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)-amide and has the following chemical 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.
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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
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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.
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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.
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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.

Dissolution Time Points (Mins) Percentage of Teriflunomide dissolved (%)

Reference product (F1) Invention product (F2)
5 28 23
10 66 65
15 67 78
20 82 85
30 88 91
45 92 95
60 95 99
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 25°C (1 Month) 40°C (1 Month)

Reference product (F1) Invention product (F2) Reference product (F1) Invention product (F2)
0.82 0.01 ND ND ND
1.17 0.02 0.03 0.03 0.03
% Total Impurities 0.03 0.03 0.03 0.03
*RRT: Relative retention time
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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 F1

S.No Ingredients Qty/Tab (mg)
1 Teriflunomide 14
2 Lactose monohydrate 76
3 Corn Starch 38
4 Hydroxy propyl cellulose 3.5
5 Micro crystalline cellulose 10.5
6 Sodium starch glycolate 7.5
7 Magnesium stearate 0.5
Film Coating Ingredients
8 Opadry blue (non aqueous coating) suspension 6
9 Isopropyl alcohol (IPA): Dichloro methane (DCM) (50:50) q.s.
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

S.No Ingredients Qty/Tab (mg) % w/w
1 Teriflunomide 14 8.97
2 Lactose monohydrate 76 48.70
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3 Corn starch 38 24.35
4 Hydroxy propyl cellulose 3.5 2.24
5 Micro crystalline cellulose 10.5 6.73
6 Sodium starch glycolate 7.5 4.81
7 Magnesium stearate 0.5 0.32
Film Coating Ingredients
8 9 10 Colloidal silicon dioxide 0.06 0.04

Opadry blue (non aqueous coating) suspension 6 3.84

Isopropyl alcohol (IPA): Dichloro methane (DCM) (50:50) q.s. q.s.
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

S.No Ingredients Qty/Tab (mg) % w/w
1 Teriflunomide 14 8.86
2 Lactose monohydrate 74.7 47.28
3 Corn Starch 38 24.05
4 Hydroxy propyl cellulose 3.5 2.22
5 Micro crystalline cellulose 10.5 6.65
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.
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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:

S.No Ingredients Qty/Tab (mg) % w/w
1 Teriflunomide 14 9.02
2 Dicalcium phosphate 90 57.97
3 Polyvinylpyrrolidone 38 24.48
4 Crospovidone 7.5 4.83
5 Polyethylene Glycol 4000 0.5 0.32
Coating composition
6 Colloidal Silicon Dioxide 0.16 0.10
7 Opadry 5.09 3.28
8 Water/ DCM: IPA (1:1) q.s q.s
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 non-aqueous coating 5% w/w suspension was prepared with dichloromethane: isopropanol (1:1).
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