DESC:FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof and the methods of preparing such compositions.

BACKGROUND OF THE INVENTION
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-(4-trifluoromethylphenyl)-amide and has the following structure:

Bartlett 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 Bartlett et al discloses compositions useful for treating autoimmune diseases in particular lupus erythematosus.

Wettstein et al in EP 1,381,356 discloses the use of Teriflunomide for the manufacture of a medicament for 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.
Hauck et al in US 8,802,735 disclose Teriflunomide compositions and process for the preparation of the same and disclose that Teriflunomide composition should be prepared without using colloidal silicon dioxide as in the presence of colloidal silicon dioxide impurity formation is accelerated.

Thus there is still a need for improved formulation of teriflunomide and present invention is directed towards the same.

SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof.

In one embodiment, the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof which is independent of critical vagaries of colloidal silicon dioxide.

In another embodiment, 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.

In still another embodiment, 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.

Typically, the present formulation contains up to 1% w/w of colloidal silicon dioxide. In the preferred embodiment, 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.

In yet another embodiment, the present invention relates to 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 remaining percentage comprising diluents.

In another embodiment, the present invention relates to methods of preparing such compositions.

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION
The present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof and method of preparation of such compositions.

As used herein the term “Teriflunomide” means the chemical compound (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. However, various salts, polymorphs, enantiomers, stereoisomers could also be used. Further the compound could be used as amorphous, crystalline or mixtures thereof.

As used herein the term “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 nm.

As used herein 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-(4-trifluoromethyl-phenyl)-acetamide. Analysis of impurities and degradant is done using HPLC techniques on extracted samples as is known in the art.

In one aspect, the present invention relates to pharmaceutical compositions of Teriflunomide or pharmaceutically acceptable salts thereof which is independent of critical vagaries of colloidal silicon dioxide. Typically, the present formulation contains up to 1% w/w of colloidal silicon dioxide. In the preferred embodiment, 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. Preferably, the colloidal silicon dioxide is present in the core of the tablet; however, it may be present in the coating of the tablet.

In another aspect, 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.

Optionally, the pH of the composition is adjusted by adding either acidifying or alkalinizing agents. In the preferred embodiment, the acidifying or alkalinizing agents are present in the present formulation in 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. Examples of 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, 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 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.

In yet another aspect, 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.

In further aspect, 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 carboxymethylcellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methylcellulose, 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, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, 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 palmitostearate, 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 lubricant is from about 0.1% w/w to about 2.0% w/w of pharmaceutical composition.

Further it has unexpectedly found antioxidants such as citric acid, ascorbic acid, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediamine 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.

In another aspect, the present invention relates to a solid pharmaceutical composition comprising
A) about 1% w/w to about 30% w/w Teriflunomide, or a pharmaceutically acceptable salt thereof,
B) about 3% w/w to about 20% w/w disintegrant,
C) about 0% w/w to about 40% w/w binder,
D) about 0.1% w/w to about 2% w/w lubricant,
E) about 0.1% w/w to about 1% w/w colloidal silicon dioxide and
F) the remaining percentage comprising diluents.
G) Optionally about 0.01% /w to about 20% w/w acidifying or alkalinizing agents compound to adjust the pH more than 2.2.

The pharmaceutical compositions of the present invention can further be coated with 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.

The pharmaceutical formulations of the present invention may be prepared by suitable conventional dry or wet process. For example,
a) Mixing Teriflunomide, binder, a portion of the diluents and optionally acidifying or alkalinizing agents to form an intragranular phase;
(b) Wet granulating the intragranular phase to form wet granules;
(c) Drying the wet granules;
(d) Sieving & mixing disintegrant, the remaining portions of diluents, to form an extragranular phase;
(e) Blending the extragranular phase with the dried granules
(f) Lubricating the above blend & mixing with glidants to form the final blend which is used for production of the tablets.
(g) Optional, coating.

When formulated according to embodiments of the present invention, it has found that 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 oC 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 oC and about 75% relative humidity for about 6 months.

The following experiments are provided to exemplarily illustrate various aspects of the inventive subject matter presented herein. However, it should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.

EXAMPLES:
Example-1
Sr no Ingredient % w/w
1 Teriflunomide 1-20
2 Lactose Monohydrate (Pharmatose 200M) 30-80
3 Corn Starch 30-80
4 Hydroxypropyl Cellulose (Klucel LXF) 0-30
5 Microcrystalline Cellulose (Avicel PH 102) 3-20
6 Sodium Starch Glycolate (Primojel TYPE A) 3-20
7 Colloidal Silicon Dioxide AEROSIL® 200 PHARMA 0.1-0.8
8 Magnesium Stearate (Ligamed MF-2-V) 0.1-2
9 Opadry Blue (optional) 1-10

The above test composition of Example 1 is prepared by following method:
Teriflunomide is mixed with hydroxypropylcellulose, lactose and corn starch. This mixture is granulated with water in rapid mixer granulator. Granules then dried at 55°C 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
Sr no Ingredient % w/w
1 Teriflunomide 1-20
2 Lactose Monohydrate (Pharmatose 200M) 30-90
3 Corn Starch 20-80
4 PVP K30 0-30
5 Crospovidone (Polyplasdone XL 10) 0.5-20
6 Colloidal Silicon Dioxide AEROSIL® 200 PHARMA 0.1-0.8
7 Magnesium Stearate (Ligamed MF-2-V) 0.1-2
8 Opadry Green (optional) 1-10

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 55°C 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
Sr no Ingredient % w/w
1 Teriflunomide 1-20
2 Lactose Monohydrate (Pharmatose 200M) 30-80
3 Corn Starch 30-80
4 Hydroxypropyl Cellulose (Klucel LXF) 0-30
5 Microcrystalline Cellulose (Avicel PH 102) 3-20
6 Sodium Starch Glycolate (Primojel TYPE A) 3-20
7 Colloidal Silicon Dioxide AEROSIL® 200 PHARMA 0.1-0.8
8 Magnesium Stearate (Ligamed MF-2-V) 0.1-2
9 Opadry Blue (optional) 1-10

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

Sr no Ingredient % w/w
1 Teriflunomide 1-20
2 Lactose Monohydrate (Pharmatose 200M) 30-80
3 Corn Starch 30-80
4 Hydroxypropyl Cellulose (Klucel LXF) 0-30
5 Citric acid anhydrous 0.1-20
6 Microcrystalline Cellulose (Avicel PH 102) 3-20
7 Sodium Starch Glycolate (Primojel TYPE A) 3-20
8 Magnesium Stearate (Ligamed MF-2-V) 0.1-2
9 Opadry Blue 1-10
10 Colloidal Silicon Dioxide in coating
AEROSIL® 200 PHARMA 0.1-0.8

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 pharmaceutical composition is observed to be more than about 2.2.

Example-5

Sr no Ingredient % w/w
1 Teriflunomide 1-20
2 Lactose Monohydrate (Pharmatose 200M) 30-80
3 Corn Starch 30-80
4 Hydroxypropyl Cellulose (Klucel LXF) 0-30
5 Citric acid anhydrous 0.01-20
6 Microcrystalline Cellulose (Avicel PH 102) 3-20
7 Sodium Starch Glycolate (Primojel TYPE A) 3-20
8 Colloidal Silicon Dioxide AEROSIL® 200 PHARMA 0.1-0.8
9 Magnesium Stearate (Ligamed MF-2-V) 0.1-2
10 Opadry Blue (optional) 1-10

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

Sr no Ingredient % w/w
1 Teriflunomide 1-20
2 Lactose Monohydrate (Pharmatose 200M) 30-80
3 Corn Starch 30-80
4 Hydroxypropyl Cellulose (Klucel LXF) 0-30
5 Meglumine 0.01-20
6 Microcrystalline Cellulose (Avicel PH 102) 3-20
7 Sodium Starch Glycolate (Primojel TYPE A) 3-20
8 Colloidal Silicon Dioxide AEROSIL® 200 PHARMA 0.1-0.8
9 Magnesium Stearate (Ligamed MF-2-V) 0.1-2
10 Opadry Blue (optional) 1-10

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.

,CLAIMS:
1. A pharmaceutical composition comprising Teriflunomide or a pharmaceutically acceptable salt thereof, colloidal silicon dioxide and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the pH of the composition is more than about 2.2.

3. The pharmaceutical composition as claimed in claim 2, wherein the pH of the composition is in the range of 4.5 to 7.0.

4. The pharmaceutical composition as claimed in claim 1, wherein colloidal silicon dioxide is up to about 1% by weight of the said pharmaceutical composition.

5. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from the group comprising of binders, diluents, disintegrants, stabilizers, glidants and lubricants.

6. The pharmaceutical composition as claimed in claim 5, wherein composition further comprises acidifying agents.

7. The pharmaceutical composition as claimed in claim 2, wherein composition further comprises alkalinizing agents.

8. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises of:
a) about 1% to about 30% w/w Teriflunomide, or a pharmaceutically acceptable salt thereof,
b) about 3% w/w to about 20% w/w disintegrant,
c) about 0% w/w to about 40% w/w binder,
d) about 0.1% w/w to about 2% w/w lubricant,
e) about 0.1% w/w to about 1.0 % w/w colloidal silicon dioxide

9. The pharmaceutical composition as claimed in claim 1, wherein the composition is prepared using conventional methods.

10. The process of preparation of pharmaceutical composition as claimed in claim 1, wherein the process involves the following steps:
(a) Mixing Teriflunomide, binder, a portion of the diluents and optionally acidifying or alkalinizing agents to form an intragranular phase;
(b) Wet granulating the intragranular phase to form wet granules;
(c) Drying the wet granules;
(d) Sieving & mixing disintegrant, the remaining portions of diluents, to form an extragranular phase;
(e) Blending the extragranular phase with the dried granules
(f) Lubricating the above blend & mixing with glidants to form the final blend which is used for production of the tablets.
(g) Optional, coating.