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WO2004074444A2 - Ferric organic compounds, uses thereof and methods of making same - Google Patents

Ferric organic compounds, uses thereof and methods of making same Download PDF

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Publication number
WO2004074444A2
WO2004074444A2 PCT/US2004/004646 US2004004646W WO2004074444A2 WO 2004074444 A2 WO2004074444 A2 WO 2004074444A2 US 2004004646 W US2004004646 W US 2004004646W WO 2004074444 A2 WO2004074444 A2 WO 2004074444A2
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WO
WIPO (PCT)
Prior art keywords
ferric
organic compound
organic
citrate
group
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Ceased
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PCT/US2004/004646
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French (fr)
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WO2004074444A3 (en
Inventor
David W. K. Kwok
Nikolay Mintchev Stoynov
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GloboAsia LLC
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GloboAsia LLC
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Priority to EP04712312.0A priority Critical patent/EP1601680B8/en
Priority to ES04712312.0T priority patent/ES2503717T3/en
Priority to JP2006503637A priority patent/JP4964585B2/en
Priority to SI200432188T priority patent/SI1601680T1/en
Priority to NZ541991A priority patent/NZ541991A/en
Priority to CA2516471A priority patent/CA2516471C/en
Priority to EA200501322A priority patent/EA010028B1/en
Priority to CNB2004800047267A priority patent/CN100386336C/en
Priority to HK05111532.7A priority patent/HK1077580B/en
Priority to DK04712312.0T priority patent/DK1601680T3/en
Priority to KR1020057014976A priority patent/KR101149706B1/en
Priority to AU2004213819A priority patent/AU2004213819B2/en
Priority to MXPA05008784A priority patent/MXPA05008784A/en
Application filed by GloboAsia LLC filed Critical GloboAsia LLC
Publication of WO2004074444A2 publication Critical patent/WO2004074444A2/en
Publication of WO2004074444A3 publication Critical patent/WO2004074444A3/en
Priority to US11/206,981 priority patent/US7767851B2/en
Anticipated expiration legal-status Critical
Priority to US12/064,058 priority patent/US8093423B2/en
Priority to US12/711,679 priority patent/US8338642B2/en
Priority to US13/289,048 priority patent/US8299298B2/en
Priority to US13/661,558 priority patent/US8754257B2/en
Priority to US13/672,900 priority patent/US8609896B2/en
Priority to US14/011,325 priority patent/US8901349B2/en
Priority to US14/011,291 priority patent/US8754258B2/en
Priority to US14/011,357 priority patent/US8846976B2/en
Priority to US14/306,756 priority patent/US9050316B2/en
Priority to US14/502,774 priority patent/US9328133B2/en
Priority to US14/701,933 priority patent/US9757416B2/en
Priority to US15/143,987 priority patent/US9913821B2/en
Priority to US15/699,025 priority patent/US20180214480A1/en
Priority to US15/918,308 priority patent/US20190055274A1/en
Priority to US16/352,455 priority patent/US20190269722A1/en
Priority to US17/091,090 priority patent/US20210299168A1/en
Priority to US17/350,267 priority patent/US20220144872A1/en
Priority to US17/405,543 priority patent/US20220213133A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/418—Preparation of metal complexes containing carboxylic acid moieties
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids

Definitions

  • This invention relates to ferric organic compounds, methods of making the ferric organic compounds, and uses of the ferric organic compounds in the treatment of various disorders .
  • Ferric iron containing compounds are useful in the treatment of a number of disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis.
  • Previous studies and inventions have reported the use of ferric compounds in binding with dietary phosphates, and such ferric compounds are potentially useful for the treatment of hyperphosphatemia in renal failure patients (U.S. Patent No. 5,753,706, 1998; CN 1315174, 2001; Yang W.C., 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.
  • 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. Patent 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, causing precipitation of phosphate as ferric or ferrous phosphates in the gastrointestinal tract thus preventing oral absorption of soluble phosphates from dietary sources. Since the 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 normally below 5 than at intestinal pH normally above 7.
  • the stomach is believed to be an important site of action for the dissolution of Fe(III) compounds. It is also believed that the stomach is also 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 the absorption of phosphates from the intestine.
  • This invention relates to novel forms of ferric organic compounds, methods of making these compounds, and uses of these compounds in the treatment of various disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis.
  • the novel forms of ferric organic compounds are synthesized by adding an alkaline metal hydroxide to a water soluble ferric iron salt.
  • the alkaline metal hydroxide can comprise sodium hydroxide, potassium hydroxide, or any other suitable alkaline metal hydroxide.
  • the soluble ferric iron salt can comprise ferric chloride hexahydrate, or any other suitable ferric iron salt.
  • the alkaline metal hydroxide is added at a specific rate and temperature to form a uniform polyiron oxo colloidal suspension.
  • the colloidal suspension is then washed, and solid crystalline organic acid is added at a specific temperature to form the ferric organic compound in solution.
  • the organic acid can comprise citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, tartaric acid, or any other suitable organic acid.
  • the novel forms of the ferric organic compounds are precipitated out of solution using an organic solvent.
  • the organic solvent can comprise ethanol, methanol, butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other suitable organic solvent.
  • the resulting novel forms of the ferric organic compounds have an enhanced dissolution rate.
  • the novel form of ferric organic compound comprises a novel form of ferric citrate.
  • the novel form of ferric citrate is synthesized by adding sodium hydroxide at a specific rate and temperature to ferric chloride hexahydrate to form a uniform colloidal suspension of ferric hydroxide. Solid crystalline citric acid is added to the colloidal suspension and heated to a specific temperature range to form ferric citrate in solution. The novel form of ferric citrate is precipitated out of solution using an organic solvent.
  • the novel form of ferric citrate has the formula C 6 H 5 C) 7 Fe and has novel physical properties as determined by dissolution rates.
  • the compound can have an intrinsic dissolution rate range, as determined by USP intrinsic dissolution assay in water, between 1.9 to 4.0 mg/cm 2 /min.
  • the novel form of ferric citrate is more aqueously soluble in a wider range of pH than commercially available forms of ferric citrate.
  • the novel form of ferric citrate can have a large active surface area compared to commercially available forms of ferric organic compounds or complexes.
  • novel form of ferric organic compounds can be used to more effectively deliver ferric organic compounds by the route of oral administration to patients suffering from illnesses which are responsive to treatment with ferric organic compounds, including, but not limited to, hyperphosphatemia and metabolic acidosis.
  • This invention relates to use of the novel form of ferric organic compounds, including novel forms of ferric citrate to treat patients suffering from disorders responsive to ferric organic compound treatment.
  • This invention also relates to methods of treating patients suffering from disorders responsive to ferric organic compound treatment by administering a therapeutically effective amount of ferric organic compound to the patients.
  • Figure 1 is a schematic diagram outlining the method of making novel forms of ferric organic compounds according to the invention.
  • Figure 2 is a plot of the dissolution profile of the novel form of ferric citrate of the invention compared to a commercially available compound.
  • Figure 3 is an isotherm graph of volume adsorbed vs. relative pressure demonstrating BET active surface area of the novel form of ferric citrate.
  • Coulter SA 3100 Serial No. zll017; Software Version 2.13; Elapsed time: 29 min.; Outgas time: 60 min.; Outgas temperature: 40°C
  • Figure 4 is an X-ray diffraction spectra of the novel form of ferric citrate. Range: 4.00 to 40.00 (Deg) ; Step Scan Rate: 0.02 Deg/min.
  • Figure 5 is a thermogravimetric analysis of the novel form of ferric citrate. Method: Heating 10°C/MIN, N2 ⁇ 40CC/MIN; Size: 10.5480 mg.
  • This invention provides a method of synthesizing a form of ferric organic compound which comprises obtaining a ferric iron salt; adding an alkaline metal hydroxide to the ferric iron salt at a rate and temperature effective to produce a uniform polyiron oxo suspension; isolating a precipitate from the suspension; adding an organic acid to the precipitate; forming a ferric-organic acid solution by heating the organic acid and the precipitate; and precipitating the form of ferric organic compound from the ferric-organic acid solution by adding an organic solvent to the solution.
  • the alkaline metal hydroxide is added at a rate of less than 20 ml/min. In another embodiment, the alkaline metal hydroxide is added at a rate of between about 10 ml/min and about 20 ml/min. In a preferred embodiment, a nominal rate of 10 to 20 ml/min is preferred.
  • the alkaline metal hydroxide is added to the ferric iron salt at a temperature of less than 40°C. In another embodiment, the alkaline metal hydroxide is added to the ferric iron salt at a temperature between about 10 °C and about 40 °C. In a preferred embodiment, a nominal temperature of 30°C is preferred.
  • heating the organic acid and the precipitate comprises heating the organic acid and the precipitate to a temperature between about 75 °C to about 95 °C. In a preferred embodiment, the range is between about 80°C and about 90°C. In another preferred embodiment, a nominal temperature of 85 °C is preferred.
  • precipitating the form of ferric organic compound from the ferric-organic acid solution by adding an organic solvent to the solution comprises cooling the ferric-organic acid solution to less than 30 °C before adding the organic solvent. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature, of 20 °C.
  • cooling the ferric-organic acid solution comprises cooling the ferric-organic acid solution to a temperature between about 10 °C and about 30 °C. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature of 20 °C.
  • the ferric iron salt comprises ferric chloride hexahydrate.
  • the organic acid includes but is not limited to succinic acid, fumaric acid or tartaric acid. In another embodiment, the organic acid comprises citric acid.
  • the alkaline metal hydroxide includes but is not limited to sodium hydroxide or potassium hydroxide. In another embodiment, the alkaline metal hydroxide comprises sodium hydroxide.
  • the organic solvent includes but is not limited to ethanol, ethanol, butanol, isopropyl alcohol, acetone or tetrahydrofuran.
  • This invention provides a method of synthesizing a form of ferric citrate which comprises obtaining ferric chloride hexahydrate; adding sodium hydroxide to the ferric chloride hexahydrate at a rate and temperature effective to produce a uniform polyiron oxo suspension; isolating a precipitate from the suspension; adding crystalline citric acid to the precipitate; forming a ferric-citric acid solution by heating the citric acid and the precipitate; and precipitating the form of ferric citrate from the ferric- citric acid solution by adding an organic solvent to the solution.
  • sodium hydroxide is added to ferric chloride hexahydrate at a rate of less than 20 ml/min. In another embodiment, sodium hydroxide is added to ferric chloride hexahydrate at a rate of between about 10 ml/min and about 20 ml/min. In a preferred embodiment, a nominal rate of 10 to 20 ml/min is preferred.
  • sodium hydroxide is added to ferric chloride hexahydrate at a temperature of less than 40 °C. In another embodiment, sodium hydroxide is added to ferric chloride hexahydrate at a temperature between about 10 °C and about 40 °C. In a preferred embodiment, a nominal temperature of 30°C is preferred.
  • the ferric-citric acid solution is formed by heating the citric acid and the precipitate to a temperature between about 75 °C to about 95 °C. In a preferred embodiment, the range is between about 80 °C and about 90 °C. In another preferred embodiment, a nominal temperature of 85°C is preferred.
  • precipitating the form of ferric citrate from the ferric-citric acid solution by adding an organic solvent to the solution comprises cooling the ferric-citric acid solution to less than 30°C before adding the organic solvent.
  • the ferric-organic acid solution is cooled to a nominal temperature of 20 °C.
  • cooling the ferric-citric acid solution comprises cooling the ferric-citric acid solution to a temperature between about 10 °C and about 30 °C. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature of 20 °C.
  • the organic solvent includes but is not limited to ethanol, methanol, butanol, isopropyl alcohol, acetone or tetrahydrofuran.
  • This invention provides a use of a form of ferric organic compound or ferric citrate as describe above for treating a person suffering from a disorder responsive to ferric organic compound therapy.
  • the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
  • This invention provides a method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of an ferric organic compound as described above.
  • the ferric organic compound is ferric citrate.
  • the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
  • This invention provides a form of a ferric organic compound having an enhanced dissolution rate.
  • the said organic compound includes but is not limited to citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, tartaric acid or other related organic compounds.
  • the said ferric organic compound has a large active surface area compared to conventional ferric organic compounds .
  • This invention provides a form of ferric citrate having the formula C 6 H 5 0 7 Fe and/or having physical properties as determined by dissolution rates.
  • the dissolution rate as determined by USP intrinsic dissolution assay in water, is between 1.9 to 4.0 mg/cm2/min.
  • This invention provides a form of ferric citrate having a BET active surface area exceeding 16 sq.m/g and a BET active surface area isotherm as shown in Figure 3.
  • This invention provides a form of ferric citrate having the x-ray diffraction pattern shown in Figure 4.
  • This invention provides a form of ferric citrate having three transition temperatures as determined by thermogravimetric analysis (TGA) and having a TGA profile as shown in Figure 5.
  • TGA thermogravimetric analysis
  • This invention provides a form of ferric citrate, wherein the form of ferric citrate has a large active surface area compared to conventional ferric organic compound complexes .
  • This invention provides a use of a form of ferric organic compound or ferric citrate to treat a person suffering from a disorder responsive to ferric organic compound therapy.
  • the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
  • This invention provides a method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of a form of ferric organic compound or ferric citrate as described above.
  • the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
  • This invention provides a form of ferric organic compound or ferric citrate as describe above, wherein said form of ferric organic compound or ferric citrate is in an orally administrable form which includes' but is not limited to a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit or a syrup.
  • the ferric organic compound or ferric citrate is in a form or in an acceptable carrier suitable for topical, sublingual, parenteral or gastrointestinal administration, or aerosolization.
  • This invention provides a composition comprising a form of ferric organic compound or ferric citrate as describe above and a suitable carrier.
  • suitable carrier includes but not limited to any suitable carrier for administering pharmaceutical compositions known to those of ordinary skill in the art.
  • the type of carrier will vary depending on the mode of administration.
  • suitable carrier includes but not limited to water, saline, alcohol, a fat, a wax or a buffer.
  • suitable carrier includes but not limited to any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, may be employed.
  • Biodegradable microspheres e.g., polylactate polyglycolate
  • This invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a form of ferric organic compound or ferric citrate as describe above and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier comprises a controlled release formulation.
  • compositions comprising an effective amount of a form of ferric organic compound or ferric citrate as describe above for treating disorders responsive to ferric organic compound therapy.
  • the disorder includes but is not limited to hyperphosphatemia and metabolic acidosis.
  • pharmaceutically acceptable carriers includes but is not limited to a liquid, an aerosol, a capsule, a tablet, a pill, a powder, a gel, an ointment, a cream, a granule, water, phosphate buffered saline, Ringer's solution, dextrose solution, serum-containing solutions,
  • Hank's solution other aqueous physiologically balanced solutions, oils, esters, glycols, biocompatible polymers, polymeric matrices, capsules, microcapsules, microparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres, cells or cellular membranes.
  • synthesis scheme 10 is a general method for synthesizing novel forms of ferric organic compounds.
  • 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 6H 2 0) , 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 addition of the alkaline metal hydroxide at a specific rate preferably between about 10 ml/min and about 20 ml/min
  • temperature range preferably below 40 °C
  • 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 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.
  • novel forms of ferric organic compounds are useful in the treatment of hyperphosphatemia, metabolic acidosis, and any other disorders responsive to ferric organic compound therapy. Because the novel forms of ferric organic compounds are more soluble than commercially available ferric organic compounds, smaller amounts of the ferric organic compounds can be used to effectively treat patients suffering from such disorders.
  • Improved aqueous solubility is particularly relevant to the use of the novel forms of ferric organic compounds in the treatment of disorders responsive to ferric organic compound therapy. Because the novel forms of ferric organic compounds are more soluble, they will be more effective when taken orally, and therefore can be taken in lower doses. The novel forms of ferric organic compounds are more soluble over a wider pH range than commercially available ferric organic compounds, therefore the novel forms of ferric organic compounds can be more effective by being soluble in the small intestine. As a result, patients can take lower doses of medication with lower incidences of side effects.
  • the novel forms of ferric organic compounds can be administered in a number of forms, including orally ad inistrable forms, which can comprise the novel forms of ferric organic compounds alone or in combination with a pharmaceutically acceptable carrier.
  • the orally administrable form can be selected from the group consisting of a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit, and a syrup.
  • the composition can be administered to human beings or other animals suffering from illnesses responsive to ferric organic compound therapy.
  • the starting materials for making a novel form of ferric citrate comprise a 1.85M solution of ferric chloride hexahydrate (FeCl 3 6H 2 0) .
  • 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 D 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 remove large particles of ferric hydroxide precipitate. The filtered ferric hydroxide suspension is then centrifuged. The supernatant is discarded, then 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.
  • the novel form of ferric citrate is precipitated from the supernatant by adding 5 volumes of organic solvent.
  • organic solvents can be used, including ethanol, methanol, butanol, acetone, isopropyl alcohol, or tetrahydrofuran. Table 1 below lists the relative amounts of ferric citrate formed in solution using various solvents. Once 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.
  • the chemical purity of the novel form of ferric citrate was ascertained by negative-ion liquid chromatography / mass spectrometry (LC/MS) flow-injection method which provided measurement of all mass ions present in solution. Specifically, the mass ions at m/z 243.6 for the novel form of ferric citrate and at m/z 190.6 for citric acid amongst other related and non-related ions in solution were observed.
  • LC/MS analysis also enabled the observation of a number of ferric citrate related and non-related substances and permitted the determination of the relative purity of the novel form of ferric citrate amongst the minor impurities. Such information is critical for application of the novel form of ferric citrate as pharmaceutical grade material.
  • Table 2 The representative chemical purity of the novel form of ferric citrate from three process batches are presented in Table 2.
  • the intrinsic dissolution rates of commercially available ferric citrate were compared with the novel form of ferric citrate.
  • 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 3.
  • Figure 2 is a graph which compares the dissolution profile of the novel form of ferric citrate to the dissolution profile of commercially available ferric citrate compounds .
  • the intrinsic dissolution rates of the novel form of ferric citrate produced by the method of the invention are approximately 3.8 times greater than that determined for a commercially available ferric citrate material. This increase in dissolution rate of the novel form of ferric citrate is believed to be a result of the significantly large active surface area of the novel form of ferric citrate compared to commercially available materials.
  • a BET active surface area isotherm of the novel form of ferric citrate is shown in Figure 3.
  • the analysis of active surface area is based on BET theory which describe 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 4 is a comparison of the active surface area of the novel form of ferric citrate compared to the active surface area of commercially available ferric citrate compounds.
  • the x-ray diffraction spectra of the novel form of ferric citrate is presented in Figure 4, showing diffraction features characteristics of crystalline materials.
  • the thermogravimetric analysis of the novel form of ferric citrate is presented in Figure 5, showing heat absorption isotherms characteristics of the novel material.

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Abstract

The present invention is directed to forms of ferric organic compounds, uses thereof, and methods of making same. The present invention discloses a novel physical form of ferric citrate with dissolution properties desirable for use in medicine, including the treatment of hyperphosphatemia and metabolic acidosis.

Description

FERRIC ORGANIC COMPOUNDS, USES THEREOF AND METHODS OF MAKING SAME
This application claims the benefit of US Provisional patent application numbers 60/447,690, filed 19 February 2003, and 60/462,684, filed 15 April 2003, the contents of which are incorporated into this application by reference.
TECHNICAL FIELD
This invention relates to ferric organic compounds, methods of making the ferric organic compounds, and uses of the ferric organic compounds in the treatment of various disorders .
BACKGROUND OF THE INVENTION Throughout this application, various publications are referenced. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
1) Uses of Iron Compounds
Ferric iron containing compounds are useful in the treatment of a number of disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis. Previous studies and inventions have reported the use of ferric compounds in binding with dietary phosphates, and such ferric compounds are potentially useful for the treatment of hyperphosphatemia in renal failure patients (U.S. Patent No. 5,753,706, 1998; CN 1315174, 2001; Yang W.C., 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. Patent 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, causing precipitation of phosphate as ferric or ferrous phosphates in the gastrointestinal tract thus preventing oral absorption of soluble phosphates from dietary sources. Since the 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.
2) Solution Chemistry of Fe(III) Compounds
Fe(III) is a lewis acid and is chemically less soluble in the stomach at pH normally below 5 than at intestinal pH normally above 7. The stomach is believed to be an important site of action for the dissolution of Fe(III) compounds. It is also believed that the stomach is also 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 the absorption of phosphates from the intestine.
SUMMARY OF THE INVENTION
In accordance with these and other objects of the invention, a brief summary of the present invention is presented. Some simplifications and omission may be made in the following summary, which is intended to highlight and introduce some aspects of the present invention, but not to limit its scope. Detailed descriptions of a preferred exemplary embodiment adequate to allow those of ordinary skill in the art to make and use the invention concepts will follow in later sections.
This invention relates to novel forms of ferric organic compounds, methods of making these compounds, and uses of these compounds in the treatment of various disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis.
The novel forms of ferric organic compounds are synthesized by adding an alkaline metal hydroxide to a water soluble ferric iron salt. The alkaline metal hydroxide can comprise sodium hydroxide, potassium hydroxide, or any other suitable alkaline metal hydroxide. The soluble ferric iron salt can comprise ferric chloride hexahydrate, or any other suitable ferric iron salt. The alkaline metal hydroxide is added at a specific rate and temperature to form a uniform polyiron oxo colloidal suspension. The colloidal suspension is then washed, and solid crystalline organic acid is added at a specific temperature to form the ferric organic compound in solution. The organic acid can comprise citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, tartaric acid, or any other suitable organic acid. The novel forms of the ferric organic compounds are precipitated out of solution using an organic solvent. The organic solvent can comprise ethanol, methanol, butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other suitable organic solvent. The resulting novel forms of the ferric organic compounds have an enhanced dissolution rate.
In one embodiment, the novel form of ferric organic compound comprises a novel form of ferric citrate. The novel form of ferric citrate is synthesized by adding sodium hydroxide at a specific rate and temperature to ferric chloride hexahydrate to form a uniform colloidal suspension of ferric hydroxide. Solid crystalline citric acid is added to the colloidal suspension and heated to a specific temperature range to form ferric citrate in solution. The novel form of ferric citrate is precipitated out of solution using an organic solvent.
The novel form of ferric citrate has the formula C6H5C)7Fe and has novel physical properties as determined by dissolution rates. The compound can have an intrinsic dissolution rate range, as determined by USP intrinsic dissolution assay in water, between 1.9 to 4.0 mg/cm2/min. The novel form of ferric citrate is more aqueously soluble in a wider range of pH than commercially available forms of ferric citrate. The novel form of ferric citrate can have a large active surface area compared to commercially available forms of ferric organic compounds or complexes.
Because it is more soluble, the novel form of ferric organic compounds, including novel forms of ferric citrate, can be used to more effectively deliver ferric organic compounds by the route of oral administration to patients suffering from illnesses which are responsive to treatment with ferric organic compounds, including, but not limited to, hyperphosphatemia and metabolic acidosis.
This invention relates to use of the novel form of ferric organic compounds, including novel forms of ferric citrate to treat patients suffering from disorders responsive to ferric organic compound treatment.
This invention also relates to methods of treating patients suffering from disorders responsive to ferric organic compound treatment by administering a therapeutically effective amount of ferric organic compound to the patients.
DETAILED DESCRIPTION OF THE FIGURES
In drawings which illustrate specific embodiments of the invention, but which should not be construed as restricting the spirit or scope of the invention in any way:
Figure 1 is a schematic diagram outlining the method of making novel forms of ferric organic compounds according to the invention.
Figure 2 is a plot of the dissolution profile of the novel form of ferric citrate of the invention compared to a commercially available compound.
Figure 3 is an isotherm graph of volume adsorbed vs. relative pressure demonstrating BET active surface area of the novel form of ferric citrate. Produced by Coulter SA 3100 (Serial No. zll017; Software Version 2.13; Elapsed time: 29 min.; Outgas time: 60 min.; Outgas temperature: 40°C)
Figure 4 is an X-ray diffraction spectra of the novel form of ferric citrate. Range: 4.00 to 40.00 (Deg) ; Step Scan Rate: 0.02 Deg/min.
Figure 5 is a thermogravimetric analysis of the novel form of ferric citrate. Method: Heating 10°C/MIN, N2Θ40CC/MIN; Size: 10.5480 mg.
DETAILED DESCRIPTION OF THE INVENTION
Throughout the following description, specific details are set forth in order to provide a more thorough understanding of the invention. However, the invention may be practiced without these particulars. In other instances, well known elements have not been shown or described in detail to avoid unnecessarily obscuring the invention. Accordingly, the specification and drawings are to be regarded in an illustrative, rather than a restrictive, sense.
This invention provides a method of synthesizing a form of ferric organic compound which comprises obtaining a ferric iron salt; adding an alkaline metal hydroxide to the ferric iron salt at a rate and temperature effective to produce a uniform polyiron oxo suspension; isolating a precipitate from the suspension; adding an organic acid to the precipitate; forming a ferric-organic acid solution by heating the organic acid and the precipitate; and precipitating the form of ferric organic compound from the ferric-organic acid solution by adding an organic solvent to the solution.
In an embodiment, the alkaline metal hydroxide is added at a rate of less than 20 ml/min. In another embodiment, the alkaline metal hydroxide is added at a rate of between about 10 ml/min and about 20 ml/min. In a preferred embodiment, a nominal rate of 10 to 20 ml/min is preferred.
In an embodiment, the alkaline metal hydroxide is added to the ferric iron salt at a temperature of less than 40°C. In another embodiment, the alkaline metal hydroxide is added to the ferric iron salt at a temperature between about 10 °C and about 40 °C. In a preferred embodiment, a nominal temperature of 30°C is preferred.
In an embodiment, heating the organic acid and the precipitate comprises heating the organic acid and the precipitate to a temperature between about 75 °C to about 95 °C. In a preferred embodiment, the range is between about 80°C and about 90°C. In another preferred embodiment, a nominal temperature of 85 °C is preferred. In an embodiment, precipitating the form of ferric organic compound from the ferric-organic acid solution by adding an organic solvent to the solution comprises cooling the ferric-organic acid solution to less than 30 °C before adding the organic solvent. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature, of 20 °C. In an embodiment, cooling the ferric-organic acid solution comprises cooling the ferric-organic acid solution to a temperature between about 10 °C and about 30 °C. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature of 20 °C.
In an embodiment, the ferric iron salt comprises ferric chloride hexahydrate.
In an embodiment, the organic acid includes but is not limited to succinic acid, fumaric acid or tartaric acid. In another embodiment, the organic acid comprises citric acid.
In an embodiment, the alkaline metal hydroxide includes but is not limited to sodium hydroxide or potassium hydroxide. In another embodiment, the alkaline metal hydroxide comprises sodium hydroxide. In an embodiment, the organic solvent includes but is not limited to ethanol, ethanol, butanol, isopropyl alcohol, acetone or tetrahydrofuran.
This invention provides a method of synthesizing a form of ferric citrate which comprises obtaining ferric chloride hexahydrate; adding sodium hydroxide to the ferric chloride hexahydrate at a rate and temperature effective to produce a uniform polyiron oxo suspension; isolating a precipitate from the suspension; adding crystalline citric acid to the precipitate; forming a ferric-citric acid solution by heating the citric acid and the precipitate; and precipitating the form of ferric citrate from the ferric- citric acid solution by adding an organic solvent to the solution.
In an embodiment, sodium hydroxide is added to ferric chloride hexahydrate at a rate of less than 20 ml/min. In another embodiment, sodium hydroxide is added to ferric chloride hexahydrate at a rate of between about 10 ml/min and about 20 ml/min. In a preferred embodiment, a nominal rate of 10 to 20 ml/min is preferred.
In an embodiment, sodium hydroxide is added to ferric chloride hexahydrate at a temperature of less than 40 °C. In another embodiment, sodium hydroxide is added to ferric chloride hexahydrate at a temperature between about 10 °C and about 40 °C. In a preferred embodiment, a nominal temperature of 30°C is preferred.
In an embodiment, the ferric-citric acid solution is formed by heating the citric acid and the precipitate to a temperature between about 75 °C to about 95 °C. In a preferred embodiment, the range is between about 80 °C and about 90 °C. In another preferred embodiment, a nominal temperature of 85°C is preferred.
In an embodiment, precipitating the form of ferric citrate from the ferric-citric acid solution by adding an organic solvent to the solution comprises cooling the ferric-citric acid solution to less than 30°C before adding the organic solvent. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature of 20 °C.
In an embodiment, cooling the ferric-citric acid solution comprises cooling the ferric-citric acid solution to a temperature between about 10 °C and about 30 °C. In a preferred embodiment, the ferric-organic acid solution is cooled to a nominal temperature of 20 °C.
In an embodiment, the organic solvent includes but is not limited to ethanol, methanol, butanol, isopropyl alcohol, acetone or tetrahydrofuran.
This invention provides a use of a form of ferric organic compound or ferric citrate as describe above for treating a person suffering from a disorder responsive to ferric organic compound therapy. In an embodiment, the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
This invention provides a method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of an ferric organic compound as described above. In an embodiment, the ferric organic compound is ferric citrate. In another embodiment, the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
This invention provides a form of a ferric organic compound having an enhanced dissolution rate. In an embodiment, the said organic compound includes but is not limited to citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, tartaric acid or other related organic compounds. In another embodiment, the said ferric organic compound has a large active surface area compared to conventional ferric organic compounds .
This invention provides a form of ferric citrate having the formula C6H507Fe and/or having physical properties as determined by dissolution rates. In an embodiment, the dissolution rate, as determined by USP intrinsic dissolution assay in water, is between 1.9 to 4.0 mg/cm2/min.
This invention provides a form of ferric citrate having a BET active surface area exceeding 16 sq.m/g and a BET active surface area isotherm as shown in Figure 3.
This invention provides a form of ferric citrate having the x-ray diffraction pattern shown in Figure 4.
This invention provides a form of ferric citrate having three transition temperatures as determined by thermogravimetric analysis (TGA) and having a TGA profile as shown in Figure 5.
This invention provides a form of ferric citrate, wherein the form of ferric citrate has a large active surface area compared to conventional ferric organic compound complexes . This invention provides a use of a form of ferric organic compound or ferric citrate to treat a person suffering from a disorder responsive to ferric organic compound therapy. In an embodiment, the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
This invention provides a method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of a form of ferric organic compound or ferric citrate as described above. In an embodiment, the disorder includes but is not limited to hyperphosphatemia or metabolic acidosis.
This invention provides a form of ferric organic compound or ferric citrate as describe above, wherein said form of ferric organic compound or ferric citrate is in an orally administrable form which includes' but is not limited to a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit or a syrup. In an embodiment, the ferric organic compound or ferric citrate is in a form or in an acceptable carrier suitable for topical, sublingual, parenteral or gastrointestinal administration, or aerosolization.
This invention provides a composition comprising a form of ferric organic compound or ferric citrate as describe above and a suitable carrier.
As used herein, the term suitable carrier includes but not limited to any suitable carrier for administering pharmaceutical compositions known to those of ordinary skill in the art. The type of carrier will vary depending on the mode of administration.
With regards to compositions for parenteral administration (e.g. subcutaneous injections), the term suitable carrier includes but not limited to water, saline, alcohol, a fat, a wax or a buffer.
With regards to compositions for oral administration, the term suitable carrier includes but not limited to any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, may be employed.
Biodegradable microspheres (e.g., polylactate polyglycolate) may also be employed as carriers for the pharmaceutical compositions of this invention.
This invention provides a pharmaceutical composition comprising a form of ferric organic compound or ferric citrate as describe above and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutically acceptable carrier comprises a controlled release formulation.
This invention provides a pharmaceutical composition comprising an effective amount of a form of ferric organic compound or ferric citrate as describe above for treating disorders responsive to ferric organic compound therapy. In an embodiment, the disorder includes but is not limited to hyperphosphatemia and metabolic acidosis. As used herein, pharmaceutically acceptable carriers includes but is not limited to a liquid, an aerosol, a capsule, a tablet, a pill, a powder, a gel, an ointment, a cream, a granule, water, phosphate buffered saline, Ringer's solution, dextrose solution, serum-containing solutions,
Hank's solution, other aqueous physiologically balanced solutions, oils, esters, glycols, biocompatible polymers, polymeric matrices, capsules, microcapsules, microparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres, cells or cellular membranes.
1 . General Method of Synthesis of Novel Forms of Ferric Organic Compounds
Referring to Figure 1, synthesis scheme 10 is a general method for synthesizing novel forms of ferric organic compounds. The starting materials, as indicated in box 20, comprise soluble ferric iron salts. The soluble ferric iron salts can comprise ferric chloride hexahydrate (FeCl36H20) , as indicated in box 21, or any other suitable soluble ferric iron salt. Next, an alkaline metal hydroxide (box 30) is added at a specific rate and temperature to the soluble ferric iron salt. The addition of the alkaline metal hydroxide at a specific rate (preferably between about 10 ml/min and about 20 ml/min) and temperature range (preferably below 40 °C) results in the formation of a uniform polyiron oxo colloidal suspension. 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. At box 60, the ferric organic compound is precipitated out of solution with an organic solvent to form a novel form of ferric organic compound (box 70) . Various 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.
2. Solubili ty Profile of Novel Forms of Ferric Organic Compounds The inventors have found that the novel forms of 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 novel ferric organic compounds is believed to be a result of the unique significantly large active surface area of the novel forms of ferric organic compounds.
3. Use of Novel Forms of Ferric Organic Compounds in the Trea tmen t of Disorders
The novel forms of ferric organic compounds are useful in the treatment of hyperphosphatemia, metabolic acidosis, and any other disorders responsive to ferric organic compound therapy. Because the novel forms of ferric organic compounds are more soluble than commercially available ferric organic compounds, smaller amounts of the ferric organic compounds can be used to effectively treat patients suffering from such disorders.
Improved aqueous solubility is particularly relevant to the use of the novel forms of ferric organic compounds in the treatment of disorders responsive to ferric organic compound therapy. Because the novel forms of ferric organic compounds are more soluble, they will be more effective when taken orally, and therefore can be taken in lower doses. The novel forms of ferric organic compounds are more soluble over a wider pH range than commercially available ferric organic compounds, therefore the novel forms of ferric organic compounds can be more effective by being soluble in the small intestine. As a result, patients can take lower doses of medication with lower incidences of side effects.
In one embodiment of the invention, the novel form of ferric citrate has a significantly higher rate of aqueous solubility under physiological conditions than commercially available forms of ferric citrate, and therefore the novel form is believed to provide a significant improvement in the orally effective use of ferric citrate at a reduced dosage. By reducing the orally effective dose of ferric citrate, it is believed that the novel form of ferric citrate will provide a lower incidence of ulcerative gastrointestinal adverse effects associated with commercially available ferric citrate compounds. In addition, it is believed that the increased rate of dissolution of the novel form of ferric citrate will provide a more rapid onset of action in binding to dietary phosphate.
The novel forms of ferric organic compounds can be administered in a number of forms, including orally ad inistrable forms, which can comprise the novel forms of ferric organic compounds alone or in combination with a pharmaceutically acceptable carrier. The orally administrable form can be selected from the group consisting of a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit, and a syrup. The composition can be administered to human beings or other animals suffering from illnesses responsive to ferric organic compound therapy.
Examples
In examples which are intended to illustrate embodiments of the invention but which are not intended to limit the scope of the invention:
1) Method of Making A Novel Form of Ferric Citrate
In one embodiment of the invention, the starting materials for making a novel form of ferric citrate comprise a 1.85M solution of ferric chloride hexahydrate (FeCl36H20) . 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 DC, preferably between about 10 °C to about 30 °C. The suspension is then filtered through a 1 mm pore filter to breakup aggregates and remove large particles of ferric hydroxide precipitate. The filtered ferric hydroxide suspension is then centrifuged. The supernatant is discarded, then 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.
The novel form of 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. Table 1 below lists the relative amounts of ferric citrate formed in solution using various solvents. Once 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.
Table 1. Comparison of relative percentage of novel orm of ferric citrate formed by different organic solvents
Figure imgf000022_0001
The following chemical equations represent the chemical reactions described in the specific embodiment of the method for making the novel form of ferric citrate:
FeCl3 + 3NaOH → Fe (OH) 3 + 3NaCl (1)
Fe(OH)3 + C6H807 → Fe(C6H507) + 3H0 (2).
2) Physical Properties of Novel Form of Ferric Ci tra te
The chemical purity of the novel form of ferric citrate was ascertained by negative-ion liquid chromatography / mass spectrometry (LC/MS) flow-injection method which provided measurement of all mass ions present in solution. Specifically, the mass ions at m/z 243.6 for the novel form of ferric citrate and at m/z 190.6 for citric acid amongst other related and non-related ions in solution were observed. The use of LC/MS analysis also enabled the observation of a number of ferric citrate related and non-related substances and permitted the determination of the relative purity of the novel form of ferric citrate amongst the minor impurities. Such information is critical for application of the novel form of ferric citrate as pharmaceutical grade material. The representative chemical purity of the novel form of ferric citrate from three process batches are presented in Table 2.
Table 2. Representative chemical purity of novel form of ferric citrate
Figure imgf000023_0001
The intrinsic dissolution rates of commercially available ferric citrate were compared with the novel form of ferric citrate. 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 3.
Table 3. Intrinsic dissolution rates of ferric citrate at 37 /C in solutions of pH 8
Figure imgf000024_0001
Figure 2 is a graph which compares the dissolution profile of the novel form of ferric citrate to the dissolution profile of commercially available ferric citrate compounds .
The intrinsic dissolution rates of the novel form of ferric citrate produced by the method of the invention, on average, are approximately 3.8 times greater than that determined for a commercially available ferric citrate material. This increase in dissolution rate of the novel form of ferric citrate is believed to be a result of the significantly large active surface area of the novel form of ferric citrate compared to commercially available materials.
A BET active surface area isotherm of the novel form of ferric citrate is shown in Figure 3. The analysis of active surface area is based on BET theory which describe the phenomenon of mass and energy interaction and phase changes during gas adsorption onto solid surfaces and in pore spaces. In 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 4 is a comparison of the active surface area of the novel form of ferric citrate compared to the active surface area of commercially available ferric citrate compounds.
Table 4. BET active surface areas of various forms of ferric citrate
Figure imgf000026_0001
The x-ray diffraction spectra of the novel form of ferric citrate is presented in Figure 4, showing diffraction features characteristics of crystalline materials. The thermogravimetric analysis of the novel form of ferric citrate is presented in Figure 5, showing heat absorption isotherms characteristics of the novel material.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof.
Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims .

Claims

What is claimed is :
1. A method of synthesizing a form of ferric organic compound which comprises: a) obtaining a ferric iron salts; b) adding an alkaline metal hydroxide to the ferric iron salt at a rate and temperature effective to produce a uniform polyiron oxo suspension; c) isolating a precipitate from the suspension; 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 form of ferric organic compound from the ferric-organic acid solution by adding an organic solvent to the solution.
2. A method according to claim 1, wherein adding the alkaline metal hydroxide comprises adding the alkaline metal hydroxide at a rate of less than 20 ml/min.
3. A method according to claim 2, wherein the rate is between about 10 ml/min and about 20 ml/min.
4. A method according to any one of claims 1 to 3, wherein adding the alkaline metal hydroxide to the ferric iron salt occurs at a temperature less than 40°C.
5. A method according to claim 4, wherein adding the alkaline metal hydroxide to the ferric iron salt occurs at a temperature between about 10 °C and about 40 °C.
6. A method according to any one of claims 1 to 5, wherein heating the organic acid and the precipitate comprises heating the organic acid and precipitate to a temperature between about 80 °C and about 90 °C.
7. A method according to any one of claims 1 to 6, wherein precipitating the form of ferric organic compound from the ferric-organic acid solution by adding an organic solvent to the solution comprises cooling the ferric- organic acid solution to less than 30°C before adding the organic solvent.
8. A method according to claim 7, wherein cooling the ferric-organic acid solution comprises cooling the ferric-organic acid solution • to a temperature between about 10 °C and about 30 °C.
9. A method according to any one of claims 1 to 8, wherein the ferric iron salt comprises ferric chloride hexahydrate .
10. A method according to any one of claims 1 to 9, wherein the organic acid is selected from the group consisting of citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid.
11. A method according to claim 10, wherein the organic acid comprises citric acid.
12. A method according to any one of claims 1 to 11, wherein the alkaline metal hydroxide comprises one of the group consisting of sodium hydroxide, and potassium hydroxide.
13. A method according to claim 12, wherein the alkaline metal hydroxide comprises sodium hydroxide.
14. A method according to any one of claims 1 to 13, wherein the organic solvent is selected from the group consisting of ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran.
15. A method of synthesizing a form of ferric citrate which comprises : a) obtaining ferric chloride hexahydrate; b) adding sodium hydroxide to the ferric chloride hexahydrate at a rate and temperature effective to produce a uniform polyiron oxo suspension; c) isolating a precipitate from the suspension; d) adding crystalline citric acid to the precipitate; e) forming a ferric-citric acid solution by heating the citric acid and the precipitate; and f) precipitating the form of ferric citrate from the ferric-citric acid solution by adding an organic solvent to the solution.
16. A method according to claim 15, wherein adding sodium hydroxide to ferric chloride hexahydrate occurs at a rate of less than 20 ml/min.
17. A method according to claim 16, wherein the rate is between about 10 ml/min and about 20 ml/min.
18. A method according to any one of claims 15 to 17, wherein adding sodium hydroxide to ferric chloride hexahydrate occurs at a temperature less than 40°C.
19. A method according to claim 18, wherein adding sodium hydroxide to ferric chloride hexahydrate occurs at a temperature between about 10 °C and about 40°C.
20. A method according to any one of claims 15 to 19, wherein the ferric-citric acid solution is formed by heating the citric acid and the precipitate to a temperature between about 80 °C and about 90 °C.
21. A method according to any one of claims 15 to 20, wherein precipitating the form of ferric citrate from the ferric-citric acid solution by adding an organic solvent to the solution comprises cooling the ferric- citric acid solution to less than 30 °C before adding the organic solvent.
22. A method according to claim 21, wherein cooling the ferric-citric acid solution comprises cooling the ferric-citric acid solution to a temperature between about 10 °C and about 30 °C.
23. A method according to any one of claims 15 to 22, wherein the organic solvent is selected from the group consisting of ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran.
24. A form of ferric organic compound made according to the method in any one of claims 1 to 14.
25. A form of ferric citrate made according to the method in any one of claims 15 to 23.
26. A use of the compound according to claim 24 to treat a person suffering from a disorder responsive to ferric organic compound therapy.
27. A use according to claim 26 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
28. A use of the compound according to claim 25 to treat a person suffering from a disorder responsive to ferric organic compound therapy.
29. A use according to claim 28 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
30. A method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of the ferric organic compound according to claim 24.
31. A method according to claim 30 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
32. A method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of the ferric organic compound according to claim 25.
33. A method according to claim 32 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
34. A form of a ferric organic compound having an enhanced dissolution rate.
35. A form of a ferric organic compound according to claim 34 wherein the organic compound is selected from the group consisting of citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, tartaric acid, and other related organic compounds.
36. A form of ferric organic compound according to claims 34 or 35, wherein the form of ferric organic compound has a large active surface area compared to conventional ferric organic compounds .
37. A form of ferric citrate having the formula CeH50Fe and having physical properties as determined by dissolution rates .
38. A form of ferric citrate according to claim 37 having an intrinsic dissolution rate range, as determined by USP intrinsic dissolution assay in water, between 1.9 to 4.0 mg/cm2/min.
39. A form of ferric citrate according to any one of claims 37 or 38 having a BET active surface area exceeding 16 sq.m/g and a BET active surface area isotherm as shown in Figure 3.
40. A form of ferric citrate according to any one of claims 37 to 39 having the x-ray diffraction pattern shown in Figure 4.
41. A form of ferric citrate according to any one of claims 37 to 40 having three transition temperatures as determined by thermogravimetric analysis (TGA) and having a TGA profile as shown in Figure 5.
42. A form of ferric citrate according to any one of claims 37 to 41, wherein the form has a large active surface area compared to conventional ferric organic compound complexes .
43. A use of the form of ferric organic compound according to any one of claims 34 to 36 to treat a person suffering from a disorder responsive to ferric organic compound therapy.
44. A use according to claim 43 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
45. A use of the form of ferric citrate according to any one of claims 37 to 42 to treat a person suffering from a disorder responsive to ferric organic compound therapy.
46. A use according to claim 45 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
47. A method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of the form of ferric organic compound according to any one of claims 34 to 36.
48. A method according to claim 47 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
49. A method of treating a person suffering from a disorder responsive to ferric organic compound therapy comprising administering to the person a therapeutically effective amount of the form of ferric citrate according to any one of claims 37 to 42.
50. A method according to claim 49 wherein the disorder is selected from the group consisting of hyperphosphatemia, and metabolic acidosis.
51. A form of ferric organic compound as claimed in any one of claims 24 and 34 to 36, wherein the form of ferric organic compound is in an orally administrable form selected from the group consisting of a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit, and a syrup.
52. A form of ferric citrate as claimed in claims 25 and 37 to 42, wherein the from of ferric citrate is in an orally administrable form selected from the group consisting of a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit, and a syrup.
53. A composition comprising the form of claim 24 or 25 or any one of claims 34 to 42 and a suitable carrier.
54. A pharmaceutical composition comprising the form of claim 24 or 25 or any one of claims 34 to 42 and a pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising an effective amount of the form of claim 24 or 25 or any one of claims 34 to 42 for treating disorders responsive to ferric organic compound therapy.
PCT/US2004/004646 2003-02-19 2004-02-18 Ferric organic compounds, uses thereof and methods of making same Ceased WO2004074444A2 (en)

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DK04712312.0T DK1601680T3 (en) 2003-02-19 2004-02-18 PROCEDURES FOR MANUFACTURING ORGANIC IRON (III)
KR1020057014976A KR101149706B1 (en) 2003-02-19 2004-02-18 Ferric organic compounds, uses thereof and methods of making same
JP2006503637A JP4964585B2 (en) 2003-02-19 2004-02-18 Ferric organic compounds, their use, and methods for their production
SI200432188T SI1601680T1 (en) 2003-02-19 2004-02-18 Methods of making ferric organic compounds
NZ541991A NZ541991A (en) 2003-02-19 2004-02-18 Ferric organic compounds, uses thereof and methods of making same
CA2516471A CA2516471C (en) 2003-02-19 2004-02-18 Ferric organic compounds, uses thereof and methods of making same
EA200501322A EA010028B1 (en) 2003-02-19 2004-02-18 Ferric organic compounds (iii), uses thereof and methods of making same
CNB2004800047267A CN100386336C (en) 2003-02-19 2004-02-18 Iron organic compound, application and preparation method thereof
HK05111532.7A HK1077580B (en) 2003-02-19 2004-02-18 Methods of making ferric organic compounds
EP04712312.0A EP1601680B8 (en) 2003-02-19 2004-02-18 Methods of making ferric organic compounds
MXPA05008784A MXPA05008784A (en) 2003-02-19 2004-02-18 Ferric organic compounds, uses thereof and methods of making same.
ES04712312.0T ES2503717T3 (en) 2003-02-19 2004-02-18 Methods of preparing organic ferric compounds
AU2004213819A AU2004213819B2 (en) 2003-02-19 2004-02-18 Ferric organic compounds, uses thereof and methods of making same
US11/206,981 US7767851B2 (en) 2003-02-19 2005-08-18 Ferric organic compounds, uses thereof and methods of making same
US12/064,058 US8093423B2 (en) 2003-02-19 2006-08-18 Pharmaceutical-grade ferric organic compounds, uses thereof and method of making same
US12/711,679 US8338642B2 (en) 2003-02-19 2010-02-24 Ferric organic compounds, uses thereof and methods of making same
US13/289,048 US8299298B2 (en) 2003-02-19 2011-11-04 Pharmaceutical-grade ferric organic compounds, uses thereof and method of making same
US13/661,558 US8754257B2 (en) 2003-02-19 2012-10-26 Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
US13/672,900 US8609896B2 (en) 2003-02-19 2012-11-09 Ferric organic compounds, uses thereof and methods of making same
US14/011,291 US8754258B2 (en) 2003-02-19 2013-08-27 Ferric organic compounds, uses thereof and methods of making same
US14/011,357 US8846976B2 (en) 2003-02-19 2013-08-27 Ferric organic compounds, uses thereof and methods of making same
US14/011,325 US8901349B2 (en) 2003-02-19 2013-08-27 Ferric organic compounds, uses thereof and methods of making same
US14/306,756 US9050316B2 (en) 2003-02-19 2014-06-17 Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
US14/502,774 US9328133B2 (en) 2003-02-19 2014-09-30 Ferric organic compounds, uses thereof and methods of making same
US14/701,933 US9757416B2 (en) 2003-02-19 2015-05-01 Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
US15/143,987 US9913821B2 (en) 2003-02-19 2016-05-02 Ferric organic compounds, uses thereof and methods of making same
US15/699,025 US20180214480A1 (en) 2003-02-19 2017-09-08 Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
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US16/352,455 US20190269722A1 (en) 2003-02-19 2019-03-13 Pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same
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