WO2017037645A1 - Stable pharmaceutical formulations of teriflunomide - Google Patents
Stable pharmaceutical formulations of teriflunomide Download PDFInfo
- Publication number
- WO2017037645A1 WO2017037645A1 PCT/IB2016/055231 IB2016055231W WO2017037645A1 WO 2017037645 A1 WO2017037645 A1 WO 2017037645A1 IB 2016055231 W IB2016055231 W IB 2016055231W WO 2017037645 A1 WO2017037645 A1 WO 2017037645A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- teriflunomide
- dosage form
- silicon dioxide
- tablet dosage
- pharmaceutical tablet
- Prior art date
Links
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 title claims abstract description 47
- 229960000331 teriflunomide Drugs 0.000 title claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 13
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- 239000000377 silicon dioxide Substances 0.000 claims description 10
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- 239000012530 fluid Substances 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 235000021472 generally recognized as safe Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- KHLVKKOJDHCJMG-QDBORUFSSA-L indigo carmine Chemical compound [Na+].[Na+].N/1C2=CC=C(S([O-])(=O)=O)C=C2C(=O)C\1=C1/NC2=CC=C(S(=O)(=O)[O-])C=C2C1=O KHLVKKOJDHCJMG-QDBORUFSSA-L 0.000 description 1
- 229960003988 indigo carmine Drugs 0.000 description 1
- 239000004179 indigotine Substances 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical class O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006824 pyrimidine synthesis Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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
- A61K31/275—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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2813—Inorganic compounds
Definitions
- Teriflunomide is the predominant active metabolite of Leflunomide, which has been marketed as a disease-modifying therapy for rheumatoid arthritis in the United States since September 1998. It is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), required for the de novo pyrimidine synthesis. As a consequence, Teriflunomide reduces the proliferation of dividing cells that need de novo synthesis of pyrimidine to expand.
- DHO-DH dihydroorotate dehydrogenase
- Teriflunomide (Z)-2-cyano-3-hydroxy-but-2-enoicacid- (4-trifluoromethylphenyl)-ami mical structure:
- Teriflunomide is formulated as film-coated tablets for oral administration and is available as Aubagio ® in the US. It is used for the treatment of patients with relapsing forms of multiple sclerosis.
- Aubagio tablets contain 7 mg or 14 mg of Teriflunomide, lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.
- the film coating for the 14 mg tablet is made of hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake. In addition to these, the 7 mg tablet film coating includes iron oxide yellow.
- U.S. patent 5,679,709 to Bartlett et al. discloses Teriflunomide compound and Teriflunomide composition useful for treating autoimmune diseases.
- U.S. patent 6,794,410 to Wettstein et al. discloses a method of treatment of multiple sclerosis with Teriflunomide or its stereoisomer, or a pharmaceutically acceptable salt thereof.
- U.S. patent 8,802,735 to Hauck et al. discloses a solid pharmaceutical composition of Teriflunomide.
- the patent teaches that Teriflunomide tablets cannot be made with colloidal silicon dioxide as it leads to an unstable product.
- the patent teaches that Teriflunomide tablets without colloidal silicon dioxide display significantly reduced formation of degradants, compared to Teriflunomide tablets containing colloidal silicon dioxide.
- the present invention is directed to stable formulations of Teriflunomide containing silicon dioxide.
- One aspect of the present invention is to provide stable pharmaceutical formulations of Teriflunomide, wherein the composition comprises colloidal silicon dioxide.
- Another aspect of the present invention is directed to the preparation of stable pharmaceutical formulations of Teriflunomide in the form of tablets comprising colloidal silicon dioxide with other pharmaceutically acceptable excipients.
- the present invention is directed to the preparation of stable pharmaceutical formulations of Teriflunomide comprising of colloidal silicon dioxide and other pharmaceutically acceptable excipients.
- Teriflunomide refers to the pharmaceutically acceptable derivatives, such as salts, solvates, hydrates and polymorphs thereof.
- the prior art references disclose that Teriflunomide tablets without colloidal silicon dioxide result in a product with lesser degradants compared to Teriflunomide tablets containing colloidal silicon dioxide.
- the presence of colloidal silicon dioxide in the formulation is preferred, as it is used to improve flowability.
- the present invention is directed to formulations of Teriflunomide tablets comprising colloidal silicon dioxide without adversely affecting the stability.
- colloidal silicon dioxide is submicroscopic fumed silica, also known as pyrogenic silica or silicon dioxide. Silicon dioxide is generally recognized as safe by the FDA.
- the present invention provides tablet dosage formulations of Teriflunomide comprising of colloidal silicon dioxide, diluent, disintegrant, binder, lubricant and optionally other pharmaceutically acceptable excipients.
- the percentage of silicon dioxide in the formulation ranges from about 0.01% to 3%, based on total weight of the formulation.
- the invention comprises one or more pharmaceutically acceptable excipients selected from the group consisting of granulating agents, solvents, glidants, surfactants, preservatives, pH adjusting agents, solubilizers, emulsifiers, plasticizers and the like.
- the number of excipients that can be included in a formulation is not limited.
- diluents/fillers include, but not limited to, celluloses, cellulose acetate, microcrystalline cellulose, co-processed microcrystalline celluloses (such as various grades of Avicel), silicified microcrystalline cellulose, dextrates, dextrin, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, glucose, trehalose, erythritol, fructose, calcium sulphate, dibasic calcium phosphate, talc and xylitol or a mixture of one or more of said diluents.
- celluloses cellulose acetate, microcrystalline cellulose, co-processed microcrystalline celluloses (such as various grades of Avicel), silic
- Suitable binders include, but not limited to, celluloses such as microcrystalline cellulose, modified celluloses such as low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, cellulose gum, xanthan gum, sugars (such as sucrose, glucose, amylose, maltodextrin, dextrose and the like), starches such as corn or potato starch, pregelatinized starches, polyvinyl alcohol- polyethylene glycol graft copolymer, copovidone, povidone, carbomers, polycarbophil, polyethylene oxide, polyethylene glycol or a combination of suitable binders.
- celluloses such as microcrystalline cellulose
- modified celluloses such as low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, cellulose gum, xanthan gum
- sugars
- disintegrants include, but not limited to starches, partially pregelatinized starches, sodium starch glycolate, pregelatinized starch, alginic acid, powdered cellulose, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, sodium alginate or a combination of one or more disintegrants.
- glidants include, but not limited to calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and the like.
- lubricants include, but not limited to, calcium stearate, zinc stearate, magnesium stearate, aluminium stearate, stearic acids, sodium stearyl fumarate, hydrogenated castor oil, light mineral oil, polyethylene glycol, magnesium lauryl sulfate and the like.
- the present invention also provides a method for preparing stable Teriflunomide tablets.
- Conventional processes such as direct compression, wet granulation (fluid bed granulation) and dry granulation (slugging and roll compaction) may be used.
- the compressed tablets are further film coated by non-aqueous coating or aqueous coating or by hydroalcoholic coating.
- This coating composition contains film-forming substances such as hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol; solvents, colloidal silicon dioxide, optionally other excipients such as plasticizers, lubricants and colourants.
- film-forming substances such as hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol; solvents, colloidal silicon dioxide, optionally other excipients such as plasticizers, lubricants and colourants.
- a preferred blend of hydroxypropyl methylcellulose, a plasticizer and a colorant is commercially available under the trade name Opadry ® .
- Colloidal silicon dioxide is added in the coating composition, to enhance disintegration and dissolution rate.
- Solvents used for granulation and coating can be either aqueous or non-aqueous solvents. Suitable non-aqueous solvents include, but are not limited to isopropyl alcohol, ethanol, dichloromethane, acetone and the like. Aqueous solvent include water.
- Teriflunomide tablet formulations prepared according to the invention were tested for dissolution using USP type II (Paddle) apparatus at 50 RPM at 37°C. Teriflunomide tablet formulation prepared without silicon dioxide was taken as a reference product. Comparative dissolution profiles of Teriflunomide tablet formulations prepared without silicon dioxide and Teriflunomide tablet formulations prepared with silicon dioxide were recorded and tabulated in table 1.
- Table 1 Comparative dissolution profile of Teriflunomide formulations.
- Teriflunomide, lactose monohydrate, corn starch, hydroxy propyl cellulose, micro crystalline cellulose, sodium starch glycolate and magnesium stearate were blended and co-sifted twice from sieve #40.
- the co-sifted material was compressed into pentagonal 8mm tablets.
- Finally the compressed tablets were coated with a coating composition comprising opadry blue and IPA: DCM (50:50).
- Teriflunomide, lactose monohydrate, corn starch, hydroxy propyl cellulose, micro crystalline cellulose, sodium starch glycolate and magnesium stearate were blended and co-sifted twice from sieve #40.
- the co-sifted material was compressed into pentagonal 8mm tablets.
- Finally the compressed tablets were coated with a coating composition comprising of colloidal silicon dioxide, opadry blue and IPA: DCM (50:50).
- Teriflunomide, lactose monohydrate, corn starch, hydroxy propyl cellulose, micro crystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate were blended and co-sifted twice from sieve #40.
- the co-sifted material was compressed into pentagonal 8mm tablets.
- Finally the compressed tablets were coated with a coating composition comprising of colloidal silicon dioxide, opadry blue and IPA: DCM (50:50).
- Binder solution paste was prepared mixing water and polyvinylpyrrolidone. Binder was added to preblend and granulated in rapid mixer granulator. The obtained granules were milled and dried in a fluid bed drier. The dried granules were further milled and lubricated with polyethylene glycol followed by compression. The compressed tablets were coated with a coating composition comprising of colloidal silicon dioxide and opadry blue in aqueous/non-aqueous solvents. For aqueous coating 15% w/w suspension was prepared with water. For nonaqueous coating 5% w/w suspension was prepared with dichloromethane: isopropanol (1:1).
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to stable pharmaceutical formulations of Teriflunomide tablets comprising of Teriflunomide, colloidal silicon dioxide and other pharmaceutically acceptable excipients. Further the invention describes method of preparing Teriflunomide tablets.
Description
STABLE PHARMACEUTICAL FORMULATIONS OF TERIFLUNOMIDE
Background of the invention
Teriflunomide is the predominant active metabolite of Leflunomide, which has been marketed as a disease-modifying therapy for rheumatoid arthritis in the United States since September 1998. It is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), required for the de novo pyrimidine synthesis. As a consequence, Teriflunomide reduces the proliferation of dividing cells that need de novo synthesis of pyrimidine to expand.
The chemical name of Teriflunomide is (Z)-2-cyano-3-hydroxy-but-2-enoicacid- (4-trifluoromethylphenyl)-ami mical structure:
Teriflunomide is formulated as film-coated tablets for oral administration and is available as Aubagio® in the US. It is used for the treatment of patients with relapsing forms of multiple sclerosis. Aubagio tablets contain 7 mg or 14 mg of Teriflunomide, lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate. The film coating for the 14 mg tablet is made of hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake. In addition to these, the 7 mg tablet film coating includes iron oxide yellow.
U.S. patent 5,679,709 to Bartlett et al., discloses Teriflunomide compound and Teriflunomide composition useful for treating autoimmune diseases.
U.S. patent 6,794,410 to Wettstein et al., discloses a method of treatment of multiple sclerosis with Teriflunomide or its stereoisomer, or a pharmaceutically acceptable salt thereof.
U.S. patent 8,802,735 to Hauck et al., discloses a solid pharmaceutical composition of Teriflunomide. The patent teaches that Teriflunomide tablets cannot be made with colloidal silicon dioxide as it leads to an unstable product. The patent teaches that Teriflunomide tablets without colloidal silicon dioxide display significantly reduced formation of degradants, compared to Teriflunomide tablets containing colloidal silicon dioxide.
The present invention is directed to stable formulations of Teriflunomide containing silicon dioxide.
Summary of the Invention
One aspect of the present invention is to provide stable pharmaceutical formulations of Teriflunomide, wherein the composition comprises colloidal silicon dioxide.
Another aspect of the present invention is directed to the preparation of stable pharmaceutical formulations of Teriflunomide in the form of tablets comprising colloidal silicon dioxide with other pharmaceutically acceptable excipients.
Detailed description of the Invention
The present invention is directed to the preparation of stable pharmaceutical formulations of Teriflunomide comprising of colloidal silicon dioxide and other pharmaceutically acceptable excipients.
In the context of this invention "Teriflunomide" refers to the pharmaceutically acceptable derivatives, such as salts, solvates, hydrates and polymorphs thereof.
The prior art references disclose that Teriflunomide tablets without colloidal silicon dioxide result in a product with lesser degradants compared to Teriflunomide tablets containing colloidal silicon dioxide. However, the presence of colloidal silicon dioxide in the formulation is preferred, as it is used to improve flowability. The present invention is directed to formulations of Teriflunomide tablets comprising colloidal silicon dioxide without adversely affecting the stability.
Colloidal silicon dioxide is submicroscopic fumed silica, also known as pyrogenic silica or silicon dioxide. Silicon dioxide is generally recognized as safe by the FDA.
The present invention provides tablet dosage formulations of Teriflunomide comprising of colloidal silicon dioxide, diluent, disintegrant, binder, lubricant and optionally other pharmaceutically acceptable excipients. The percentage of silicon dioxide in the formulation ranges from about 0.01% to 3%, based on total weight of the formulation.
The invention comprises one or more pharmaceutically acceptable excipients selected from the group consisting of granulating agents, solvents, glidants, surfactants, preservatives, pH adjusting agents, solubilizers, emulsifiers, plasticizers and the like. The number of excipients that can be included in a formulation is not limited.
Examples of diluents/fillers include, but not limited to, celluloses, cellulose acetate, microcrystalline cellulose, co-processed microcrystalline celluloses (such as various grades of Avicel), silicified microcrystalline cellulose, dextrates, dextrin, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, glucose, trehalose, erythritol, fructose, calcium sulphate, dibasic calcium phosphate, talc and xylitol or a mixture of one or more of said diluents.
Suitable binders include, but not limited to, celluloses such as microcrystalline cellulose, modified celluloses such as low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, cellulose gum, xanthan gum, sugars (such as sucrose,
glucose, amylose, maltodextrin, dextrose and the like), starches such as corn or potato starch, pregelatinized starches, polyvinyl alcohol- polyethylene glycol graft copolymer, copovidone, povidone, carbomers, polycarbophil, polyethylene oxide, polyethylene glycol or a combination of suitable binders.
Examples of disintegrants include, but not limited to starches, partially pregelatinized starches, sodium starch glycolate, pregelatinized starch, alginic acid, powdered cellulose, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, sodium alginate or a combination of one or more disintegrants.
Examples of glidants include, but not limited to calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and the like.
Examples of lubricants include, but not limited to, calcium stearate, zinc stearate, magnesium stearate, aluminium stearate, stearic acids, sodium stearyl fumarate, hydrogenated castor oil, light mineral oil, polyethylene glycol, magnesium lauryl sulfate and the like.
The present invention also provides a method for preparing stable Teriflunomide tablets. Conventional processes such as direct compression, wet granulation (fluid bed granulation) and dry granulation (slugging and roll compaction) may be used.
The compressed tablets are further film coated by non-aqueous coating or aqueous coating or by hydroalcoholic coating. This coating composition contains film-forming substances such as hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol; solvents, colloidal silicon dioxide, optionally other excipients such as plasticizers, lubricants and colourants. A preferred blend of hydroxypropyl methylcellulose, a plasticizer and a colorant is commercially
available under the trade name Opadry®. Colloidal silicon dioxide is added in the coating composition, to enhance disintegration and dissolution rate.
Solvents used for granulation and coating can be either aqueous or non-aqueous solvents. Suitable non-aqueous solvents include, but are not limited to isopropyl alcohol, ethanol, dichloromethane, acetone and the like. Aqueous solvent include water. Teriflunomide tablet formulations prepared according to the invention were tested for dissolution using USP type II (Paddle) apparatus at 50 RPM at 37°C. Teriflunomide tablet formulation prepared without silicon dioxide was taken as a reference product. Comparative dissolution profiles of Teriflunomide tablet formulations prepared without silicon dioxide and Teriflunomide tablet formulations prepared with silicon dioxide were recorded and tabulated in table 1.
Table 1: Comparative dissolution profile of Teriflunomide formulations.
From table 1 it is evident that formulations prepared with and without colloidal silicon dioxide exhibit a comparative dissolution profile.
Teriflunomide formulations prepared according to the invention and formulations prepared without silicon dioxide were tested for stability at 25 °C and 40°C for 1 month. The comparative stability data is summarized in table 2.
Table 2: Comparative stability data
RRT: Relative retention time
The data confirms the inventors' finding that the impurity profile of the invention product was comparable to that of the reference product.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof.
Example 1 - Reference example
Manufacturing process
Teriflunomide, lactose monohydrate, corn starch, hydroxy propyl cellulose, micro crystalline cellulose, sodium starch glycolate and magnesium stearate were blended and
co-sifted twice from sieve #40. The co-sifted material was compressed into pentagonal 8mm tablets. Finally the compressed tablets were coated with a coating composition comprising opadry blue and IPA: DCM (50:50).
Example 2 - F2
Manufacturing process
Teriflunomide, lactose monohydrate, corn starch, hydroxy propyl cellulose, micro crystalline cellulose, sodium starch glycolate and magnesium stearate were blended and co-sifted twice from sieve #40. The co-sifted material was compressed into pentagonal 8mm tablets. Finally the compressed tablets were coated with a coating composition comprising of colloidal silicon dioxide, opadry blue and IPA: DCM (50:50).
Example 3
6 Sodium starch glycolate 7.5 4.75
7 Magnesium stearate 0.5 0.32
8 Colloidal silicon dioxide 1.3 0.82
Film Coating Ingredients
9 Colloidal silicon dioxide 0.25 0.16
10 Opadry blue (non aqueous coating) suspension 7.75 4.91
11 IPA : DCM (50:50) q.s. q.s.
Manufacturing process
Teriflunomide, lactose monohydrate, corn starch, hydroxy propyl cellulose, micro crystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate were blended and co-sifted twice from sieve #40. The co-sifted material was compressed into pentagonal 8mm tablets. Finally the compressed tablets were coated with a coating composition comprising of colloidal silicon dioxide, opadry blue and IPA: DCM (50:50).
Example 4:
Manufacturing process:
Teriflunomide, dicalcium phosphate and crospovidone were co-sifted through sieve#60 and blended. Binder solution paste was prepared mixing water and polyvinylpyrrolidone. Binder was added to preblend and granulated in rapid mixer
granulator. The obtained granules were milled and dried in a fluid bed drier. The dried granules were further milled and lubricated with polyethylene glycol followed by compression. The compressed tablets were coated with a coating composition comprising of colloidal silicon dioxide and opadry blue in aqueous/non-aqueous solvents. For aqueous coating 15% w/w suspension was prepared with water. For nonaqueous coating 5% w/w suspension was prepared with dichloromethane: isopropanol (1:1).
Claims
We Claim
Claim 1: A stable pharmaceutical tablet dosage form of Teriflunomide, comprising of Teriflunomide, colloidal silicon dioxide and other pharmaceutically acceptable excipients.
Claim 2: A stable pharmaceutical tablet dosage form of Teriflunomide according to claim 1, wherein the percentage of colloidal silicon dioxide in the formulation ranges from about 0.01% to 3%, based on total weight of the formulation.
Claim 3: A stable pharmaceutical tablet dosage form of Teriflunomide, comprising of Teriflunomide, colloidal silicon dioxide, diluent, disintegrant, glidant/lubricant and other pharmaceutically acceptable excipients.
Claim 4: The pharmaceutical tablet dosage form of Teriflunomide according to claim 3, wherein said diluent is selected from the group comprising of celluloses, microcrystalline cellulose, co-processed microcrystalline celluloses, silicified microcrystalline cellulose, dextrates, dextrin, dextrose, kaolin, lactitol, lactose, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, glucose, trehalose, erythritol, fructose, maltose and dibasic calcium phosphate or a mixture of one or more of said diluents.
Claim 5: The pharmaceutical tablet dosage form of Teriflunomide according to claim 3, wherein said disintegrant is selected from the group comprising of crospovidone, sodium starch glycolate, starches, celluloses, methylcellulose, hydroxypropyl cellulose, croscarmellose sodium and or a mixture of one or more of said disintegrants.
Claim 6: The pharmaceutical tablet dosage form of Teriflunomide according to claim 3, wherein said glidant is selected from the group comprising of calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous and maize starch.
Claim 7: The pharmaceutical tablet dosage form of Teriflunomide according to claim 3, wherein said lubricant is selected from the group comprising of calcium stearate, zinc stearate, magnesium stearate, aluminium stearate, stearic acids and sodium stearyl fumarate.
Claim 8: The pharmaceutical tablet dosage form according to claims 1 and 3, wherein the tablet dosage form is film coated.
Claim 9: The pharmaceutical tablet dosage form according to claim 8, wherein the coating composition comprises of colloidal silicon dioxide and film coating substances.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN4638CH2015 | 2015-09-02 | ||
| IN4638/CHE/2015 | 2015-09-02 |
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| Publication Number | Publication Date |
|---|---|
| WO2017037645A1 true WO2017037645A1 (en) | 2017-03-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2016/055231 WO2017037645A1 (en) | 2015-09-02 | 2016-09-01 | Stable pharmaceutical formulations of teriflunomide |
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| Country | Link |
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| WO (1) | WO2017037645A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020005189A3 (en) * | 2018-06-27 | 2020-03-12 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions comprising teriflunomide |
| WO2020095319A1 (en) * | 2018-11-05 | 2020-05-14 | Sarudbhava Formulations Private Limited | Teriflunomide topical pharmaceutical compositions |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011032929A1 (en) * | 2009-09-18 | 2011-03-24 | Sanofi-Aventis | (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluormethylphenyl)-amide tablet formulations with improved stability |
| WO2013062442A2 (en) * | 2011-10-27 | 2013-05-02 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Composition for the treatment of multiple sclerosis (variants) |
-
2016
- 2016-09-01 WO PCT/IB2016/055231 patent/WO2017037645A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011032929A1 (en) * | 2009-09-18 | 2011-03-24 | Sanofi-Aventis | (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluormethylphenyl)-amide tablet formulations with improved stability |
| WO2013062442A2 (en) * | 2011-10-27 | 2013-05-02 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Composition for the treatment of multiple sclerosis (variants) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020005189A3 (en) * | 2018-06-27 | 2020-03-12 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions comprising teriflunomide |
| WO2020095319A1 (en) * | 2018-11-05 | 2020-05-14 | Sarudbhava Formulations Private Limited | Teriflunomide topical pharmaceutical compositions |
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