WO2017125841A1 - Compositions pharmaceutiques de tériflunomide - Google Patents

Compositions pharmaceutiques de tériflunomide Download PDF

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Publication number
WO2017125841A1
WO2017125841A1 PCT/IB2017/050214 IB2017050214W WO2017125841A1 WO 2017125841 A1 WO2017125841 A1 WO 2017125841A1 IB 2017050214 W IB2017050214 W IB 2017050214W WO 2017125841 A1 WO2017125841 A1 WO 2017125841A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition
teriflunomide
pharmaceutically acceptable
silicon dioxide
Prior art date
Application number
PCT/IB2017/050214
Other languages
English (en)
Inventor
Deepak Pragjibhai GONDALIYA
Ketan Tulsidas SAVJANI
Harshil Prakashbhai SHAH
Anshuman Anil AMBIKE
Mukund Keshav Gurjar
Original Assignee
Emcure Pharmaceuticals Limited
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 Emcure Pharmaceuticals Limited filed Critical Emcure Pharmaceuticals Limited
Publication of WO2017125841A1 publication Critical patent/WO2017125841A1/fr

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Classifications

    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof and the methods of preparing such compositions.
  • Teriflunomide is an immunomodulatory agent which is approved for the treatment of patients with relapsing forms of multiple sclerosis. Chemically, Teriflunomide is (Z)- 2-Cyano-3-hydroxy-but-2-enoic acid-( -trifluoromethylphenyl)-amide and has the foil owing structure:
  • Bartiett et al in US 4,965,276 discloses Teriflunomide and its use in treating chronic graft-versus-host disease.
  • the synthesis of Teriflunomide has been disclosed in US 5,990,141 by Hirth et al.
  • US 5,459,163 and US 5,679,709 of Bartiett et al discloses compositions useful for treating autoimmune diseases in particular lupus erythematosus.
  • Wettstein et al in E P 1,381,356 discloses the use of Teriflunomide for the manufacture of a medicamentfor treating multiple sclerosis wherein said medicament is administered orally.
  • WO 2007/118684 of Ruchatz Dieter discloses Leflunomide containing solid pharmaceutical compositions including an organic or inorganic acid characterized by improved stability. The decompositions of Leflunomide to Teriflunomide when compared with that in commercial Arava ⁇ tablets is minimized by acidic substances.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceuti cal ly acceptabl e salts thereof.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof which is independent of critical vagaries of colloidal silicon dioxide.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof wherein the composition has a pH of more than 2.2. More preferably, the pH of the formulation is in the range of 4.5 to 7.0.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof comprising colloidal silicon dioxide and has a pH of the composition more than 2.2.
  • the present formulation contains up to 1% w/W of colloidal silicon dioxide.
  • the colloidal silicon dioxide content ranges from about 0.1% w/W to about 0.8% w/W of solid pharmaceutical composition and preferably from about 0.3% w/W to about 0.7% w/W of solid pharmaceutical composition and even more preferably from about 0.5% w/W to about 0.6% w/W of solid pharmaceutical composition.
  • the present invention relates to solid pharmaceutical composition
  • solid pharmaceutical composition comprising about 1% w/W to about 30% w/W Teriflunomide, or a pharmaceutically acceptable salt thereof, about 0.1% w/W to about 1.0% w/W colloidal silicon dioxide, about 3% w/W to about 20% w/W disintegrant, about 0% w/W to about 40% w/W binder, about 0.1% w/W to about 2% w/W lubricant and the remai ni ng percentage comprisi ng di I uents.
  • the present invention relates to methods of preparing such compositions.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof and method of preparation of such compositions.
  • Teriflunomide means the chemical compound (Z)-2- Cyano-3-hydroxy-but-2-enoic aci d-(4-trifl uoromethy I phenyl )-amide.
  • various salts, polymorphs, enantiomers, stereoisomers could also be used. Further the compound could be used as amorphous, crystalline or mixtures thereof.
  • Colloidal silicon dioxide refers to submicroscopic fumed silica, also known as pyrogenic silica. It is a non-crystalline, fine grain, low density and high surface area silica. Primary particle size is from 5 nm to 50 n
  • the term ' Degradant . or ' impurity refers to any drug-based materials generated after the preparation of the unit dosage form.
  • One such degradant observed during stability studies is 2-cyano-N-( -trifluoromethyl-phenyl)-acetamide. Analysis of impurities and degradant is done using H PLC techniques on extracted samples as is known in the art
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof which is independent of critical vagaries of colloidal silicon dioxide.
  • the present formulation contains up to 1% w/W of colloidal silicon dioxide.
  • the colloidal silicon dioxide content ranges from about 0.1% w/W to about 0.8% w/W of solid pharmaceutical composition and preferably from about 0.3% w/w to about 0.7% w/W of solid pharmaceutical composition and even more preferably from about 0.5% w/W to about 0.6% w/W of solid pharmaceutical composition.
  • the colloidal silicon dioxide is present in the core of the tablet; however, it may be present i n the coati ng of the tabl et.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof and having the pH of the formulation more than about 2.2. More preferably, the pH of the formulation is in the range of 4.5 to 7.0, when water is adsorbed to the pharmaceutical composition or when water is added in small amounts to the pharmaceutical composition.
  • the pH determination is performed by suspending one tablet in about 1 ml of purified water. The pH of the supernatant is determined with a pH sensitive probe.
  • the pH of the composition is adjusted by adding either acidifying or alkalinizing agents.
  • the acidifying or alkalinizing agents are present i n the present formulati on i n an amount of about 0.01 % w/W to about 20% w/W of pharmaceutical composition.
  • the suitable acidifying agents may be organic or inorganic compounds.
  • suitable acidifying agents include, but are not limited to, citric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxy benzoic acid, phenyl acetic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, sulfonic acids, methanesulfonic acid and 2-hydroxyethanesulfonic acid or a mixture of one or more of said acidic reacting compounds.
  • the suitable alkalinizing agents which could be utilized in the formulation of present invention could be any basic compounds which are normally utilized in the pharmaceutical compositions. Suitable examples of such agents include, but are not limited to, basic salts of sodium, potassium, aluminum, magnesium, calcium.
  • the preferred alkalinizing agents are selected from meglumine, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminate metasilicate, magnesium silicate, magnesium aluminate, calcium carbonate, calcium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide or a mixture of one or more said basic inorganic salts.
  • the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof comprising colloidal silicon dioxide and has a pH of the composition more than 2.2.
  • the pharmaceutical composition of Teriflunomide or pharmaceutically acceptable salts thereof according to present invention comprises of suitable excipients such as binders, disintegrants, antioxidants and lubricants.
  • the suitable disintegrants are selected from the carboxymethyl cellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methyl cellulose, polacrilin potassium, sodium alginate, sodium starch glycolate or a mixture of one or more of said disintegrants, wherein the amount of disintegrant is from about 3% w/W to about 20% w/W of pharmaceutical composition.
  • the suitable binders are selected from acacia, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrin, gelatin, guar gum, hydroxypropyl methyl cellulose, maltodextrin, methyl cellulose, sodium alginate, pregelatinized starch, starches such as potato starch, corn starch or cereal starch and zein or a mixture of one or more of said binders, wherein the amount of binder is up to about 40% w/W of pharmaceutical composition.
  • the suitable lubricants are selected from calcium stearate, glyceryl pa!mitostearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate or a mixture of one or more of said lubricants, wherein the amount of ubricant is from about 0.1% w/W to about 2.0% w/W of pharmaceutical composition.
  • antioxidants such as citric acid, ascorbic acid, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, ethyl enedi amine tetraacetic acid, thioglycerol and thioglycollic acid are useful to prevent the degradation and reduce the impurity formation in the present formulation.
  • the antioxidant can be provided at a concentration in the range of, for example, about 0.001 wt% to about 1 wt%, or about 0.01 to about 0.5 wt% of the material in which it is dispensed.
  • the present invention relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising
  • compositions of the present invention can further be coated with non-functional coatings like hypromellose based coatings, sugar, shellac, or other enteric coating agents.
  • non-functional coatings like hypromellose based coatings, sugar, shellac, or other enteric coating agents.
  • the compositions disclosed herein can be in a form chosen from, for example, tablets, capsules, and powders.
  • compositions of the present invention may be prepared by suitable conventional dry or wet process.
  • suitable conventional dry or wet process for example,
  • the pharmaceutical composition contains no more than about 0.5% or particularly no more than about 0.2% of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after storage at about 40 °C and about 75% relative humidity for about 6 months. Further the total impurities are less than 1% or more preferably less than 0.5% after storage at about 40 °C and about 75% relative humidity for about 6 months.
  • Teriflunomide is mixed with hydroxypropyl cellulose, lactose and corn starch. This mixture is granulated with water in rapid mixer granulator. Granules then dried at 55eC until the desired LOD is attained. Dried granules further blended with microcrystalline cellulose and sodium starch glycolate. The blend is lubricated with magnesium stearate. Lubricated blend further mixed with colloidal silicon dioxide and compressed using suitable dies and punches. Compressed tablets were coated with Opadry blue solution until the desired weight is achieved. The pH of the solid pharmaceutical composition is observed to be more than about 2.2.
  • Example-2 Example-2
  • Example 2 The above test composition of Example 2 is prepared by following method:
  • Teriflunomide is mixed with, Crospovidone, lactose and corn starch. This mixture is granulated with water in rapid mixer granulator. Granules then dried at 55eC until the desired LOD is attained. Dried granules further blended with Crospovidone and Colloidal Silicon Dioxide. The blend is lubricated with magnesium stearate and compressed using suitable dies and punches. Compressed tablets were coated with Opadry green solution until the desired weight is achieved. The pH of the solid pharmaceutical composition is observed to be more than about 2.2.
  • Example 3 The above test composition of Example 3 is prepared by following method as described in Example 1. Except that colloidal silicon dioxide is dispersed in the coating solution before coating the compressed tablets. The pH of the above solid pharmaceutical composition is observed to be more than about 2.2.
  • Example 4 The above test composition of Example 4 is prepared using the process same as described in Example 1. Except that colloidal silicon dioxide is dispersed in the coating solution before coating the compressed tablets. The pH of the above solid pharmaceuti cal compositi on i s observed to be more than about 2.2.
  • Example 6 The above test composition of Example 5 is prepared using the process same as described in Example 1. The pH of the above solid pharmaceutical composition is observed to be more than about 2.2.
  • Example-6 The pH of the above solid pharmaceutical composition is observed to be more than about 2.2.
  • Example 6 The above test composition of Example 6 is prepared using the process same as described in Example 1. The pH of the above solid pharmaceutical composition is observed to be more than about 4.5.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques de tériflunomide ou des sels pharmaceutiquement acceptables de ce dernier, et un procédé de préparation de telles compositions. En règle générale, la composition selon la présente invention comprend entre environ 1 % en poids et environ 30 % en poids de tériflunomide, ou d'un sel pharmaceutiquement acceptable de ce dernier, entre environ 0,1 % en poids et environ 0,8 % en poids de dioxyde de silicium colloïdal, entre environ 5 % en poids et environ 20 % en poids d'un délitant, entre environ 0 % en poids et environ 40 % en poids de liant, entre environ 0,1 % en poids et environ 2 % en poids de lubrifiant, le pourcentage restant comprenant des diluants et éventuellement des agents permettant d'ajuster le pH de la composition dans une plage située entre environ 4,5 et 7,0.
PCT/IB2017/050214 2016-01-20 2017-01-16 Compositions pharmaceutiques de tériflunomide WO2017125841A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201621002138 2016-01-20
IN201621002138 2016-01-20

Publications (1)

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WO2017125841A1 true WO2017125841A1 (fr) 2017-07-27

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020095319A1 (fr) * 2018-11-05 2020-05-14 Sarudbhava Formulations Private Limited Compositions pharmaceutiques topiques de tériflunomide
WO2022128156A1 (fr) * 2020-12-15 2022-06-23 Pharmathen S.A. Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011032929A1 (fr) * 2009-09-18 2011-03-24 Sanofi-Aventis Formulations de comprimés de (4'-trifluorométhylphényl)-amide de l'acide (z)-2-cyano-3-hydroxy-but-2-énoïque de stabilité améliorée

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011032929A1 (fr) * 2009-09-18 2011-03-24 Sanofi-Aventis Formulations de comprimés de (4'-trifluorométhylphényl)-amide de l'acide (z)-2-cyano-3-hydroxy-but-2-énoïque de stabilité améliorée

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020095319A1 (fr) * 2018-11-05 2020-05-14 Sarudbhava Formulations Private Limited Compositions pharmaceutiques topiques de tériflunomide
WO2022128156A1 (fr) * 2020-12-15 2022-06-23 Pharmathen S.A. Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation

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