WO2016079687A1 - Oral pharmaceutical composition of teriflunomide - Google Patents
Oral pharmaceutical composition of teriflunomide Download PDFInfo
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- WO2016079687A1 WO2016079687A1 PCT/IB2015/058918 IB2015058918W WO2016079687A1 WO 2016079687 A1 WO2016079687 A1 WO 2016079687A1 IB 2015058918 W IB2015058918 W IB 2015058918W WO 2016079687 A1 WO2016079687 A1 WO 2016079687A1
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- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- teriflunomide
- silicon dioxide
- colloidal silicon
- oral pharmaceutical
- Prior art date
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- 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
Definitions
- the invention relates to an oral pharmaceutical composition and a process of preparing a pharmaceutical composition comprising teriflunomide, colloidal silicon dioxide and pharmaceutically acceptable excipients.
- Teriflunomide is a metabolite of leflunomide, with the chemical name (Z)-2-Cyano-3- hydroxy-but-2-enoic acid- 4'-trifluoromethylphenyl)-amide and represented by the formula I;
- Teriflunomide has been disclosed in US4965276, US5268382, US5459163 and US5679709. Teriflunomide is marketed by Sanofi Aventis under the trade name Aubagio ⁇ 1 in 7 m2 and 14 mg strengths; administered orally once daily, with or without food. Aubagio is indicated for the treatment of the patient with multiple sclerosis.
- US20120208880 addresses the issues of stability of teriflunomide in the pharmaceutical dosage form.
- degradants like 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide and 4-trifluoromethyl-aniline (4- TFMA).
- Said application necessitates the avoidance of colloidal silicon dioxide in the composition.
- the application further suggests the addition of acidic reacting compound to the composition to avoid the degradation due to colloidal silicon dioxide.
- the inventors of the present invention have surprisingly found that the pharmaceutical composition of teriflunomide containing colloidal silicon dioxide has improved stability profile without addition of any acidic reacting compound.
- the invention is directed to an oral pharmaceutical composition of teriflunomide.
- composition is free of acidic reacting compound.
- oral pharmaceutical composition contains no more than about 0.5% of 2-cyano- N-(4-trifluoromethyl-phenyl)-acetamide after storage at about 40°C and about 75% relative humidity for about 06 months.
- Another embodiment of the invention is an oral pharmaceutical composition
- an oral pharmaceutical composition comprising: a. teriflunomide
- an oral pharmaceutical composition comprising:
- pH of the pharmaceutical composition is greater than about 3.5.
- the invention relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising; teriflunomide, colloidal silicon dioxide and pharmaceutically acceptable excipients.
- Teiflunomide refers to teriflunomide as free base as well as pharmaceutically acceptable salts; derivatives; solvates; isomers or mixtures thereof.
- “Pharmaceutically acceptable salts” means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the invention.
- Teriflunomide is the generic name for the compound (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide.
- Teriflunomide can be used in the form in which it is chemically prepared, or it can be subjected to a process which changes the physical nature of the particles. For example, the material can be milled by any process known in the art.
- Teriflunomide is used from about 0.1% to about 50% based on total weight of composition, preferably from about 0.1% to about 30% based on total weight of composition.
- US 20120208880 discloses that the teriflunomide composition with colloidal silicon dioxide increases amount of degradants like 2-cyano-N-(4-trifluoromethyl- phenyl)-acetamide and 4-trifluoromethyl-aniline.
- the inventors of the present invention have surprisingly found that the presence of colloidal silicon dioxide in the composition does not have effect on the stability profile of the composition. Further the presence of colloidal silicon dioxide does not have any effect on the degradation of the teriflunomide in composition.
- Colloidal silicon dioxide can be used from about 0.01% to about 5%; preferably colloidal silicon dioxide is present in an amount from about 0.1% to about 3%, more preferably colloidal silicon dioxide is present in an amount from about 0.1% to about 1% based on total weight of composition.
- the colloidal silicon dioxide may be added intragranularly, extragranularly or may be present in the coating of the composition.
- Colloidal silicon dioxide is a 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 nm. The particles are non-porous and have a surface from 50 m 2 /g to 600 m 2 /g.
- Colloidal Silicon dioxide is synonymously
- Aerosil a silica .
- Cab-O-Sil Cab-O-Sil M-5P
- colloidal silica fumed silica; light anhydrous silicic acid; silicic anhydride; silicon dioxide fumed or Wacker HDK ® .
- pharmaceutically acceptable excipients refers to one or more non-active pharmaceutical ingredient substances such as binders, fillers or diluents, disintegrants, stabilizers, glidants and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration.
- the oral pharmaceutical composition of the invention may comprises from about 1% to about 50% of binder, about 1% to about 80% of fillers or diluents, about 1% to about 50% of disintegrants, about 0.1% to about 10% of glidants, and about 0.1% to about 10% of lubricants based on total weight of the composition.
- the oral pharmaceutical composition disclosed in the specification includes but not limited to tablets (single layered tablets, multi layered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules and microspheres, matrix formulations, microencapsulation powders and powder/pellets/granules for suspension.
- binders includes potato starch; pregelatinized starch; modified starch; wheat starch; corn starch; cereal starch, celluloses such as methyl cellulose hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, ethyl cellulose, carboxymethylcellulose and sodium carboxymethylcellulose; hydroxypropylstarch; polymethacrylates, carbomers; natural gums such as acacia, tragacanth, ceratonia, alginic acid and guar gum; lactose (anhydrous, monohydrate, spray dried); liquid glucose; dextrin; dextrates; maltodextrin; sodium alginate; povidone opovidone; polyethylene oxide; poly vinyl alcohol; polyethylene glycol; poly propylene glycol; sucrose; polydextrose; gelatin; glycerylbehenate; hydrogenated vegetable oil; zein; agar; chitosan; magnesium aluminum silicate; inulin; waxes
- fillers or diluents includes microcrystalline cellulose; lactose; lactose monohydrate; cellulose powdered; ethyl cellulose; cellulose silicified; cellulose acetate; methyl cellulose; dibasic or tribasic calcium phosphate; saccharides; compressible sugar; sugar spheres; dextrates; dextrin; dextrose; sucrose; fructose; maltose; mannitol; maltitol; xylitol; erythritol; isomalt; sorbitol; lactitol; sodium chloride; maltodextrin; glycerylpalmitostearate; magnesium aluminum silicate; starches; pregelatinized starch; sulfobutyletherP-cyclodextrin; polymethacrylates; talc; trehalose; hydrogenated vegetable oil; kaolin; ammonium alginate; calcium carbonate; magnesium carbonate, magnesium oxide and calcium
- the pharmaceutical composition of the invention may comprise from about 1 % to about 80% of filler or diluent.
- disintegrants includes povidone; low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; carboxymethylcellulose; cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrilin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; cellulose powdered; methyl cellulose; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate and colloidal silicon dioxide or a mixture of one or more of said disintegrants.
- the pharmaceutical composition of the invention may comprise from about 1% to about 50% of disintegrant, preferably form
- Example of stabilizers may include surfactants, chelating agents and/or antioxidants and preferably selected from glycerylmonostearate; ethylene glycol palmitostearate; glycerylmonooleate, alpha tocopherol; antioxidants such as butylatedhydroxyanisole, butylatedhydroxytoluene, sodium metabisulfite, potassium metabisulfite, sodium sulfite, propyl gallate and cysteine; chelating agents such as edetic acid, dipotassium edetate, disodium edetate, edetate calcium disodium, sodium edetate and trisodium edetate or a mixture of one or more of said stabilizers.
- the pharmaceutical composition of the invention may comprise from about 0.01% to about 20% of stabilizer.
- glidants includes magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide and silicon hydrogels or a mixture of one or more of said glidants.
- the pharmaceutical composition of the invention may comprise from about 0.1% to about 10% of glidant, preferably form about 0.1% to about 5% of glidant.
- lubricants include magnesium, aluminum, calcium or zinc stearate; polyethylene glycol; polyvinyl alcohol; glycerylbehenate; glycerylmonostearate; glycerylpalmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearylfumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; ethylene oxide polymers; poloxamer; octyldodecanol; sodium stearylfumarate and sodium lauryl sulfate or a mixture of one or more of said lubricants.
- the pharmaceutical composition of the invention may comprise from about 0.1% to about 10% of lubricant, preferably form about 0.1% to about 5% of lubricant.
- an oral pharmaceutical composition comprising about 0.1% to about 50% of teriflunomide, about 0.01% to about 5% of colloidal silicon dioxide; about 1% to about 50% of disintegrant, about 1% to about 50% of binder, about 0.1% to about 10% of lubricant and the remaining percentage comprising filler or diluent.
- the oral pharmaceutical composition comprises from about 1% to about 30% of teriflunomide, about 0.01% to about 5% of colloidal silicon dioxide; about 1% to about 20% of disintegrant, about 1% to about 30% of binder, about 0.1% to about 5% of lubricant and about 0.1% to about 80% of filler or diluent. All the percentages given are based on total weight of the composition.
- composition is free of acidic reacting compound.
- An "Acidic reacting compound” refers to organic acids.
- Examples of acidic reacting compound are 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, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, sulfonic acids, methanesulfonic acid and 2-hydroxyethanesulfonic acid or a mixture thereof.
- Another embodiment discloses an oral pharmaceutical composition comprising:
- pH of the pharmaceutical composition is greater than about 2.3, preferably greater than about 3.5, more preferably greater than about 4.5.
- the pharmaceutical composition is free of acidic reacting compound and the pH of the pharmaceutical composition is greater than about 2.3, preferably greater than about 3.5, more preferably greater than about 4.5.
- compositions described in various embodiments of the invention can be formed by various methods known in the art such as dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like.
- the process of dry granulation involves mixing of drug and excipients, the slugging process followed by milling, sizing, addition of extragranular excipients and lubrication.
- the process of wet granulation includes aqueous or non-aqueous granulation.
- the wet granulation process comprises admixing the active ingredient with the excipients, and granulating the blend with the binder mass to form the wet mass followed by drying and sizing.
- the binder may optionally be admixed with the dry blend and granulation performed with aqueous, non-aqueous solvent or mixture thereof.
- the solvent for the non-aqueous granulation includes but not limited to ethanol, isopropyl alcohol, dichlorome thane, acetonitrile, chloroform, ethyleneglycol, N-methyl- pyrrolidone and acetone or a mixture of one or more of non-aqueous solvents.
- the excipients may be added intragranularly, extragranularly or both. Further the granules can be coated by any suitable method.
- 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.
- the pharmaceutical composition is free of acidic reacting compound and 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.
- composition contains no more than about 0.2% or particularly no more than about 0.1% of 4-trifluoromethyl-aniline after storageat about 40°C and about 75% relative humidity for about 6 months.
- oral pharmaceutical composition comprising:
- 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.
- the pharmaceutical composition is free of acidic reacting compound and 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.
- the dosage forms may optionally be coated with one or more materials suitable to provide ease of swallowing, identification, appearance, protection of the composition and/or the regulation of drug release.
- film coating is provided for the ease of swallowing, identification, appearance and/or protection of the composition from moisture and/or light.
- the coating may include nonfunctional coating agents like carboxymethyl cellulose, methyl cellulose, hydroxyethyl methylcellulose, hydroxyethylcellulose, hydroxylpropyl methylcellulose, povidone, acrylate polymers, polydextrose and polyvinyl alcohol or a mixture of one or more of said polymers.
- the oral pharmaceutical composition disclosed in the specification is suitable for treating autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.
- the following examples can be prepared by any convenient method of preparation of oral pharmaceutical composition disclosed in the specification.
- the dissolution study was carried out in 0.05 M Phosphate Buffer, pH 6.8 using USP type II (Paddle) apparatus at 50 rpm.
Abstract
The invention relates to an oral pharmaceutical composition of teriflunomide for treatment of the subjects suffering from autoimmune diseases such as multiple sclerosis or rheumatoid arthritis. The oral pharmaceutical composition includes teriflunomide, colloidal silicon dioxide and pharmaceutically acceptable excipients.
Description
ORAL PHARMACEUTICAL COMPOSITION OF TERIFLUNOMIDE
FIELD OF INVENTION
The invention relates to an oral pharmaceutical composition and a process of preparing a pharmaceutical composition comprising teriflunomide, colloidal silicon dioxide and pharmaceutically acceptable excipients.
BACKGROUND OF INVENTION
Teriflunomide is a metabolite of leflunomide, with the chemical name (Z)-2-Cyano-3- hydroxy-but-2-enoic acid- 4'-trifluoromethylphenyl)-amide and represented by the formula I;
Formula I
Teriflunomide has been disclosed in US4965276, US5268382, US5459163 and US5679709. Teriflunomide is marketed by Sanofi Aventis under the trade name Aubagio^1 in 7 m2 and 14 mg strengths; administered orally once daily, with or without food. Aubagio is indicated for the treatment of the patient with multiple sclerosis.
US20120208880 addresses the issues of stability of teriflunomide in the pharmaceutical dosage form. At room temperature storage there is an increase in concentration of degradants like 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide and 4-trifluoromethyl-aniline (4- TFMA). Said application necessitates the avoidance of colloidal silicon dioxide in the composition. The application further suggests the addition of acidic reacting compound to the composition to avoid the degradation due to colloidal silicon dioxide.
The inventors of the present invention have surprisingly found that the pharmaceutical composition of teriflunomide containing colloidal silicon dioxide has improved stability profile without addition of any acidic reacting compound.
SUMMARY OF THE INVENTION
The invention is directed to an oral pharmaceutical composition of teriflunomide.
One embodiment of the invention is an oral pharmaceutical composition comprising:
a. teriflunomide,
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the composition is free of acidic reacting compound.
Other embodiment of the invention is an oral pharmaceutical composition comprising:
a. teriflunomide,
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the oral pharmaceutical composition contains no more than about 0.5% of 2-cyano- N-(4-trifluoromethyl-phenyl)-acetamide after storage at about 40°C and about 75% relative humidity for about 06 months.
Another embodiment of the invention is an oral pharmaceutical composition comprising: a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pH of the pharmaceutical composition is greater than about 2.3.
Another embodiment of the invention an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pH of the pharmaceutical composition is greater than about 3.5.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to an oral pharmaceutical composition comprising; teriflunomide, colloidal silicon dioxide and pharmaceutically acceptable excipients.
As used herein, the term "Teriflunomide" refers to teriflunomide as free base as well as pharmaceutically acceptable salts; derivatives; solvates; isomers or mixtures thereof.
"Pharmaceutically acceptable salts" means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the invention.
"Teriflunomide" is the generic name for the compound (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide. Teriflunomide can be used in the form in which it is chemically prepared, or it can be subjected to a process which changes the physical nature of the particles. For example, the material can be milled by any process known in the art. Teriflunomide is used from about 0.1% to about 50% based on total weight of composition, preferably from about 0.1% to about 30% based on total weight of composition.
As mentioned above, US 20120208880 discloses that the teriflunomide composition with colloidal silicon dioxide increases amount of degradants like 2-cyano-N-(4-trifluoromethyl- phenyl)-acetamide and 4-trifluoromethyl-aniline. However the inventors of the present invention have surprisingly found that the presence of colloidal silicon dioxide in the composition does not have effect on the stability profile of the composition. Further the presence of colloidal silicon dioxide does not have any effect on the degradation of the
teriflunomide in composition. Colloidal silicon dioxide can be used from about 0.01% to about 5%; preferably colloidal silicon dioxide is present in an amount from about 0.1% to about 3%, more preferably colloidal silicon dioxide is present in an amount from about 0.1% to about 1% based on total weight of composition. The colloidal silicon dioxide may be added intragranularly, extragranularly or may be present in the coating of the composition.
Also, US20120208880 describes that "Colloidal silicon dioxide" is a 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 nm. The particles are non-porous and have a surface from 50 m 2 /g to 600 m 2 /g.
As per Handbook of Pharmaceutical excipients, Colloidal Silicon dioxide is synonymously
® ® ®
called as Aerosil ; Cab-O-Sil ; Cab-O-Sil M-5P; colloidal silica; fumed silica; light anhydrous silicic acid; silicic anhydride; silicon dioxide fumed or Wacker HDK®.
The term "about" refers to plus or minus 10% by weight of the stated value.
The term "pharmaceutically acceptable excipients" refers to one or more non-active pharmaceutical ingredient substances such as binders, fillers or diluents, disintegrants, stabilizers, glidants and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration. The oral pharmaceutical composition of the invention may comprises from about 1% to about 50% of binder, about 1% to about 80% of fillers or diluents, about 1% to about 50% of disintegrants, about 0.1% to about 10% of glidants, and about 0.1% to about 10% of lubricants based on total weight of the composition.
The oral pharmaceutical composition disclosed in the specification includes but not limited to tablets (single layered tablets, multi layered tablets, mini tablets, bioadhesive tablets, caplets,
matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules and microspheres, matrix formulations, microencapsulation powders and powder/pellets/granules for suspension.
Examples of binders includes potato starch; pregelatinized starch; modified starch; wheat starch; corn starch; cereal starch, celluloses such as methyl cellulose hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, ethyl cellulose, carboxymethylcellulose and sodium carboxymethylcellulose; hydroxypropylstarch; polymethacrylates, carbomers; natural gums such as acacia, tragacanth, ceratonia, alginic acid and guar gum; lactose (anhydrous, monohydrate, spray dried); liquid glucose; dextrin; dextrates; maltodextrin; sodium alginate; povidone opovidone; polyethylene oxide; poly vinyl alcohol; polyethylene glycol; poly propylene glycol; sucrose; polydextrose; gelatin; glycerylbehenate; hydrogenated vegetable oil; zein; agar; chitosan; magnesium aluminum silicate; inulin; waxes and sunflower oil or a mixture of one or more of said binders. The pharmaceutical composition of the invention may comprise from about 1% to about 50% of binder, preferably from about 1% to about 30% of binder.
Examples of fillers or diluents includes microcrystalline cellulose; lactose; lactose monohydrate; cellulose powdered; ethyl cellulose; cellulose silicified; cellulose acetate; methyl cellulose; dibasic or tribasic calcium phosphate; saccharides; compressible sugar; sugar spheres; dextrates; dextrin; dextrose; sucrose; fructose; maltose; mannitol; maltitol; xylitol; erythritol; isomalt; sorbitol; lactitol; sodium chloride; maltodextrin; glycerylpalmitostearate; magnesium aluminum silicate; starches; pregelatinized starch; sulfobutyletherP-cyclodextrin; polymethacrylates; talc; trehalose; hydrogenated vegetable oil; kaolin; ammonium alginate; calcium carbonate; magnesium carbonate, magnesium oxide and calcium sulphate or a mixture of one or more of said diluents. The pharmaceutical composition of the invention may comprise from about 1 % to about 80% of filler or diluent.
Examples of disintegrants includes povidone; low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; carboxymethylcellulose; cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrilin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; cellulose powdered; methyl cellulose; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate and colloidal silicon dioxide or a mixture of one or more of said disintegrants. The pharmaceutical composition of the invention may comprise from about 1% to about 50% of disintegrant, preferably form about 1% to about 20% of disintegrant.
Example of stabilizers may include surfactants, chelating agents and/or antioxidants and preferably selected from glycerylmonostearate; ethylene glycol palmitostearate; glycerylmonooleate, alpha tocopherol; antioxidants such as butylatedhydroxyanisole, butylatedhydroxytoluene, sodium metabisulfite, potassium metabisulfite, sodium sulfite, propyl gallate and cysteine; chelating agents such as edetic acid, dipotassium edetate, disodium edetate, edetate calcium disodium, sodium edetate and trisodium edetate or a mixture of one or more of said stabilizers.The pharmaceutical composition of the invention may comprise from about 0.01% to about 20% of stabilizer.
Examples of glidants includes magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide and silicon hydrogels or a mixture of one or more of said glidants.The pharmaceutical composition of the invention may comprise from about 0.1% to about 10% of glidant, preferably form about 0.1% to about 5% of glidant.
Examples of lubricants include magnesium, aluminum, calcium or zinc stearate; polyethylene glycol; polyvinyl alcohol; glycerylbehenate; glycerylmonostearate; glycerylpalmitostearate;
potassium benzoate; sodium benzoate; mineral oil; sodium stearylfumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; ethylene oxide polymers; poloxamer; octyldodecanol; sodium stearylfumarate and sodium lauryl sulfate or a mixture of one or more of said lubricants. The pharmaceutical composition of the invention may comprise from about 0.1% to about 10% of lubricant, preferably form about 0.1% to about 5% of lubricant.
One embodiment discloses an oral pharmaceutical composition comprising about 0.1% to about 50% of teriflunomide, about 0.01% to about 5% of colloidal silicon dioxide; about 1% to about 50% of disintegrant, about 1% to about 50% of binder, about 0.1% to about 10% of lubricant and the remaining percentage comprising filler or diluent. Preferably the oral pharmaceutical composition comprises from about 1% to about 30% of teriflunomide, about 0.01% to about 5% of colloidal silicon dioxide; about 1% to about 20% of disintegrant, about 1% to about 30% of binder, about 0.1% to about 5% of lubricant and about 0.1% to about 80% of filler or diluent. All the percentages given are based on total weight of the composition.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pharmaceutical composition is free of acidic reacting compound.
An "Acidic reacting compound" refers to organic acids. Examples of acidic reacting compoundare 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, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, sulfonic acids, methanesulfonic acid and 2-hydroxyethanesulfonic acid or a mixture thereof.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pH of the pharmaceutical composition is greater than about 2.3, preferably greater than about 3.5, more preferably greater than about 4.5.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pharmaceutical composition is free of acidic reacting compound and the pH of the pharmaceutical composition is greater than about 2.3, preferably greater than about 3.5, more preferably greater than about 4.5.
The oral pharmaceutical compositions described in various embodiments of the invention can be formed by various methods known in the art such as dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like.
The process of dry granulation involves mixing of drug and excipients, the slugging process followed by milling, sizing, addition of extragranular excipients and lubrication. The process of wet granulation includes aqueous or non-aqueous granulation. The wet granulation process comprises admixing the active ingredient with the excipients, and granulating the blend with the binder mass to form the wet mass followed by drying and sizing. The binder may optionally be admixed with the dry blend and granulation performed with aqueous, non-aqueous solvent or mixture thereof. The solvent for the non-aqueous
granulation includes but not limited to ethanol, isopropyl alcohol, dichlorome thane, acetonitrile, chloroform, ethyleneglycol, N-methyl- pyrrolidone and acetone or a mixture of one or more of non-aqueous solvents. The excipients may be added intragranularly, extragranularly or both. Further the granules can be coated by any suitable method.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein 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.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. Teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pharmaceutical composition is free of acidic reacting compound and 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.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pharmaceutical composition contains no more than about 0.2% or particularly no more than about 0.1% of 4-trifluoromethyl-aniline after storageat about 40°C and about 75% relative humidity for about 6 months.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide
c. stabilizer(s) and
d. pharmaceutically acceptable excipients,
wherein 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.
Another embodiment discloses an oral pharmaceutical composition comprising:
a. teriflunomide
b. colloidal silicon dioxide
c. stabilizer(s) and
d. pharmaceutically acceptable excipients,
wherein the pharmaceutical composition is free of acidic reacting compound and 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.
In another embodiment the dosage forms may optionally be coated with one or more materials suitable to provide ease of swallowing, identification, appearance, protection of the composition and/or the regulation of drug release. In another embodiment, film coating is provided for the ease of swallowing, identification, appearance and/or protection of the composition from moisture and/or light. The coating may include nonfunctional coating agents like carboxymethyl cellulose, methyl cellulose, hydroxyethyl methylcellulose, hydroxyethylcellulose, hydroxylpropyl methylcellulose,
povidone, acrylate polymers, polydextrose and polyvinyl alcohol or a mixture of one or more of said polymers.
The oral pharmaceutical composition disclosed in the specification is suitable for treating autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.
The invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
The following examples can be prepared by any convenient method of preparation of oral pharmaceutical composition disclosed in the specification. The dissolution study was carried out in 0.05 M Phosphate Buffer, pH 6.8 using USP type II (Paddle) apparatus at 50 rpm.
Comparative Example 01 :
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 58.33
Pregelatinized starch 16.67
Citric Acid 1.67
Hydroxypropyl cellulose 3.33
Macrocrystalline cellulose 10.00
Croscarmellose Sodium 4.50
Colloidal Silicon Dioxide 0.33
Magnesium stearate 0.50
Comparative Example 02:
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 50.00
Pregelatinized starch 10.00
Citric Acid 16.67
Hydroxypropyl cellulose 3.33
Microcrystalline cellulose 10.00
Croscarmellose Sodium 4.50
Colloidal Silicon Dioxide 0.33
Magnesium stearate 0.50
Example 01 :
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 60.00
Pregelatinized starch 20.00
Hydroxypropyl cellulose 3.33
Microcrystalline cellulose 6.67
Croscarmellose Sodium 4.50
Colloidal Silicon Dioxide 0.33
Magnesium stearate 0.50
Example 02:
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 59.40
Pregelatinized starch 13.33
Hydroxypropyl cellulose 2.33
Microcrystalline cellulose 13.33
Butylated Hydroxy Anisole 0.17
Croscarmellose Sodium 5.17
Colloidal Silicon Dioxide 0.93
Stearic acid 0.67
Example 03:
Ingredients %w/w
Teriflunomide 4.67
Mannitol 60.00
Pregelatinized starch 20.00
Hydroxypropyl cellulose 3.33
Microcrystalline cellulose 6.67
Croscarmellose Sodium 4.50
Colloidal Silicon Dioxide 0.33
Magnesium stearate 0.50
Example 04:
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 60.00
Pregelatinized starch 13.33
Hydroxypropyl cellulose 2.33
Microcrystalline cellulose 13.33
Butylated Hydroxy Anisole 0.17
Croscarmellose Sodium 5.17
Colloidal Silicon Dioxide 0.33
Stearic acid 0.67
Example 05:
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 59.90
Pregelatinized starch 13.33
Hydroxypropyl cellulose 2.47
Microcrystalline cellulose 13.33
Butylated Hydroxy Anisole 0.10
Croscarmellose Sodium 5.00
Colloidal Silicon Dioxide 0.20
Stearic acid 1.00
Example 06:
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 60.00
Pregelatinized starch 16.67
Hydroxypropyl cellulose 3.33
Microcrystalline cellulose 9.33
Croscarmellose Sodium 4.50
Colloidal Silicon Dioxide 0.33
Edetic Acid 0.67
Magnesium stearate 0.50
Example 07:
Ingredients %w/w
Teriflunomide 4.67
Lactose Monohydrate 59.66
Pregelatinized starch 13.33
Hydroxypropyl cellulose 2.33
Microcrystalline cellulose 13.33
Butylated Hydroxy Anisole 0.17
Croscarmellose Sodium 5.17
Colloidal Silicon Dioxide 0.67
Stearic acid 0.67
Example 08:
Ingredients %w/w
Teriflunomide 3.50
Lactose Monohydrate 60.00
Pregelatinized starch 20.00
Hydroxypropyl cellulose 2.50
Microcrystalline cellulose 10.00
Croscarmellose Sodium 3.38
Colloidal Silicon Dioxide 0.25
Magnesium stearate 0.37
Example 09:
Ingredients %w/w
Teriflunomide 7.00
Lactose Monohydrate 60.00
Pregelatinized starch 15.00
Hydroxypropyl cellulose 2.70
Macrocrystalline cellulose 10.00
Croscarmellose Sodium 4.50
Colloidal Silicon Dioxide 0.30
Magnesium stearate 0.50
Claims
Claim 1: An oral pharmaceutical composition comprising teriflunomide, colloidal silicon dioxide and pharmaceutically acceptable excipients, wherein the composition is free of acidic reacting compound.
Claim 2: The composition according to claim 1 wherein the pharmaceutically acceptable excipients are selected from the group comprising of binders, diluents, disintegrants, stabilizers, glidants and lubricants.
Claim 3: The composition according to claim 1 comprising about 1% to about 50% teriflunomide, about 0.01% to about 5% colloidal silicon dioxide; about 1% to about 50% disintegrant, about 1% to about 50% binder, about 0.1% to about 5% lubricant and about 1% to about 80% of fillers or diluents.
Claim 4: The composition according to claim 1 wherein the oral pharmaceutical composition contains no more than about 0.5% of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after storage at about 40°C and about 75% relative humidity for about 06 months. Claim 5:An oral pharmaceutical composition comprising;
a. teriflunomide
b. colloidal silicon dioxide and
c. pharmaceutically acceptable excipients,
wherein the pH of the pharmaceutical composition is greater than about 2.3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3637MU2014 | 2014-11-18 | ||
| IN3637/MUM/2014 | 2014-11-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016079687A1 true WO2016079687A1 (en) | 2016-05-26 |
Family
ID=56013367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2015/058918 WO2016079687A1 (en) | 2014-11-18 | 2015-11-18 | Oral pharmaceutical composition of teriflunomide |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2016079687A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017056104A1 (en) * | 2015-09-28 | 2017-04-06 | Natco Pharma Limited | Stable pharmaceutical compositions of teriflunomide |
| EP3813822A4 (en) * | 2018-06-27 | 2022-03-16 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions comprising teriflunomide |
| WO2022098828A1 (en) * | 2020-11-05 | 2022-05-12 | Exelixis, Inc. | Pharmaceutical compositions of a kinase inhibitor |
| US11723896B2 (en) | 2017-03-14 | 2023-08-15 | Actelion Pharmaceuticals Ltd | Pharmaceutical combination comprising ponesimod |
Citations (1)
| 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 |
-
2015
- 2015-11-18 WO PCT/IB2015/058918 patent/WO2016079687A1/en active Application Filing
Patent Citations (1)
| 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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017056104A1 (en) * | 2015-09-28 | 2017-04-06 | Natco Pharma Limited | Stable pharmaceutical compositions of teriflunomide |
| US11723896B2 (en) | 2017-03-14 | 2023-08-15 | Actelion Pharmaceuticals Ltd | Pharmaceutical combination comprising ponesimod |
| EP3813822A4 (en) * | 2018-06-27 | 2022-03-16 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions comprising teriflunomide |
| WO2022098828A1 (en) * | 2020-11-05 | 2022-05-12 | Exelixis, Inc. | Pharmaceutical compositions of a kinase inhibitor |
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