US20090186939A1 - Method of Treating Chronic Kidney Disease - Google Patents

Method of Treating Chronic Kidney Disease Download PDF

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US20090186939A1
US20090186939A1 US12/162,543 US16254307A US2009186939A1 US 20090186939 A1 US20090186939 A1 US 20090186939A1 US 16254307 A US16254307 A US 16254307A US 2009186939 A1 US2009186939 A1 US 2009186939A1
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ferric
organic compound
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kidney disease
chronic kidney
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Keith Chan
Winston Town
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Panion and BF Biotech Inc
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Priority claimed from PCT/US2006/032385 external-priority patent/WO2007022435A2/en
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Definitions

  • This invention relates to the uses of pharmaceutical-grade ferric organic compounds to treat chronic kidney disease.
  • Chronic kidney disease is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. Unlike acute kidney failure with its abrupt but reversible of kidney function, the kidney functions in chronic kidney disease progress and deteriorate irreversibly towards end stage renal disease (ESRD). Patients suffering from ESRD cannot survive without dialysis or kidney transplantation.
  • ESRD end stage renal disease
  • the U.S. National Kidney Foundation defines chronic kidney disease according to the presence or absence of kidney damage and the level of kidney function, regardless of the type (clinical diagnosis) of kidney disease.
  • the primary measure of kidney function is glomerular filtration rate (GFR), which is often estimated as creatinine clearance from serum and urine creatinine concentrations.
  • GFR glomerular filtration rate
  • Chronic kidney disease or failure is defined as having glomerular filtration rate less than 60 ml/min for three months or more.
  • the U.S. National Kidney Foundation has suggested a live stage classification of renal dysfunction based on glomerular filtration rate:
  • Progression of chronic kidney disease occurs from chronic tubulointerstitial inflammation caused by increases in single nephron filtered load of phosphate, absolute tubular re-absorption of phosphate, calcium phosphate product in the tubular lumen and by precipitation of calcium phosphate in the tubules and interstitium, which is facilitated by reduced concentration of citrate in the tubular fluid (precipitation-calcification hypothesis).
  • Hyperparathyroidism is one of the earliest manifestations of impaired renal function, and minor changes in bone have been found in patients with a glomerular filtration rate of 60 ml/min (chronic kidney disease stage 2 to 3). With the worsening of kidney condition and phosphorus accumulation, parathyroid will continuously increase the release of parathyroid hormone (PTH) and lead to the development of hyperparathyroidism. High PTH will increase calcium release from bone to serum. The result is abnormal serum concentrations of calcium and phosphor us and lead to bone disease and extraskeletal calcification. Precipitation of calcium phosphate in renal tissue begins early. This may influence the rate of progression of renal disease, and is closely related to hyperphosphatemia and calcium phosphate (CaxP) product.
  • PTH parathyroid hormone
  • CaxP calcium phosphate
  • Acid-base balance is normally maintained by renal excretion of the daily acid load. As renal function declines, the acid-base balance is maintained by various compensatory mechanisms, of which an increase in the synthesis of ammonia by proximal tubule is the most important. A defective trapping of ammonia in the medulla poses further demands on proximal tubules to increase synthesis of ammonia and results in an enhanced concentration of ammonia in renal cortex. High concentration of free-base ammonia in renal cortex can result in complement activation and interstitial inflammation which has been reported to be one of the major determinant of progressive renal injury. Renal acidosis result in bone demineralization, hyperparathyroidism, increase protein catabolism, insulin resistance and stunted growth. Recent observations suggest that acidosis triggers inflammation and accelerates progression of chronic kidney disease.
  • kidney stone could cause urine obstruction, urinary tract infection and may result in development of chronic kidney disease.
  • NaHCO3 is used to ameliorate one of the uremic syndromes such as metabolic acidosis which leads to osteopenia and urinary calcium excretion.
  • Ferric iron containing compounds are useful in the treatment of a number of disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis. See Hsu et al., New Phosphate Binding Agents: Ferric Compounds, J Am Soc Nephrol. 10:1274-1280 (1999). Previous studies and inventions have reported the use of ferric compounds in binding dietary phosphates, and such ferric compounds are potentially useful for the treatment of hyperphosphatemia in renal failure patients (U.S. Pat. No. 5,753,706; U.S. Pat. No. 6.903.235; CN 1315174; Yang et al. Nephrol. Dial. Transplant 17:265 270 (2002)).
  • Elevated amounts of phosphate in the blood can be removed by administering compounds such as ferric citrate. Once in solution, the ferric iron binds phosphate, and the ferric phosphate compounds precipitate in the gastrointestinal tract, resulting in effective removal of dietary phosphate from the body. It is also believed that the absorbed citrate from ferric citrate is converted to bicarbonate which corrects metabolic acidosis, a condition common in renal failure patients.
  • U.S. Pat. No. 5,753,706 discloses the use of ferric containing compounds, including ferric citrate and ferric acetate in the crystalline form, in an orally effective 1 gram dosage form to bind to soluble dietary phosphate, thus causing precipitation of phosphate as ferric or ferrous phosphates in the gastrointestinal tract and preventing oral absorption of soluble phosphates from dietary sources. Since binding of ferric ions to soluble phosphate in the gastrointestinal tract would require dissolution of the orally administered ferric citrate, and since the rate of dissolution of crystalline ferric citrate is slow (over 10-12 hours at 37° C.), oral administration of a substantially large dose of 1 g of ferric citrate is required.
  • a related Chinese patent application (CN 1315174) also discloses a similar use of ferric citrate and related compounds in an oral solution dosage form for the treatment of hyperphosphatemia in renal failure patients.
  • Fe (III) is a Lewis acid and is chemically less soluble in the stomach at pH below 5 than at intestinal pH normally above 7.
  • the stomach is, however, believed to be an important site of action for the dissolution of Fe (III) compounds. It is believed that the stomach is an important site of action for Fe (III) to mediate its action in binding to dietary phosphates, preventing phosphate from reaching the intestine and thus reducing absorption of phosphates from the intestine.
  • the present invention discloses these novel forms of ferric organic compounds possess several characteristics beneficial for the treatment or modification of chronic kidney disease.
  • the present invention provides a met hod of treating a subject, having chronic kidney disease, comprising administering to said subject an effective amount of a ferric organic compound that has a dissolution rate of at least approximately 2 mg/cm 4 /min.
  • a ferric organic compound is ferric citrate.
  • Representative ranges of the dissolution rate include, but are not limited to, from about 2.5 mg/cm 2 /min to about 3.0 mg/cm 2 /min., or from about 3.0 mg/cm 2 /min to about 3.5 mg/cm 2 /min., or from about 3.5 mg/cm 2 /min to about 4.0 trig/cm 2 /min.
  • the ferric organic compound is prepared according a method comprising the steps of: (a) obtaining a ferric iron salt; (b) adding an alkaline metal hydroxide to the ferric iron salt under conditions effective to produce a mixture comprising polyiron oxide; (c) isolating a precipitate from the mixture; (d) adding an organic acid to the precipitate; (e) forming a ferric organic acid solution by heating the organic acid and the precipitate; and (f) precipitating the ferric organic compound from the ferric organic acid solution by adding an organic solvent to the solution.
  • a subject is a human or an animal.
  • the subject may have any stage of chronic kidney disease (e.g. end stage renal disease), or is undergoing renal dialysis.
  • the ferric organic compound may be administered orally or any other appropriate route generally known in the art and the ferric organic compound can be formulated into a number of formats generally known in the art. Representative formats include, but are not limited to, a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • treatment with the ferric organic compound results in decreased serum creatinine and BUN level in the subject. In another embodiment, treatment with the ferric organic compound results in decreased phosphorus and calcium and phosphorus product (CaxP) levels in serum.
  • CaxP calcium and phosphorus product
  • treatment with the ferric organic compound would prevent, reverse, maintain, or delay progression of chronic kidney disease.
  • development of hyperparathyroidism, bone disorder, or cardiovascular disease in the subject is prevented, reversed, maintained or delayed.
  • calcium phosphate precipitation in the subject's renal tissue is prevented, reversed, maintained or delayed.
  • kidney stone formation is prevented, reversed, maintained or delayed.
  • development of metabolic acidosis in the subject is prevented, reversed, maintained or delayed.
  • the present invention also provides uses of a ferric organic compound described herein for preparation of a medicament for treating a subject having chronic kidney disease.
  • the present invention also provides a method of treating a subject having chronic kidney disease, comprising administering to said subject an effective amount of a ferric organic compound.
  • a ferric organic compound is ferric citrate.
  • the ferric organic compound has a dissolution rate of at least approximately 2 mg/cm 2 /min.
  • the present invention also provides a therapeutic regimen for treating a subject having chronic kidney disease; the regiment comprises a pharmaceutical composition comprising an acceptable carrier and an effective amount of ferric organic compound having a dissolution rate of at least 2 mg/cm 2 /min., wherein the pharmaceutical composition is administered in single or multiple doses regimens.
  • the present invention also provides a pharmaceutical composition for treating a subject having chronic kidney disease, the composition comprising an effective amount of a ferric organic compound having a dissolution rate of at least approximately 2 mg/cm 2 /min.
  • the present invention also provides a use of the above pharmaceutical composition in preparation of a medicament for treating a subject having chronic kidney disease.
  • FIG. 1 is a schematic diagram outlining the method of making novel forms of ferric organic compounds according to the present invention.
  • FIG. 2 is a comparison of the safety profiles o chemical grade and pharmaceutical grade ferric citrates
  • FIG. 3 is a comparison of the efficacy profiles of chemical grade and pharmaceutical grade ferric citrates
  • FIG. 4 shows a bar graph of the relationship between the rate of dialysis patient mortality and hyperphosphatemia
  • FIG. 5 shows the serum creatinine levels of a patient (patient code: 2-01-1-029) treated with 6 g/day of ferric citrate.
  • FIG. 6 shows the serum creatinine levels of a patient (patient code: 2-01-1-032) treated with 6 g/day of ferric citrate.
  • ferric citrate an example of ferric organic compounds produced according to the methods described herein, would reduce serum concentrations of creatinine, phosphorus, calcium, and phosphorus product (CaxP) in patients with chronic kidney disease.
  • ferric organic compounds of the present invention including but not limited to ferric citrate, can be used to modify the progression of chronic kidney disease (CKD) in a subject; for example, the progression of CKD can be prevented, reversed, maintained, or delayed.
  • ferric citrate disclosed herein.
  • Other ferric citrate compounds, or their salts, derivatives, analogs, metabolites, or preparations that are suitable for use in the methods of the present invention will be readily apparent to a person of ordinary skill in the art by following the teaching of this application.
  • methods of the present invention also encompass using other ferric organic compounds synthesized according to the methods described herein. These ferric organic compounds preferably have or include the following properties:
  • the present invention is not limited to using ferric organic compounds produced according to the method disclosed herein.
  • the present invention encompasses methods of using ferric organic compounds to treat chronic kidney disease, wherein the ferric organic compounds possess certain characteristics as described herein.
  • ferric organic compounds produced according to the methods described herein are useful in the treatment of hyperphosphatemia, metabolic acidosis, and any other disorders responsive to ferric organic compound therapy. Because the ferric organic compounds of the present invention are more soluble than commercially available ferric organic compounds, smaller amounts of the ferric organic compounds of the present invention can be used to effectively treat patients suffering from such disorders.
  • the ferric citrate of the present invention has a significantly higher rate of aqueous solubility under physiological conditions than commercially available forms of ferric citrate, and therefore the ferric citrate of the present invention is believed to provide a significant improvement in the orally effective use of ferric citrate at a reduced dosage.
  • the ferric citrate of the present invention will provide a lower incidence of ulcerative gastrointestinal adverse effects associated with commercially available ferric citrate compounds.
  • the increased rate of dissolution of the ferric citrate of the present invention will provide a more rapid onset of action in binding to dietary phosphate.
  • the ferric organic compounds of the present invention are more soluble over a wider pH range than commercially available ferric organic compounds; therefore, the ferric organic compounds of the present invention can be more effective by being soluble in the small intestine.
  • the ferric organic compounds of the present invention can be administered in a number of forms generally known in the art.
  • Pharmaceutical compositions comprising the ferric organic compounds of the present invention include, but are not limited to solids, liquids, or semi-solid forms, such as gels, syrups, chewables or pastes.
  • the ferric organic compounds of the present invention can be administered alone or in combination with a pharmaceutically acceptable carrier.
  • Orally administrable forms include, but are not limited, to, a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • the composition can be administered to human beings or other animals suffering from illnesses responsive to ferric organic compound therapy.
  • an effective amount of pharmaceutical-grade ferric citrate can be readily determined by one of ordinary skill in the art.
  • an effective dose may be from 2 to 100 grams per day, preferably between 2 and 60 grams per day.
  • a daily effective amount may be 2, 4, 6, or 8 grams.
  • compositions comprising pharmaceutical grade ferric organic compounds of the present invention, such as ferric citrate, are suitable for treating hyperphosphatemia, or other disorders characterized by high serum phosphate levels. Therefore, the invention encompasses treating subjects or patients with various renal diseases; e.g., End Stage Renal Diseases (ESRD), Chronic Kidney Disease (CKD) or other relate kidney diseases, or subjects and patients who are on dialysis but no: limited to hemodialysis
  • ESRD End Stage Renal Diseases
  • CKD Chronic Kidney Disease
  • compositions comprising pharmaceutical grade ferric organic compounds of the present invention, such as ferric citrate, may be used to treat subjects or patients with metabolic acidosis.
  • Other disorders that may be ameliorated by the conversion of citrate to bicarbonate are also encompassed by the invention described.
  • a method for using the pharmaceutical composition encompasses treating a human or non-human subject or patient with chronic kidney disease.
  • chronic kidney disease There are generally five clinical stages of chronic kidney disease, numbered 1 to 5, wherein stage 1 is the least severe and stage 5 the most severe.
  • stage 1 is the least severe and stage 5 the most severe.
  • stage 5 the most severe.
  • dialysis is not required.
  • a patient may require dialysis treatment three times per week.
  • an embodiment of the invention is a method of treating a subject or person with early or mid-stage chronic kidney disease, with a composition comprising pharmaceutical-grade ferric citrate in order to achieve a lower serum phosphate level.
  • a method of treating a human or non-human subject or patient with late-stage chronic kidney disease who is undergoing hemodialysis by administering a composition comprising pharmaceutical-grade ferric citrate of the present invention. It is generally known that hemodialysis is not sufficiently effective in reducing serum phosphate level.
  • the treatment of a subject or person with late stage kidney disease is applicable whether or not the subject or person is currently undergoing hemodialysis treatment.
  • An additional embodiment of the invention is a method of treating a subject or person with chronic kidney disease and undergoing peritoneal dialysis with the pharmaceutical-grade ferric citrate-containing compositions described herein. It is known that peritoneal dialysis is not sufficiently effective in reducing serum phosphate levels.
  • the present invention provides a method of treating a subject having chronic kidney disease.
  • the subject is a human or an animal.
  • the subject may have end stage renal disease, or is undergoing renal dialysis.
  • the method comprises the steps of administering to said subject an effective amount of a ferric organic compound that has a dissolution rate of at least approximately 2 mg/cm 2 /min.
  • Representative ranges of the dissolution rate include, but are not limited to, from about 2.5 mg/cm 2 /min to about 3.0 mg/cm 2 /min., or from about 3.0 mg/cm 2 /min to about 3.5 mg/cm 2 /min., or from about 3.5 mg/cm 2 /min to about 4.0 mg/cm 2 /min.
  • the ferric organic compound is prepared according a method comprising the steps of: (a) obtaining a ferric iron salt; (b) adding an alkaline metal hydroxide to the ferric iron salt under conditions effective to produce a mixture comprising polyiron oxide; (c) isolating a precipitate from the mixture; (d) adding an organic acid to the precipitate; (e) forming a ferric organic acid solution by heating the organic acid and the precipitate; and (f) precipitating the ferric organic compound from the ferric organic acid solution by adding an organic solvent to the solution.
  • the alkaline metal hydroxide is sodium hydroxide
  • the ferric iron salt is ferric chloride hexahydrate
  • the organic acid is crystalline citric acid.
  • the alkaline metal hydroxide e.g. sodium hydroxide or potassium hydroxide
  • the alkaline metal hydroxide is added at a rate of less than 20 ml/min, preferably between a hour 20 ml/min to about 20 ml/min
  • the alkaline metal hydroxide is added to the ferric iron salt at a temperature o less than 40° C., preferably between about 10° C. to about 40° C.
  • the organic acid and the precipitate are heated to a temperature of between about 80° C. to about 90° C.
  • Precipitating the ferric organic compound from the ferric organic acid solution by an organic solvent comprises cooling the ferric organic acid solution to less than 30° C. before adding the organic solvent, preferably the ferric organic acid solution is cooled to a temperature between about 10° C. to about 30° C.
  • a number of organic acids such as citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid can be used in the method of synthesizing the ferric organic compound.
  • the organic acid is in crystalline form.
  • a number of organic solvent such as ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran can be used in synthesizing the ferric organic compound described herein.
  • the ferric organic compound can be administered at an effective dose determined by one of ordinary skill in the art, for example 2-20 gm/day.
  • the ferric organic compound can be administered orally or any other appropriate route readily determined by one of ordinary skill in the art.
  • the ferric organic compound can be formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • treatment with the ferric organic compound results in decreased serum creatinine and BUN level in the subject. In another embodiment, treatment with the ferric organic compound results in decreased phosphorus, calcium, and phosphorus product (CaxP) levels in serum.
  • treatment with the ferric organic compound would prevent, reverse, maintain, or delay progression of chronic kidney disease.
  • development of hyperparathyroidism, bone disorder, or cardiovascular disease in the subject is prevented, reversed, maintained or delayed.
  • calcium phosphate precipitation in the subject's renal tissue is prevented, reversed, maintained or delayed.
  • kidney stone formation is prevented, reversed, maintained or delayed.
  • development of metabolic acidosis in the subject is prevented, reversed, maintained or delayed.
  • the present invention also provides a method of treating a subject having chronic kidney disease, comprising administering to said subject an effective amount of a ferric organic compound, wherein the ferric organic compound is prepared according a method comprising the steps of: (a) obtaining a ferric iron salt; (b) adding an alkaline metal hydroxide to the ferric iron salt under conditions effective to produce a mixture comprising polyiron oxide; (c) isolating a precipitate from the mixture; (d) adding an organic acid to the precipitate; (e) forming a ferric organic acid solution by heating the organic acid and the precipitate; and (f) precipitating the ferric organic compound from the ferric organic acid solution by an organic solvent.
  • This method of synthesis has been described herein to produce ferric organic compound (e.g. ferric citrate) that has enhanced dissolution rate (e.g. a dissolution rate of at least about 2 mg/cm 2 /min.). This method of treatment would produce therapeutic effects described above.
  • the present invention also provides a method of treating a subject having chronic kidney disease, comprising administering to said subject an effective amount of a ferric organic compound.
  • ferric organic compound include, but are not limited to, ferric citrate.
  • the subject is a human or an animal.
  • the subject may have end stage renal disease, or is undergoing renal dialysis.
  • the ferric organic compound has a dissolution rate of at least approximately 2 mg/cm 2 /min.
  • the present invention also provides a therapeutic regimen for treating a subject having chronic kidney disease, the regiment comprises a pharmaceutical composition comprising an acceptable carrier and an effective amount of ferric organic compound having a dissolution rate of at least 2 mg/cm 2 /min., wherein the pharmaceutical composition is administered in single or multiple doses regimens.
  • ferric organic compound is ferric citrate. As shown in Table 1, a ferric organic compound such as ferric citrate having a dissolution rate of at least 2 mg/cm 2 /min. would be useful in the present method.
  • the dissolution rate of the ferric organic compound can be from approximately 2.5 mg/cm 2 /min to approximately 3.0 mg/cm 2 /min., or from approximately 3.0 mg/cm 2 /min to approximately 3.5 mg/cm 2 /min., or from approximately 3.5 mg/cm 2 /min to approximately 4.0 mg/cm 2 /min.
  • at least a portion of the pharmaceutical composition is administered orally.
  • the subject is having end stage renal disease, and the method may optionally comprise renal dialysis or peritoneal dialysis.
  • the present invention also provides a pharmaceutical composition for treating a subject having chronic kidney disease, the composition comprising an effective amount of a ferric organic compound (e.g. ferric citrate) having a dissolution rate of at least approximately 2 mg/cm 2 /min.
  • the dissolution rate is from about 2 mg/cm 2 /min to about 4 mg/cm 2 /min.
  • the composition is in a form suitable for oral administration, e.g. as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • the present, invention also provides a use of the above pharmaceutical composition in preparation of a medicament for treating a subject having chronic kidney disease.
  • the subject is having end stage renal disease or undergoing renal dialysis.
  • ferric organic compounds include, but are not limited to, ferric citrate.
  • the flowchart 10 is a general process for synthesizing a form of ferric organic compound or ferric citrate compound which can be used in the present invention.
  • the starting materials as indicated in box 20 , comprise soluble ferric iron salts.
  • the soluble ferric iron salts can comprise ferric chloride hexahydrate (FeCl 3 6 H 2 O), as indicated in box 21 , or any other suitable soluble ferric iron salt.
  • an alkaline metal hydroxide (box 30 ) is added at a specific rate and temperature to the soluble ferric iron salt.
  • the alkaline metal hydroxide can comprise sodium hydroxide, potassium hydroxide, or any other suitable alkaline metal hydroxide as indicated in box 31 .
  • the colloidal suspension precipitate is collected and rinsed (box 40 with distilled water to remove any soluble impurities. After rinsing, the precipitate is re-suspended and, as indicated in box 50 , crystalline organic acid is added to the precipitate and heated to a particular temperature range, preferably between about 80° C. to about 90° C.
  • the organic acid can comprise any suitable organic acid. Box 51 lists some of the possible organic acids which can be used, including, but not limited to, citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid. The addition of the organic acid allows the acid to form complexes with the precipitate in solution.
  • the ferric organic compound is precipitated out of solution with an organic solvent to form a novel form of ferric organic compound (box 70 ).
  • organic solvents can be used, including, but not limited to, the solvents described in box 61 , such as ethanol, methanol, butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other suitable organic solvent.
  • the ferric organic compound is ferric citrate.
  • the starting materials for making a ferric citrate comprise a 1.85M solution of ferric chloride hexahydrate (FeCl 3 6H 2 O).
  • a volume of 5M sodium hydroxide necessary to produce a 1:3 ratio of ferric iron to hydroxide ion is added to the ferric chloride hexahydrate solution at a rate of less than 20 ml per minute, preferably between about 10 ml per minute and about 20 ml per minute.
  • the temperature of the mixture is maintained below 40° C., preferably between about 10° C. to about 40° C., while the sodium hydroxide is added to form a polyiron oxide colloidal suspension of ferric hydroxide.
  • the pH of the suspension is measured while the sodium hydroxide is added. Once the pH is above 7.0, the suspension is cooled until it is less than 30° C., preferably between about 10° C. to about 30° C. The suspension is then filtered through a 1 mm pore filter to breakup aggregates and large particles of ferric hydroxide precipitate are then removed. The filtered ferric hydroxide suspension is then centrifuged. The supernatant is discarded, and the precipitated ferric hydroxide is centrifuged again to remove any remaining supernatant.
  • the ferric hydroxide precipitate is then resuspended with distilled water
  • the centrifugation-resuspension steps are repeated two more times to wash the ferric hydroxide precipitate and remove water soluble impurities.
  • the resulting ferric hydroxide precipitate is then homogenized.
  • An amount of citric acid necessary to produce a 1:1 ratio of ferric iron to citrate is added to the precipitate.
  • the mixture is heated to between about 80° C. to about 90° C. in an oil bath until the color of the mixture changes from orange-brown to a clear black-brown, or until all of the ferric hydroxide precipitate is dissolved.
  • the reaction is cooled until it is less than 30° C., preferably between about 10° C. to about 30° C., and the pH is measured to determine that it is within 0.8 and 1.5.
  • the reaction is centrifuged, and the supernatant is collected.
  • Ferric citrate is precipitated from the supernatant by adding 5 volumes of organic solvent.
  • Various organic solvents can be used, including ethanol, methanol, butanol, acetone, isopropyl alcohol, or tetrahydrofuran.
  • the solvent is added, the mixture is stirred until a light beige precipitate forms.
  • the suspension is centrifuged and the supernatant is discarded.
  • the precipitate is washed and centrifuged with the solvent two more times.
  • the precipitate is then dried in a vacuum oven for 8 to 16 hours at ambient temperature or by any other suitable industrial processes such as fluidized-bed drying.
  • the dried precipitate is ground with a mortar and pestle and dried for another 8 to 24 hours at ambient temperature.
  • the fine precipitate is finely ground by milling again and screened through a 45 mesh size (35 micron) sieve.
  • the novel form of ferric citrate powder is dried in the vacuum oven again or fluidized-bed drying again and dried at ambient temperature until 1 hour of drying leads to less than 0.25% loss in weight.
  • ferric organic compounds produced according to the methods described above are more soluble than commercially available ferric organic compounds, over a wider range of pH levels. This increase in solubility of the ferric organic compounds of the present invention is believed to be a result of the unique significantly large active surface area of the ferric organic compounds of the present invention. For example, at pH 8.0, the intrinsic dissolution rate of ferric citrate of the present invention is 3.32 times greater than the commercially available ferric citrate. See Table 1.
  • the intrinsic dissolution rates of commercially available ferric citrate were compared with the ferric citrate of the present invention.
  • the intrinsic dissolution rate is defined as the dissolution rate of pure substances under the condition of constant surface area.
  • the dissolution rate and bioavailability of a drug substance is influence by its solid state properties: crystallinity, amorphism, polymorphism, hydration, solvation, particle size and particle surface area.
  • the measured intrinsic dissolution rate is dependent on these solid-state properties and is typically determined by exposing a constant surface area of a material to an appropriate dissolution medium while maintaining constant temperature, stirring rate, and pH.
  • the intrinsic dissolution rates are presented in Table 1.
  • the BET active surface area of the ferric citrate of the present invention is at least 16 times larger than the commercially available ferric citrate. See Table 2.
  • active surface area is based on BET theory which describes the phenomenon of mass and energy interaction and phase changes during gas adsorption onto solid surfaces and in pore spaces.
  • BET active surface area measurement the volume of a monolayer of gas is determined which allows the surface area of the sample to be determined using the area occupied by a single layer of adsorbed gas molecule.
  • Table 2 is a comparison of the active surface area of the ferric citrate of the present invention compared to the active surface area of commercially available ferric citrate compounds.
  • Ferric citrate is supplied in 500 mg capsules, whereas the placebo will be provided in identical-looking capsules (indistinguishable from those containing the active drug); the placebo capsules will contain sorbitol and colorant to match the powder color of the active capsules.
  • the placebo capsule shells will be identical to the active capsule shells.
  • study drug supplies must be stored under secure conditions and are not to be used after their expiration date, which is imprinted on the study drug container.
  • the study drugs should be kept under controlled conditions (15 to 30° C.; 59 to 86° F.) in a tightly closed container, protected from light.
  • ferric citrate (3 g daily) to calcium carbonate (3 g daily) for reducing serum P0 4 in patients with End Stage Renal Disease (ESRD). This dose of ferric citrate was associated with mild, but tolerable GI symptoms.
  • ferric citrate chosen for study or treatment may be from 1 to 30 grams of ferric citrate per day. In part, this may depend on the nature of the formulation provided. For example, ferric citrate capsules may be administered up to a daily dose of about 15 grams/day, whereas the tablet form may be administered up to 30 grams/day. Thus, there is a very broad range of dosing regimens encompassed by the invention.
  • the term “subject” refers to either a human or non-human animal.
  • the optimal dosage of an individual subject or groups may be determined as follows. A dose of approximately one or two grams per day is merely suggested as an illustrative starting dose. The daily dose may be increased as needed until the desired result is observed.
  • the intent of the invention is to not limit the dose range employed. Therefore, depending on the subject(s) the daily dose administered may approximate thirty, forty, fifty, sixty, seventy, eighty, ninety or one hundred grams per day.
  • the safety profile of the pharmaceutical-grade ferric citrate allows the implementation of a broad range of doses.
  • a dosing regimen is provided below. This is not meant to limit the invention as to how an effective amount of ferric citrate is selected, or the form in which it is provided or the frequency of administering the composition per day.
  • the following merely illustrates how ferric citrate and placebo may be administered; e.g, as 500 mg capsules of identical appearance. All patients may receive (in a blinded fashion) 4 capsules with each of three meals, on a daily basis, for 28 days. Patients will be instructed to take the study medication within 10 minutes of finishing their meals (breakfast, lunch, and dinner).
  • the number of placebo, and active capsules to be taken at each meal are as follows:
  • Each patient's participation in the trial lasts for up to 8 weeks: the screening period (approximately 1-2 weeks), a 1-2 week washout, and 4 weeks of treatment with study medication.
  • Dietary interview using 24 hour recall method, to assess dietary intake of calcium and phosphorous, three times during screening period, to include one dialysis day, one non-dialysis day, and one weekend day. Note: Dietary interview may be also performed, in part or in whole, during the washout period.
  • CBC complete blood count
  • Chemistries sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose (random), aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, total protein, albumin, serum calcium, serum phosphate, magnesium
  • Iron panel serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity.
  • Iron panel serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity. The Baseline Laboratory Assessments may be done up to 3 days prior to Day 0.
  • Hematology CBC with differential, platelets.
  • Chemistries sodium, potassium, chloride, bicarbonate, BON, creatinine, glucose (random), AST, ALT, ALP, total bilirubin, total protein, albumin, calcium, phosphate, magnesium.
  • Iron panel serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity.
  • BUN creatinine, glucose (random), AST, ALT.
  • ALP total bilirubin, total protein, albumin, calcium, phosphate, magnesium.
  • Iron panel serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity.
  • GloboMax will be the primary data management, monitoring, and coordinating center. Case report forms (CRF) will be provided for each subject. Subjects will not be identified by name or initials on CRFs. The CRF will be monitored at the clinical sites and collected by GloboMax's study monitor. Audited CRFs will be used to create electronic data files.
  • CRF Case report forms
  • endpoints reflect biochemical and clinical issues being addressed at the outset. Additional clinical and biochemical issues are addressed as they arise. Therefore, the endpoints are not meant to limit the totality of relevant findings and measurements collected in these, or future studies.
  • Study Design Randomized, double-blind, placebo-controlled, dose-ranging study to assess the effect of ferric citrate on serum phosphate concentrations in patients with ESRD on hemodialysis. Patients are assessed at Study Days 14 and 28 for effectiveness as measured by serum phosphate concentrations Patients who received one or more dosed of study medication are also assessed for safety.
  • Study Duration 8 weeks (including the screening period, 2 weeks washout, 4 weeks treatment)
  • Results show a decrease in serum PO4 and Ca*PO4 at 0, 2, 4 and 6 gm/day (given as TID immediately after meals, i.e., within 10 minutes). Ferric citrate is administered orally, and is given equally three times a day.
  • treatments using pharmaceutical-grade ferric citrate provide several advantages over chemical grade ferric citrate.
  • pharmaceutical-grade ferric citrate demonstrates an efficacy approximately equal to that of chemical grade ferric citrate, it achieves this result with less adverse side effects than chemical grade ferric citrate.
  • FIG. 2 also indicates that adverse side effects associated with administering pharmaceutical-grade ferric citrate were not statistically different from those associated with the placebo.
  • An advantage of this safety profile is that an individual patient may have his dosing of pharmaceutical-grade ferric citrate titrated over a broad range of doses with less concern about side effect. In this way, a patients individual treatment may be tailored to suit his specific needs and tolerances
  • Glomerular filtration rate (GFR) level correlates with structural kidney damage and is used as a golden standard to measure kidney function.
  • GFR can be estimated by the biomarkers serum creatinine. As renal function deteriorates, kidney lost its function to excrete creatinine effectively and lead to creatinine retention in the body. Therefore, increase of serum creatinine indicates lowering GFR and is an important sign of kidney deterioration.

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060020026A1 (en) * 2003-02-19 2006-01-26 Kwok David W Ferric organic compounds, uses thereof and methods of making same
US20080274210A1 (en) * 2003-02-19 2008-11-06 Globoasia, Llc Pharmaceutical-Grade Ferric Organic Compounds, Uses Thereof and Method of Making Same
US20090326060A1 (en) * 2006-01-30 2009-12-31 Keith Chan Method of Reversing, Preventing, Delaying or Stabilizing Soft Tissue Calcification
US20110021629A1 (en) * 2009-07-21 2011-01-27 Deanna Jean Nelson Iron preparation suitable for pharmaceutical formulation and process for the preparation thereof
KR20150036131A (ko) * 2012-06-21 2015-04-07 케릭스 바이오파마슈티컬스 인코포레이티드 만성 신장 질환 환자의 치료에서 시트르산 제2철의 용도
WO2015066593A1 (en) * 2013-11-04 2015-05-07 Keryx Biopharmaceuticals, Inc. Ferric citrate for reducing cardiac failure in chronic kidney disease patients
US9387191B2 (en) 2009-07-21 2016-07-12 Keryx Biopharmaceuticals, Inc. Ferric citrate dosage forms
US10092593B2 (en) * 2012-09-04 2018-10-09 The Board Of Regents Of The University Of Texas System Citrate-rich calcium-magnesium supplement and uses thereof
CN111031813A (zh) * 2017-07-26 2020-04-17 法尔曼特拉公司 用于预防和治疗心血管器官病症的组合物

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220144872A1 (en) * 2003-02-19 2022-05-12 Panion & Bf Biotech Inc. Pharmaceutical-Grade Ferric Organic Compounds, Uses Thereof and Methods of Making Same
US7658952B2 (en) 2007-10-11 2010-02-09 Baxter International Inc. Dialysis solutions containing pyrophosphates
EP2299998B1 (de) * 2007-11-02 2018-01-03 Prometic Pharma Smt Limited Mittelkettige fettalkohole und glyzeride als nierenschutzmittel
EP3192506A3 (de) * 2008-10-27 2017-10-25 SBI Pharmaceuticals Co., Ltd. Mittel zur prophylaxe/linderung von erwachsenenkrankheiten mit 5-aminolevulinsäure, einem 5-aminolevulinsäure-derivat oder einem 5-aminolevulinsäure-salz oder 5-aminolevulinsäure-derivat als wirkstoff
WO2012005340A1 (ja) * 2010-07-07 2012-01-12 日本たばこ産業株式会社 クエン酸第二鉄を含む錠剤
JP2012112785A (ja) * 2010-11-24 2012-06-14 Tohoku Univ 透析膜の評価方法
EP3971162A1 (de) * 2011-01-18 2022-03-23 Japan Tobacco Inc. Eisen(iii)citrat im wesentlichen frei von beta-eisenhydroxidoxid
WO2015198304A1 (en) * 2014-06-22 2015-12-30 Dexcel Pharma Technologies Ltd. Pharmaceutical compositions comprising ferric citrate and methods for the production thereof
JP2018526349A (ja) * 2015-08-05 2018-09-13 ルピン・リミテッド 医薬品グレードのクエン酸第二鉄の調製のためのプロセス
JP7219898B2 (ja) * 2017-04-18 2023-02-09 国立大学法人東北大学 アルカリ性化剤による血液浄化
WO2018193648A1 (ja) * 2017-04-18 2018-10-25 国立大学法人東北大学 アルカリ性化剤による血液浄化
JP2018177752A (ja) * 2017-04-18 2018-11-15 国立大学法人東北大学 アルカリ性化剤による血液浄化
WO2019140224A2 (en) * 2018-01-12 2019-07-18 Thomas Marylaura Systems and methods for the detection and quantification of ammonia and ammonium in fluids
EP3823610A4 (de) * 2018-07-17 2022-08-31 The Regents of the University of California Verfahren zur behandlung einer nierenerkrankung
US20210386696A1 (en) * 2018-10-17 2021-12-16 Tohoku University Novel pharmaceutical composition
US20210378997A1 (en) * 2018-10-17 2021-12-09 Kyoto Prefectural Public University Corporation Inhibitor of renal fibrosis in diabetic nephropathy
CA3137691A1 (en) * 2019-04-28 2020-11-05 Tohoku University Novel pharmaceutical composition
US20220273707A1 (en) * 2021-02-24 2022-09-01 MoxxiTech, LLC Compositions and methods for treating canine parvovirus infection
WO2022251563A1 (en) 2021-05-27 2022-12-01 Keryx Biopharmaceuticals, Inc. Pediatric formulations of ferric citrate

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3591616A (en) * 1967-07-04 1971-07-06 Pharmazeutische Fabrik Montavit Gmbh Organic complex ferric compounds
US4180567A (en) * 1977-09-02 1979-12-25 Pharmachem Corporation Iron preparations and methods of making and administering the same
US4689322A (en) * 1982-07-28 1987-08-25 Algina Aktiengesellschaft Pharmaceutical products, calcium mixed salts of polymeric, anionic carboxylic acids and/or their esters of sulfuric acid, and methods for their preparation and use
US4970079A (en) * 1989-06-05 1990-11-13 Purdue Research Foundation Method and composition of oxy-iron compounds for treatment of hyperphosphatemia
US5206265A (en) * 1987-09-14 1993-04-27 Schering Aktiengesellschaft Iron citrate complex, process for its production, and its pharmaceutical
US5707980A (en) * 1988-08-02 1998-01-13 Bone Care International, Inc. Method for treating and preventing secondary hyperparathyroidism
US5753706A (en) * 1996-12-16 1998-05-19 Hsu; Chen Hsing Methods for treating renal failure
US20050080283A1 (en) * 2003-10-08 2005-04-14 Yih-Ming Hsiao Pharmaceutical-grade ferric citrate
US6887897B2 (en) * 2001-07-31 2005-05-03 Mission Pharmacal Company Calcium glutarate supplement and phosphorus binder
US20060260026A1 (en) * 2005-05-19 2006-11-23 Doria Mason T Protective padding and protective padding systems
US20080274210A1 (en) * 2003-02-19 2008-11-06 Globoasia, Llc Pharmaceutical-Grade Ferric Organic Compounds, Uses Thereof and Method of Making Same
US20090326060A1 (en) * 2006-01-30 2009-12-31 Keith Chan Method of Reversing, Preventing, Delaying or Stabilizing Soft Tissue Calcification
US7767851B2 (en) * 2003-02-19 2010-08-03 Panion & Bf Biotech, Inc. Ferric organic compounds, uses thereof and methods of making same

Family Cites Families (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2081547A (en) 1934-02-14 1937-05-25 Parke Davis & Co Therapeutic agent
DE1131360B (de) 1957-11-26 1962-06-14 Vitarine Company Inc Verfahren zum Stabilisieren von waessrigen Loesungen, die neben Vitamin B noch Vitamin B und Vitamin C enthalten
SU142643A1 (ru) 1961-03-25 1961-11-30 В.Б. Тихомиров Способ извлечени соединений железа из водной фазы
US3549614A (en) 1967-07-13 1970-12-22 Jan Zbigniew Mioduszewski Method of manufacture of mixed complex compounds of ferric iron with hydrogenated dextran and citric acid or sodium citrate
GB1224589A (en) 1969-10-06 1971-03-10 Gerhard Gergely Complex iron salts
US5089644A (en) 1985-01-04 1992-02-18 Salutar Inc. Preparation of oxamine complexes
US4851221A (en) 1985-02-19 1989-07-25 Mission Pharmacal Company Liquid calcium supplementation from readily soluble mixtures of calcium compound and citric acid
GB2212396A (en) 1987-12-18 1989-07-26 Procter & Gamble Dietary supplement comprising calcium and delayed release coated iron
NL194959C (nl) 1988-10-04 2003-09-02 Otsuka Pharma Co Ltd Preparaat voor het toedienen van ijzer.
WO1990009102A1 (en) 1989-02-17 1990-08-23 Baxter International Inc. Calcification mitigation of bioprosthetic implants
JP2523057B2 (ja) 1990-10-31 1996-08-07 有限会社丸吉商事 多重ポリ袋の製造方法及び製造装置
DE4239442C2 (de) 1992-11-24 2001-09-13 Sebo Gmbh Verwendung eines mit polynuklearen Metalloxidhydroxiden modifizierten Adsorptionsmaterials zur selektiven Elimination von anorganischem Phosphat aus proteinhaltigen Flüssigkeiten
JP3302178B2 (ja) 1994-06-22 2002-07-15 日本クラウンコルク株式会社 合成樹脂製容器蓋
JPH08198760A (ja) 1995-01-20 1996-08-06 Japan Organo Co Ltd 経口用リン酸イオン吸着剤
US20040043971A1 (en) * 1995-04-03 2004-03-04 Bone Care International, Inc. Method of treating and preventing hyperparathyroidism with active vitamin D analogs
DE19638044A1 (de) 1996-09-18 1998-03-19 Bayer Ag Immunogene Peptide von Maul- und Klauenseuchen-Viren
RU2188033C2 (ru) 1997-03-18 2002-08-27 Рош Диагностикс Гмбх Комбинированные фармацевтические препараты, содержащие эритропоэтин и препараты железа
US6254635B1 (en) * 1998-02-02 2001-07-03 St. Jude Medical, Inc. Calcification-resistant medical articles
US6706287B2 (en) * 2001-05-15 2004-03-16 Kibow Biotech Inc. Prebiotic and probiotic compositions and methods for their use in gut-based therapies
CN1315174A (zh) 2000-03-31 2001-10-03 苏荣仁 治疗肾衰的药物组合物
CA2492035A1 (en) 2002-07-11 2004-01-15 Vicuron Pharmaceuticals, Inc. N-hydroxyamide derivatives possessing antibacterial activity
CN1202067C (zh) * 2002-09-09 2005-05-18 苏荣仁 药用级枸橼酸铁的制备方法
KR100511227B1 (ko) 2003-06-27 2005-08-31 박상래 휴대용 감시 카메라 및 이를 이용한 개인 방범 시스템
TWI259772B (en) 2003-09-04 2006-08-11 Panion & Bf Biotech Inc Medical composition comprising ferric citrate, ferric citrate in medical grade and preparation thereof, and dietary nutriment comprising ferric citrate
CN1600302A (zh) 2003-09-22 2005-03-30 宝龄富锦生技股份有限公司 含有柠檬酸铁的医药组合物以及药用级柠檬酸铁及其制法和含有药用级柠檬酸铁的膳食营养品
WO2006015055A1 (en) * 2004-07-27 2006-02-09 Shire Pharmaceuticals, Inc. Method of treating hyperphosphataemia using lanthanum hydroxycarbonate
US7733285B2 (en) * 2005-05-18 2010-06-08 Qualcomm Incorporated Integrated, closely spaced, high isolation, printed dipoles
NZ566743A (en) 2005-08-18 2010-07-30 Globoasia Llc Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
JP4692234B2 (ja) 2005-11-10 2011-06-01 ソニー株式会社 変調テーブル、変調装置および方法、プログラム、並びに記録媒体
EA200870204A1 (ru) 2006-01-27 2009-04-28 Юниверсити Оф Массачусетс Системы и способы производства биотоплива и связанных с этим материалов
KR20080094013A (ko) 2006-01-30 2008-10-22 글로보아시아 엘엘씨 연조직의 석회화 역전, 예방, 지연 또는 안정화 방법
CN101019848B (zh) 2006-11-17 2010-09-15 苏荣仁 枸橼酸铁在制备防治血管钙化的药物中的应用
KR100971367B1 (ko) 2007-05-31 2010-07-20 주식회사 엘지화학 조립방식의 전기적 접속부재 및 이를 포함하고 있는이차전지 팩
JP5526466B2 (ja) 2007-07-17 2014-06-18 株式会社大林組 耐火セグメントの製造方法
CN101235186B (zh) 2008-01-03 2010-08-11 中国船舶重工集团公司第七二五研究所 一种无溶剂可自分层固化的环氧-有机硅组合物
MX2012000892A (es) 2009-07-21 2012-06-01 Keryx Biopharmaceuticals Inc Formas de dosificacion de citrato ferrico.

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3591616A (en) * 1967-07-04 1971-07-06 Pharmazeutische Fabrik Montavit Gmbh Organic complex ferric compounds
US4180567A (en) * 1977-09-02 1979-12-25 Pharmachem Corporation Iron preparations and methods of making and administering the same
US4689322A (en) * 1982-07-28 1987-08-25 Algina Aktiengesellschaft Pharmaceutical products, calcium mixed salts of polymeric, anionic carboxylic acids and/or their esters of sulfuric acid, and methods for their preparation and use
US5206265A (en) * 1987-09-14 1993-04-27 Schering Aktiengesellschaft Iron citrate complex, process for its production, and its pharmaceutical
US5707980A (en) * 1988-08-02 1998-01-13 Bone Care International, Inc. Method for treating and preventing secondary hyperparathyroidism
US4970079A (en) * 1989-06-05 1990-11-13 Purdue Research Foundation Method and composition of oxy-iron compounds for treatment of hyperphosphatemia
US5753706A (en) * 1996-12-16 1998-05-19 Hsu; Chen Hsing Methods for treating renal failure
US6887897B2 (en) * 2001-07-31 2005-05-03 Mission Pharmacal Company Calcium glutarate supplement and phosphorus binder
US20080274210A1 (en) * 2003-02-19 2008-11-06 Globoasia, Llc Pharmaceutical-Grade Ferric Organic Compounds, Uses Thereof and Method of Making Same
US7767851B2 (en) * 2003-02-19 2010-08-03 Panion & Bf Biotech, Inc. Ferric organic compounds, uses thereof and methods of making same
US20100217025A1 (en) * 2003-02-19 2010-08-26 Panion & Bf Biotech, Inc. Ferric organic compounds, uses thereof and methods of making same
US20050080283A1 (en) * 2003-10-08 2005-04-14 Yih-Ming Hsiao Pharmaceutical-grade ferric citrate
US6903235B2 (en) * 2003-10-08 2005-06-07 Panion & Bf Biotech Inc. Pharmaceutical-grade ferric citrate
US20060260026A1 (en) * 2005-05-19 2006-11-23 Doria Mason T Protective padding and protective padding systems
US20090326060A1 (en) * 2006-01-30 2009-12-31 Keith Chan Method of Reversing, Preventing, Delaying or Stabilizing Soft Tissue Calcification

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Kraut, "Metabolic Acidosis of CKD: Diagnosis, Clinical Characteristics, and Treatment", American Journal of Kidney Diseases, Vol 45, No 6, June 2005, pp. 978-993. *
Yang, "An Open-Label Crossover Study of a New Phosphate-Binding Agent in Haemodialysis Patients:Ferric Citrate", Nephrol Dial Transplant, 2002, 17, pp. 265-270. *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8299298B2 (en) 2003-02-19 2012-10-30 Globoasia, Llc Pharmaceutical-grade ferric organic compounds, uses thereof and method of making same
US8846976B2 (en) 2003-02-19 2014-09-30 Panion & Bf Biotech Inc. Ferric organic compounds, uses thereof and methods of making same
US8338642B2 (en) 2003-02-19 2012-12-25 Panion & Bf Biotech, Inc. Ferric organic compounds, uses thereof and methods of making same
US8609896B2 (en) 2003-02-19 2013-12-17 Panion & Bf Biotech Inc. Ferric organic compounds, uses thereof and methods of making same
US20100217025A1 (en) * 2003-02-19 2010-08-26 Panion & Bf Biotech, Inc. Ferric organic compounds, uses thereof and methods of making same
US9913821B2 (en) 2003-02-19 2018-03-13 Panion & Bf Biotech Inc. Ferric organic compounds, uses thereof and methods of making same
US8093423B2 (en) 2003-02-19 2012-01-10 Globoasia, Llc Pharmaceutical-grade ferric organic compounds, uses thereof and method of making same
US20060020026A1 (en) * 2003-02-19 2006-01-26 Kwok David W Ferric organic compounds, uses thereof and methods of making same
US9050316B2 (en) 2003-02-19 2015-06-09 Panion & Bf Biotech Inc. Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
US9328133B2 (en) 2003-02-19 2016-05-03 Panion & Bf Biotech Inc. Ferric organic compounds, uses thereof and methods of making same
US7767851B2 (en) 2003-02-19 2010-08-03 Panion & Bf Biotech, Inc. Ferric organic compounds, uses thereof and methods of making same
US8754258B2 (en) 2003-02-19 2014-06-17 Panion & Bf Biotech Inc. Ferric organic compounds, uses thereof and methods of making same
US8754257B2 (en) 2003-02-19 2014-06-17 Panion & Bf Biotech Inc. Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
US20080274210A1 (en) * 2003-02-19 2008-11-06 Globoasia, Llc Pharmaceutical-Grade Ferric Organic Compounds, Uses Thereof and Method of Making Same
US8901349B2 (en) 2003-02-19 2014-12-02 Panion & Bf Biotech Inc. Ferric organic compounds, uses thereof and methods of making same
US9757416B2 (en) 2003-02-19 2017-09-12 Panion & Bf Biotech Inc. Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
US9750715B2 (en) 2006-01-30 2017-09-05 Panion & Biotech Inc. Method of reversing, preventing, delaying or stabilizing soft tissue calcification
US20090326060A1 (en) * 2006-01-30 2009-12-31 Keith Chan Method of Reversing, Preventing, Delaying or Stabilizing Soft Tissue Calcification
US8178709B2 (en) 2009-07-21 2012-05-15 Biolink Life Sciences, Inc. Iron preparation suitable for pharmaceutical formulation and process for the preparation thereof
US9387191B2 (en) 2009-07-21 2016-07-12 Keryx Biopharmaceuticals, Inc. Ferric citrate dosage forms
US20110021629A1 (en) * 2009-07-21 2011-01-27 Deanna Jean Nelson Iron preparation suitable for pharmaceutical formulation and process for the preparation thereof
US10300039B2 (en) 2009-07-21 2019-05-28 Keryx Biopharmaceuticals, Inc. Ferric citrate dosage forms
WO2013192565A3 (en) * 2012-06-21 2015-10-15 Keryx Biopharmaceuticals, Inc. Use of ferric citrate in the treatment of chronic kidney disease patients
KR20150036131A (ko) * 2012-06-21 2015-04-07 케릭스 바이오파마슈티컬스 인코포레이티드 만성 신장 질환 환자의 치료에서 시트르산 제2철의 용도
AU2018203205B2 (en) * 2012-06-21 2020-03-12 Keryx Biopharmaceuticals, Inc. Use of ferric citrate in the treatment of chronic kidney disease patients
KR102150135B1 (ko) * 2012-06-21 2020-08-31 케릭스 바이오파마슈티컬스 인코포레이티드 만성 신장 질환 환자의 치료에서 시트르산 제2철의 용도
US10092593B2 (en) * 2012-09-04 2018-10-09 The Board Of Regents Of The University Of Texas System Citrate-rich calcium-magnesium supplement and uses thereof
US20160256486A1 (en) * 2013-11-04 2016-09-08 Keryx Biopharmaceuticals, Inc. Use of ferric citrate in the treatment of and the reduction of mortality and morbidity related to adverse cardiac events in chronic kidney disease patients
WO2015066593A1 (en) * 2013-11-04 2015-05-07 Keryx Biopharmaceuticals, Inc. Ferric citrate for reducing cardiac failure in chronic kidney disease patients
CN111031813A (zh) * 2017-07-26 2020-04-17 法尔曼特拉公司 用于预防和治疗心血管器官病症的组合物

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