WO2019012552A1 - Compositions de composés organiques ferriques - Google Patents

Compositions de composés organiques ferriques Download PDF

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Publication number
WO2019012552A1
WO2019012552A1 PCT/IN2018/050441 IN2018050441W WO2019012552A1 WO 2019012552 A1 WO2019012552 A1 WO 2019012552A1 IN 2018050441 W IN2018050441 W IN 2018050441W WO 2019012552 A1 WO2019012552 A1 WO 2019012552A1
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WO
WIPO (PCT)
Prior art keywords
ferric citrate
ferric
core
surface area
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2018/050441
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English (en)
Other versions
WO2019012552A4 (fr
Inventor
Thilek Kumar Muniyappan
Rama Chandra Rao MOLLETI
Balaji PANDYA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RA Chem Pharma Ltd
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RA Chem Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by RA Chem Pharma Ltd filed Critical RA Chem Pharma Ltd
Publication of WO2019012552A1 publication Critical patent/WO2019012552A1/fr
Publication of WO2019012552A4 publication Critical patent/WO2019012552A4/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes

Definitions

  • This invention relates to pharmaceutical composition of pharmaceutical grade ferric organic compounds, such as Ferric citrate.
  • Ferric iron containing compounds are useful in the treatment of a number of disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis.
  • Ferric iron containing compounds existing in the art are for example Ferric chloride, Ferric oxide, Ferric fluoride, and Ferric citrate. 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.
  • Ferric citrate has the following structure, and can be referred to as FCT.
  • the novel form of Ferric citrate has the formula C 6 H 5 O 7 Fe and has novel physical properties as determined by dissolution rates, and has a molecular weight of 244.94 g/mole.
  • Ferric citrate is approved in 2014 in USA, and the NDA applicant is Keryx Pharmaceuticals.
  • Pharmaceutical grade Ferric citrate is suitable for treating hyperphosphatemia, or other disorders characterized by high serum phosphate levels. Specifically, for treating subjects or patients with various renal diseases; e.g., End Stage Renal Diseases (ESRD), Chronic Kidney Disease (CKD) or other related kidney diseases, or subjects and patients who are on dialysis but not limited to hemodialysis.
  • Ferric citrate is characterized as a light brown to beige powder, odorless and slightly ferruginous tasting. According to the Merck Index, Ferric citrate is slowly but completely soluble in cold water and readily soluble in hot water but diminishes in solubility with age.
  • US 5,753,706 discloses that Ferric citrate compounds can be used to control phosphate metabolism and prevent metabolic acidosis in patients. Ferric citrate compounds can be used with patients suffering from renal failure associated with hyperphosphatemia or patients predisposed to development of a hyperphosphatemic condition. Ferric citrate also is used as a food supplement and additive.
  • US 6,903,235 discloses that Ferric citrate is commercially available in the form of a combination of iron and citric acid of indefinite composition. It explains that the indefinite composition is likely due to difficulties encountered in its preparation but that those knowledgeable in the art understand and necessarily accept that commercially available Ferric citrate contains different molar ratios of iron and citric acid and also contains different amounts of water.
  • WO 2004/074444 discloses processes for making Ferric organic compounds, such as Ferric citrate, with enhanced dissolution rates
  • WO 2007/022435 is a continuation-in-part of WO 2004/074444 and discloses processes for making Ferric organic compounds soluble over a wide pH range and having a large surface area.
  • WO 2007/089577 is directed to methods of treating soft tissue calcification using Ferric organic compounds, such as a Ferric citrate.
  • WO 2007/089571 is directed to methods of treating chronic kidney disease using Ferric organic compounds, such as Ferric citrate.
  • US 9,387,191/US 2013/274328 A1/US 2016/0263075 A relates to a composition of Ferric citrate comprising Pregelatinized starch, a lubricant and coating.
  • IN 2016/28011726 which is an equivalent of US 9,387,191 relates to Ferric citrate tablet wherein the mean surface area to mass ratio of said granule particles is equal to or greater than 1 m 2 /g.
  • IN 305/MUMNP/2012 which is an equivalent of US 9,387,191 relates to a tablet containing Ferric citrate with a mean surface area to mass ratio of 1 m 2 /g, and a binder, with LOD limitation.
  • US 2016/0263038 which is assigned to Keryx pharma relates to FCT composition containing Pregelatinized starch.
  • US 2009/0186939 which is an equivalent of US 7,767,851 relates to Ferric citrate having BET surface area ⁇ 16m 2 /g.
  • WO2016/162794 relates to FCT tablet, wherein Ferric citrate having a specific surface area less than 16m 2 /g.
  • WO2016/162888 relates to Ferric citrate having a BET active surface area of less than 16 m 2 /g.
  • WO 2015/110968 relates to Ferric citrate having a BET active surface area in the range of 1-15 m 2 /g.
  • WO 2015/198304 discloses FCT tablet preparation and process for preparation FCT composition using wet granulation.
  • IN241/MUM/2014 / IN 201627024694 relates to Ferric citrate having a BET active surface area in the range of 1-15 m 2 /gm.
  • IN 996/DEL/2015 relates to pharmaceutical grade Ferric citrate having a BET active surface area of less than 16 m 2 /g and a mean dissolution rate of 4 to 9 mg/cm 2 /min.
  • IN 253106 which is an equivalent of WO 2007/022435 relates to Ferric citrate having intrinsic dissolution of 1.9 to 4 mg/cm 2 /min, and BET active surface area greater than 16 m 2 /g.
  • the main aspect of the invention is to provide a pharmaceutical composition comprising Ferric citrate, along with disintegrant and other pharmaceutically acceptable excipients.
  • the composition disintegrates within 15 minutes, and the BET surface area of Ferric citrate of the composition is the in the range of 6-12 m 2 /g.
  • the other aspect of the present invention is to provide an oral pharmaceutical composition of Ferric organic compound such as Ferric citrate.
  • the other aspect of the invention provides a pharmaceutical composition comprising: Ferric organic compound; and a disintegrant.
  • the invention provides a pharmaceutical composition in the form of a tablet that comprises Ferric organic compound, a disintegrant selected from crospovidone, low substituted hydroxypropyl cellulose, cross linked cellulose, sodium starch glycolate, and microcrystalline cellulose or a combination thereof, and one or more pharmaceutically acceptable excipients, for example, a binder, a lubricant or any combination thereof.
  • a disintegrant selected from crospovidone, low substituted hydroxypropyl cellulose, cross linked cellulose, sodium starch glycolate, and microcrystalline cellulose or a combination thereof
  • one or more pharmaceutically acceptable excipients for example, a binder, a lubricant or any combination thereof.
  • the invention provides a pharmaceutical composition consisting of a tablet that comprises a powder blend or granules comprising Ferric organic compound; a disintegrant, and one or more pharmaceutically acceptable excipients, for example, a binder, and a lubricant.
  • composition of the invention disintegrates within 15 minutes.
  • the pharmaceutical composition is directed to a tablet comprising Ferric citrate having a BET surface area in the range of 6-12 m 2 /g.
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising Ferric organic compound, and disintegrant, which is prepared by either dry granulation or wet granulation.
  • the Ferric organic compounds which include Ferric citrate, Iron Sucrose, Sucroferric Oxyhydroxide, preferably Ferric citrate.
  • the pharmaceutical composition is directed to a tablet comprising Ferric citrate, having a BET surface area of compound is in the range of 6-12 m 2 /g.
  • the tablet can include at least 70 weight percent Ferric citrate, at least 80 weight percent Ferric citrate, or at least 90 weight percent Ferric citrate.
  • the disintegrant can be one or more of crospovidone, low substituted hydroxypropyl cellulose, cross linked cellulose, microcrystalline cellulose, crosspovidone, sodium starch glycolate or a combination thereof.
  • the tablet can include various additional components including, for example, one or more binders and/or one or more lubricants, and optionally other pharmaceutical excipients.
  • composition excipients include excipients, for example, diluents, glidants etc.... Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).
  • composition contains a definite composition and a definite hydrate.
  • the binder can be selected from one or more of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate, alginic acid, guar gum, acacia gum, xanthan gum, carbopol, cellulose gum (carboxymethyl cellulose), ethyl cellulose, PVP/VA, povidone, starch (partially or fully pregelatinized starch) and methyl cellulose.
  • the lubricant can be one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol (molecular weight above 3350), talc, mineral and vegetable oil.
  • compositions and process for the preparation of compositions containing Ferric organic compounds which can include Ferric citrate.
  • the formulations can include Ferric citrate as the active ingredient and a disintegrant.
  • compositions containing Ferric organic compounds which can include Ferric citrate.
  • the composition can be prepared by dry granulation, where roller compactor is widely used as one of dry granulation process.
  • a dry granulation is prepared by compacting a dry powder blend of the drug and inactive tableting ingredients using roller compactor or slugging by using compression machine, milling the compacts and blending the resultant granulation with other inactive ingredients followed by lubrication. This method is commonly used for drug substance that has better or moderate compressibility but not having good flow characteristics.
  • a typical granulation is prepared by blending Ferric organic compound with inactive tableting ingredients in a blender, compacting the blend using a roller compactor, milling to a desired particle size and lubrication.
  • Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls. More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then milled and sieved before the addition of other ingredients and finally compressed into tablets.
  • a wet granulation technique requires preparation of a blend, wetting the blend with a binder solution to get a wet mass, milling the wet mass into moist granules agglomerated with a binder and drying the granules, followed by further milling and blending with other inactive ingredients.
  • this process of agglomeration with a binder results in a compressible granulation.
  • a typical granulation is prepared in a conventional granulator, high sheer granulator or fluid bed granulator. Drying of the wet granular mass is usually achieved in a fluid bed dryer.
  • this invention relates to an improved process for preparing Ferric organic compound tablets by a modified wet granulation technique; and especially, but not exclusively, tablets which have a high active matter content, in particular, tablets containing poorly compressible medicinally active matter.
  • a modified wet granulation technique involves no more than the incorporation of a granulating fluid into the mixed, powdery tablet ingredients (including at least some tabletting aids) in such an amount and manner as to convert them into a uniform, moist, coherent, non-pasty mass, which then is formed into moist granules of fairly uniform size, usually by forcing the mass through a screen. Thereafter the moist granules are dried and rescreened to break down agglomerates, and finally blended with other tabletting aids so as thus to arrive at the granulate ready for tabletting.
  • the invention provides a process for making the pharmaceutical compositions described herein by roller compaction process comprising the steps of weighing Ferric organic compound and excipients, screening, blending Ferric organic compound and excipients for a suitable amount of time; roller compacting the blend into ribbons and milling the ribbons into granules; blending the granules with extra-granular excipients for a suitable amount of time; compressing the blend into tablets; coating the tablets.
  • the method for producing a pharmaceutical composition comprises providing an admixture of solid forms, e.g. an admixture of powdered ingredients, the admixture comprising Ferric organic compound, a disintegrant and one or more excipients selected from: a dry binder, a glidant, a diluent, a lubricant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing/compacting the admixture into a granular form using a roller compactor using a dry granulation composition as set forth in the Examples below.
  • an admixture of solid forms e.g. an admixture of powdered ingredients, the admixture comprising Ferric organic compound, a disintegrant and one or more excipients selected from: a dry binder, a glidant, a diluent, a lubricant, and a filler
  • mixing the admixture until the
  • the method for producing a pharmaceutical composition comprises providing an admixture of solid forms, e.g. an admixture of powdered ingredients, the admixture comprising Ferric organic compound, a disintegrant and one or more excipients selected from: a binder, a glidant, a diluent, a lubricant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing/compacting the admixture into a granular form using a wet granulation composition as set forth in the Examples below.
  • an admixture of solid forms e.g. an admixture of powdered ingredients, the admixture comprising Ferric organic compound, a disintegrant and one or more excipients selected from: a binder, a glidant, a diluent, a lubricant, and a filler
  • mixing the admixture until the admixture is substantially homogen
  • Example 1 Ferric citrate formulation was prepared by using dry granulation technique, where L-HPC has been used as the disintegrant.
  • Example 2 Ferric citrate formulation was prepared by using dry granulation technique, where Crospovidone has been used as the disintegrant.
  • Example 3 Ferric citrate formulation was prepared by using dry granulation technique, where Croscarmellose sodium has been used as the disintegrant.
  • Example 4 Ferric citrate formulation was prepared by using dry granulation technique, where L-HPC has been used as the disintegrant.
  • Manufacturing Process a) The drug substance and dry binder were sifted and loaded into blender and blended for about 10 min, b) The intragranular lubricant was sifted and added to above step and blended for about 5 min, c) The above material was loaded into hopper of Compactor and compacted with suitable hardness of ribbons with preset roller RPM, GAP, Vertical and horizontal feeder screw speed. d) The above flakes were milled in multimill fitted with suitable screen at suitable speed and suitable direction, e) The milled material was sifted using suitable ASTM mesh. The compaction followed by milling process will be continued till desired particle size of granules obtained.
  • Example 5 Ferric citrate formulation was prepared by using wet granulation technique, where L-HPC has been used as the disintegrant.
  • Example 6 Ferric citrate formulation was prepared by using wet granulation technique, where crospovidone has been used as the disintegrant.
  • Example 7 Ferric citrate formulation was prepared by using wet granulation technique, where crospovidone has been used as the disintegrant.
  • Example 8 Ferric citrate formulation was prepared by using wet granulation technique, where L-HPC has been used as the disintegrant.
  • PROCESS a) The drug substance along with intragranular ingredients was sifted through # 20 ASTM. b) The binding agent was dissolved in purified water under stirring to get clear solution. c) Step no 1 material was loaded into top bowl of fluid bed processer and coated with step no b binder solution until consistence granules obtained. The set bed temperature during the process is 40 ° C ⁇ 10 ° C. d) The above material was dried at set inlet temperature 50 ° C ⁇ 10 ° C till target LOD achieved. e) The dried granules were sifted through # 18 ASTM mesh and retained are milled in multimill fitted with suitable screen at optimum speed and milled granules were sifted through # 18 ASTM.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne des compositions contenant un composé organique ferrique. Les compositions pharmaceutiques de l'invention comprennent du citrate ferrique en tant que principe actif, un agent de désintégration et un ou plusieurs excipients pharmaceutiquement acceptables, conjointement avec une couche de film facultative, le citrate ferrique ayant une surface BET de 6 à 12 m2/g.
PCT/IN2018/050441 2017-07-12 2018-07-07 Compositions de composés organiques ferriques Ceased WO2019012552A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741024528 2017-07-12
IN201741024528 2017-07-12

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WO2019012552A1 true WO2019012552A1 (fr) 2019-01-17
WO2019012552A4 WO2019012552A4 (fr) 2019-09-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114392249A (zh) * 2022-01-13 2022-04-26 上海医药集团青岛国风药业股份有限公司 一种多糖铁复合物的肠溶微丸及粉末直压片剂
WO2022251563A1 (fr) * 2021-05-27 2022-12-01 Keryx Biopharmaceuticals, Inc. Formulations pédiatriques de citrate ferrique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074444A2 (fr) * 2003-02-19 2004-09-02 Globoasia Llc Composes organiques ferriques, utilisations desdits composes et procedes de fabrication associes
WO2015110968A1 (fr) * 2014-01-23 2015-07-30 Lupin Limited Citrate ferrique de qualité pharmaceutique et son procédé de production
WO2016162794A1 (fr) * 2015-04-08 2016-10-13 Leiutis Pharmaceuticals Pvt Ltd Compositions pharmaceutiques de citrate ferrique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074444A2 (fr) * 2003-02-19 2004-09-02 Globoasia Llc Composes organiques ferriques, utilisations desdits composes et procedes de fabrication associes
WO2015110968A1 (fr) * 2014-01-23 2015-07-30 Lupin Limited Citrate ferrique de qualité pharmaceutique et son procédé de production
WO2016162794A1 (fr) * 2015-04-08 2016-10-13 Leiutis Pharmaceuticals Pvt Ltd Compositions pharmaceutiques de citrate ferrique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022251563A1 (fr) * 2021-05-27 2022-12-01 Keryx Biopharmaceuticals, Inc. Formulations pédiatriques de citrate ferrique
CN114392249A (zh) * 2022-01-13 2022-04-26 上海医药集团青岛国风药业股份有限公司 一种多糖铁复合物的肠溶微丸及粉末直压片剂
CN114392249B (zh) * 2022-01-13 2023-09-12 上海医药集团青岛国风药业股份有限公司 一种多糖铁复合物的肠溶微丸及粉末直压片剂

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