosphate to phosphate in the presence of ferric ion, preferably from about 15.degree. C. to about 39.degree. C.

The inventor has discovered that organic solvents such as methanol, ethanol, propanol, 2-propanol, acetonitrile, acetone, and 2-butanone are useful in precipitating the desired chelate composition.

A volume of 14 milliliters (.+-.10%) of methanol for each gram of ferric salt starting material may be used. The addition of substantially smaller volumes may result in incomplete precipitation of the desired chelate composition. The addition of larger volumes could increase the risk of contamination with unwanted by-products. Suitable amounts of methanol and/or other organic solvents may range from about 10 to about 25 milliliters per gram of ferric ion source.

If a wet cake of the desired chelate composition (i.e., a mass of the product that contains water and methanol) is dried at a temperature that exceeds about 80.degree. C., pyrophosphate is hydrolyzed to phosphate. Thus, it is preferred that the precipitate is dried at a temperature of 80.degree. C. or less.

While not wishing to be bound by any particular hypothesis or theory, the inventor expects that the soluble ferric pyrophosphate citrate chelate compositions of the invention afford the significant advantages that (a) the ferric iron is strongly chelated by both pyrophosphate and citrate; and (b) the chelate composition is very water-soluble.

The strength of the electrostatic bond between a ligand and a metal ion is conventionally described by a stability constant, K.sub.stab, and frequently expressed as the logarithm of that constant. [Martell A E, Smith R M. Critical Stability Constants. Volumes 1-6. New York: Plenum Press; 1974, 1975, 1976, 1977, 1982, and 1989.] The log K.sub.stab for ferric ion with citrate is 12 and the log K.sub.stab for ferric ion with pyrophosphate is 22.2. [Gupta A J, Crumbliss A L. Treatment of iron deficiency anemia: Are monomeric iron compounds suitable for parenteral administration? J Lab Clin Med 2000; 136: 371-178.] These stability constants are several orders of magnitude greater than the stability constants for ferric ion with other anions such as chloride or gluconate, indicating that the electrostatic bonds between ferric ion and citrate and between ferric ion and pyrophosphate are stronger than the bonds to other ligands. Chelate compositions of the present invention have a solubility in water that exceeds 1 gram per milliliter. Chelate compositions of the present invention contain, by weight, from about 10% to about 20% pyrophosphate. Recent studies have shown that polyphosphate compounds are possible candidates for intracellular iron transport, and among these polyphosphate compounds, pyrophosphate has been shown to be the most effective agent in triggering iron exchange with transferrin. [Konopka K, Mareschal J C, Crichton R R. Iron transfer from transferrin to ferritin mediated by pyrophosphate. Biochem Biophys Res Commun 1980; 96(3):1408-13. Pollack S, Vanderhoff G, Lasky F. Iron removal from transferrin. An experimental study. Biochim Biophys Acta 1977; 497(2):481-7. Muralidhara B K, Hirose M. Anion-mediated iron release from transferrins. The kinetic and mechanistic model for N-lobe of ovotransferrin. J Biol Chem 2000; 275(17):12463-9.] The structure of the ferric pyrophosphate citrate chelate of the invention resembles the putative structure of the pyrophosphate enzyme complex that enables iron transfer to transferrin. [Cowart R E, Swope S, Loh T T, Chasteen N D, Bates G W. The exchange of Fe3+ between pyrophosphate and transferrin. Probing the nature of an intermediate complex with stopped flow kinetics, rapid multimixing, and electron paramagnetic resonance spectroscopy. Journal of Biological Chemistry 1986; 261(10):4607-14.] Further, pyrophosphate, in micromolar concentrations, is known to bind tightly to ferric iron, thereby inhibiting its pro-oxidation activity. [Cervato G, Viani P, Cestaro B. Studies on peroxidation processes of model membranes: role of pyrophosphate. Chem Phys Lipids 1990; 56(2-3): 91-9. Cervato G, Viani P, Gatti P, Cazzola R, Cestaro B. Further studies on the antioxidant role of pyrophosphate in model membranes. Chem Phys Lipids 1993; 66(1-2): 87-92.] Neither citrate nor phosphate, for example, exhibits this activity at micromolar concentrations. Compositions of the present invention may contain, by weight, less than about 2% phosphate, less than about 1.5% phosphate, less than about 1% phosphate, or less than about 0.1% phosphate. Higher concentrations of phosphate could increase the risk that water-insoluble phosphate salts will precipitate, either in the solution dosage forms of the composition or in the body following administration. In the body, deposition of phosphate salts in the circulatory system causes endothelial dysfunction. For these reasons, it is expected that pyrophosphate citrate chelate compositions of the present invention will exhibit advantageous biocompatibility as compared to conventional soluble ferric pyrophosphates, ferric salts, ferric polysaccharide complexes, and ferrous salts.

A soluble ferric pyrophosphate citrate chelate composition of the invention can be prepared from stoichiometric portions of a ferric salt, citric acid or a citrate salt, and disodium dihydrogen pyrophosphate or tetrasodium pyrophosphate in a molar ratio of 1:1:0.5 in water. Ferric sulfate, ferric sulfate hydrate, ferric chloride, and ferric ammonium sulfate can be used as the ferric salt (ferric ion source material). Preferably the ferric salt is ferric sulfate hydrate. Citric acid, monosodium citrate, disodium citrate, and trisodium citrate can be used as the citrate (citrate ion source material). Disodium dihydrogen pyrophosphate or tetrasodium pyrophosphate can be used as the pyrophosphate (pyrophosphate ion source material). A suitable reaction temperature is from about 20.degree. C. to about 85.degree. C.

According to a preferred aspect of the present invention, a soluble ferric pyrophosphate citrate chelate composition of the invention can be recovered from a solution of ferric ion, citrate, and pyrophosphate by precipitation. A soluble ferric pyrophosphate citrate chelate composition of the invention may be recovered after a reaction time sufficient to provide a solution of a chelate composition by adding an organic solvent. Suitable organic solvents may be selected from methanol, ethanol, propanol, 2-propanol, acetonitrile, acetone, and 2-butanone.

Advantageously, from an industrial perspective, a process for preparation of solid compositions of a soluble ferric pyrophosphate citrate chelate may employ conventional apparatuses and reagents. Selected process apparatuses may enable control of reaction temperature, monitoring of the progress of reaction for extent of completion, and facilitate removal of impurities.

The ferric pyrophosphate citrate chelate compositions obtained by the methods of the present invention are reproducible and do not contain solvents, chemical contaminants, or biological contaminants. The ferric pyrophosphate citrate chelate compositions of the present invention are easily milled and/or processed into formulary dosage forms using conventional methods and techniques.

The compositions of this invention can be administered by any means that effects contact of the therapeutically active ingredients (i.e., active ingredients) with the site of action in the body of a warm-blooded animal. The active ingredients can be administered by the oral route in solid dosage forms, such as tablets, capsules, powders, chewable compositions, and rapidly dissolving film, or in liquid dosage forms, such as elixirs, syrups, and suspensions. Capsules or tablets for oral administration may contain a controlled-release formulation, and may be provided as a dispersion of active compound in hydroxypropyl methylcellulose or related material known to alter the kinetics of release of the active agent. Solid dosage forms can be manufactured as sustained release products to provide continuous release of medication over a period of hours using known pharmaceutical techniques. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Both the solid and liquid oral dosage forms can contain coloring and flavoring to increase patient acceptance.

The active ingredients can be administered by an intravenous route in liquid dosage forms, such as solutions, suspensions, or emulsions.

By way of example, parenteral nutrition (PN), also known as parenteral hyperalimentation, is a medical treatment that supplies nutrition-maintaining compositions intravenously, and is indicated for a variety of mammalian disorders, such as cancer, gastrointestinal diseases, major body burns, extensive wounds, and AIDS. Partial parenteral nutrition supplies only part of daily nutritional requirements, supplementing oral intake. Many hospitalized patients receive dextrose or amino acid solutions by this method. Total parenteral nutrition treatment (TPN) supplies all daily nutritional requirements intravenously, circumventing the gut. TPN may be employed following surgery, when feeding by mouth or using the gut is not possible, when a patient's digestive system cannot absorb nutrients due to chronic disease, or, if nutrition cannot be met by enteral feeding and supplementation. Premature and sick infants often require extended periods of TPN. Compositions for parenteral nutrition typically contain at least water, glucose, amino acids, and optionally emulsified fats. They may be aseptically compounded from amino acid solutions, dextrose solutions, and/or lipid emulsions. PN compositions may further contain vitamins, electrolytes and essential trace elements. The inventors have discovered that a soluble ferric pyrophosphate composition of the present invention is compatible with PN compositions and when admixed with a PN composition provides supplemental iron and pyrophosphate. Supplemental iron and pyrophosphate are useful, by way of example, to treat iron deficiency (anemia) and bone disorders, respectively, in humans and other warm-blooded animals.

Dialysis is a clinical treatment procedure by which metabolic by-products, toxins, and excess fluid are removed from the blood of a subject with chronic kidney disease (CKD) by transfer across a dialysis membrane. Dialysis may be conventionally performed as hemodialysis, in which a synthetic membrane constitutes the dialysis membrane, or as peritoneal dialysis, in which a patient's peritoneal membrane constitutes the dialysis membrane. Dialysis-related iron deficiency affects about 90 percent of CKD patients by six months of treatment, and the inventor expects that a ferric pyrophosphate citrate chelate composition of the invention may be substituted for convention iron fortificants that are administered to CKD patients undergoing dialysis.

In general, the pharmaceutical compositions of this invention can be prepared by conventional techniques, as are described in Remington's Pharmaceutical Sciences, a standard reference in this field [Gennaro A R, Ed. Remington: The Science and Practice of Pharmacy. 20.sup.th Edition. Baltimore: Lippincott, Williams & Williams, 2000]. For therapeutic purposes, the active components of this invention are ordinarily combined with one or more excipients appropriate to the indicated route of administration.
 

Claim 1 of 23 Claims

1. A water-soluble solid ferric pyrophosphate citrate chelate composition comprising: iron citrate pyrophosphate; and phosphate in an amount of 2% or less by weight.
 

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