STABLE PHARMACEUTICAL COMPOSITIONS OF TERIFLUNOMIDE
FIELD OF THE INVENTION
The invention relates to oral pharmaceutical compositions of teriflunomide and process for the preparation of such compositions.
BACKGROUND OF THE INVENTION
Teriflunomide is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme and is chemically designated as (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide with a molecular formula C12 H9F3N2O2 and following structural formula:
Teriflunomide is commercially available as film-coated tablets for oral administration under the trade name AUBAGIO®. AUBAGIO tablets contain 7 mg or 14 mg of teriflunomide and lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate as inactive ingredients. 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. AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
US Patent No. 4,965,276 discloses Teriflunomide use in the treatment of chronic graft-versus-host disease.

US Patent No. 5,459,163 and US Patent No. 5,679,709 discloses Teriflunomide compositions useful for the treatment of autoimmune diseases in particular lupus erythematosus.
US Patent No. 8,802,735 discloses teriflunomide tablet formulations with improved stability, wherein the said tablet formulation does not contain colloidal silicon dioxide. In few examples, colloidal silicon dioxide is present in an amount of 0.33% of weight of the tablet and the tablets are acidified with colloidal silicon dioxide. Also discloses the pH of the tablet composition from 4.5 to 2.0.
PCT publication No. WO2015088380 discloses method for producing teriflunomide tablets comprises sifting teriflunomide and excipients through a sieve with average pore size of 0.14-0.20 mm, stirred until homogeneous, followed by forming the mixture into a tablet at a compression pressure of 15-20 kN / cm and applying film coating. Though, this prior art listed colloidal silicon dioxide as lubricant, the preferred lubricant is magnesium stearate and this prior art is silent regarding the acidification of compositions comprising teriflunomide.
The prior art disparaged the lubrication of teriflunomide compositions with colloidal silicon dioxide. The composition has to be acidified if it is lubricated with colloidal sil icon dioxide. According to the prior art, presence of colloidal silicon dioxide in the un-acidified tablet compositions of teriflunomide leads to the increased formation 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide or 4-trifluoromethyl-aniline (4-TFMA) compared to teriflunomide tablets containing colloidal silicon dioxide. The prioir art disclosed that it is advangeous to add acidic reacting compound to teriflunomide compositions containing colloidal silicon dioxide or without colloidal silicon dioxide.
Hence there still remains a need for alternative pharmaceutical compositions comprising teriflunomide with acceptable stability.

SUMMARY OF THE INVENTION
In one general aspect there is provided a pharmaceutical composition comprising teriflunomide or salts thereof and colloidal silicon dioxide.
In another general aspect there is provided an oral solid dosage form comprising teriflunomide or salts thereof and colloidal silicon dioxide.
In another general aspect there is provided an oral solid dosage form comprising teriflunomide or salts thereof, colloidal silicon dioxide and an alkalizer.
In another general aspect there is provided a pharmaceutical composition comprising teriflunomide or salts thereof and colloidal silicon dioxide, wherein the pH of the composition is more than 5.0.
In another general aspect there is provided a process for preparing a pharmaceutical composition of teriflunomide or salts thereof. The process includes the steps of admixing, granulating and/or coating.
In another general aspect there is provided a pharmaceutical composition comprising teriflunomide or salts thereof and colloidal silicon dioxide, wherein the composition is packaged with moisture absorber.
In another general aspect there is provided an oral solid dosage form comprising teriflunomide or salts thereof and colloidal silicon dioxide, wherein the composition is packaged with moisture absorber.
Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients. The pharmaceutical acceptable excipients may include diluent, disintegrant, surfactant, binder, lubricant, glidant, plasticizer, antitacking agent, opacifying agent, sweeteners/taste masking agents, colorants and flavors and the like.
The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have developed non-acidified pharmaceutical compositions comprising teriflunomide or salts thereof, where in the composition is lubricated with colloidal silicon dioxide. The developed compositions do not have the disadvantages mentioned in the prior art due to the presence of colloidal silicon dioxide i.e., increase in 2-cyano-N-( 4-trifluoromethyl-phenyl )-acetamide and formation of 4-TFMA
Embodiments of the present invention relate to pharmaceutical compositions of teriflunomide or salts thereof comprising one or more pharmaceutically acceptable excipients.
As used herein, the term 'teriflunomide' is used in broad sense to include not only the teriflunomide per se but also its pharmaceutical ly acceptable salts, pharmaceutical ly acceptable solvates, pharmaceutical ly acceptable hydrates, pharmaceutical^ acceptable enantiomers, pharmaceutical^ acceptable derivatives, pharmaceutical^ acceptable polymorphs and pharmaceutical^ acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
In an embodiment the pharmaceutical composition comprises teriflunomide or salts thereof and colloidal silicon dioxide.
The pharmaceutical compositions of teriflunomide or salts thereof comprises about 0.1 to about 10% of colloidal silicon dioxide. Preferably, about 0.3 to about 5%, more preferably, 0.5 to 3%.
In an embodiment the pharmaceutical compositions of teriflunomide or salts thereof is not acidified.
In another embodiment the pharmaceutical compositions of teriflunomide comprises teriflunomide or salts, colloidal silicon dioxide and an alkalizer.
Alkalizer includes, but are not limited to, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium oxide, sodium hydroxide and mixtures thereof. Preferably, the alkalizer is magnesium oxide. The alkalizer may be present in an amount of 1% to 20% by weight of the composition.

In another embodiment pH of the pharmaceutical composition comprising teriflunomide or salts thereof and colloidal silicon dioxide is more than 5.0.
Preferably, the pH of the pharmaceutical composition of teriflunomide or salts thereof is in between 5.5 to 12.0, more preferably, 6 to 10.5.
The pharmaceutical composition of teriflunomide or salts thereof is an oral solid dosage from, preferably, tablet.
The pharmaceutical composition of teriflunomide or salts thereof can be prepared by any suitable method known in the art such as direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation.
In another embodiment the pharmaceutical composition is provided as a tablet, which can be film coated with one or more coating agents. The coating agents may include hypromellose, polyvinyl alcohol, and sodium carboxymethyl cellulose.
In a further embodiment the pharmaceutical composition of teriflunomide is packed with moisture absorber.
In a further embodiment the pharmaceutical composition comprising teriflunomide or salts thereof and colloidal silicon dioxide, wherein the pharmaceutical composition contains no more than about 0.5% by weight of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored at about 40° C and 75% relative humidity for about 6 months.
The final dosage form is packaged using procedures known in the art. Preferably in the form of foil-foil cold form blisters, plastic blisters or HDPE bottles.
The moisture absorbers include activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth. The particular moisture -retaining materials used will depend upon the humidity level of the environment. For example, in a very low-humidity environment, a moisture-carrying material such as a hydrogel that partially binds water may be preferred. The moisture absorber can be supplied in the form of a sachet, cartridge or canister. A preferred form is a canister of silica gel, such as SorBit™ (commercially supplied by Sud-Chemie Corporation).

Multisorb provides variety of moisture absorbers under trade name of Natrasorb M, Natrasorb S, Natrasorb C, and Hi-dry, which comprise diatomaceous earth, silica gel, calcium oxide and molecular sieve, respectively.
In a further embodiment the pharmaceutical composition comprising teriflunomide or salts thereof contains no more than about 0.5% of 2-cyano-N-( 4-trifluoromethyl-phenyl )-acetamide after being stored at about 40°C.and about 75% relative humidity for about 3 months.
Diluent includes, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitot, sorbitol, erythritol; and mixtures thereof. Diluent may generally be added to increase the bulk volume of the powder to facilitate granulation or compression. The diluent may be present in an amount ranging from 1% to 90% by weight of the composition.
Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof. The disintegrant may be present in an amount ranging from 1% to 20% by weight of the composition.
Surfactants includes, but are not limited to, anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. The amount of surfactant present in the pharmaceutical composition ranges from about 0.1% to about 10% by total weight of the composition.
Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers,
carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. Binder may be used as a component of the coat to

ensure proper adhesion of the subsequent coats. The binder may be present in an amount ranging from 0.1% to 25% by weight of the composition.
Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof. Glidant includes talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof. The lubricant and/or glidant may be present in an amount ranging from 0.1% to 10% by weight of the composition.
Plasticizer may be used in a coat to increase the flexibility and strength of the layer and includes, but are not limited to, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. The plasticizer may be present in an amount ranging from 0.1% to 20% by weight of the composition.
Anti-tacking agent may be used in a coat to aid bulk build-up and form a smooth surface and includes, but are not limited to, talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-tacking agent may be present in an amount ranging from 0.1% to 20% by weight of the composition.
Opacifying agent may be used in a coat to prevent photo-degradation and includes, but are not limited to, titanium dioxide, iron oxides, and the like. The opacifying agent may be present in an amount ranging from 0.1% to 10% by weight of the composition.
Taste masking agents includes, but are not limited to one or more of polymers, surfactants, sweeteners and flavors. Examples of polymers include one or more of cellulose acetate, polymethacrylates, cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose; and the like.

Sweeteners includes, but are not limited to saccharides such as aspartame, sugar derivatives. Other examples of sweeteners comprise sodium saccharin; aspartame; sugarless sweeteners, hydrogenated starch hydrolysates, alone or in combination.
Flavors includes, but are not limited to citric acid, cinnamon, wintergreen, eucalyptus, spearmint, peppermint, menthol, anise as well as fruit flavors such as apple, pear, peach, vanilla, strawberry, cherry, apricot, orange, watermelon, banana and the like; bean-derived flavors, such as coffee, cocoa and the like or mixtures thereof.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Example 1-
Process:
Mixture of teriflunomide, lactose monohydrate and corn starch, hydroxy propyl cellulose and microcrystalline cellulose (if present) was lubricated with Sodium starch glycolate

type A, colloidal silicon dioxide and magnesium stearate and compressed to form tablets. Optionally, tablets were film coated using commercially available film coating solutions.
Process:
Mixture of teriflunomide, lactose monohydrate, corn starch and magnesium oxide was granulated using hydroxy propyl cellulose dispersion in water as binder. The granules were dried and mixed with microcrystalline cellulose (if present), Sodium starch glycolate type A, colloidal silicon dioxide and magnesium stearate and compressed to form tablets. Optionally, tablets were film coated using commercially available film coating solutions.

Process:
Mixture of teriflunomide, lactose monohydrate and corn starch, hydroxy propyl cellulose was lubricated with Sodium starch glycolate type A and colloidal silicon dioxide and compressed to form tablets. Optionally, tablets were film coated using commercially available film coating solutions. Stability Data:
Teriflunomide Tablets of example 3 are packed in Alu-Alu blisters and stored at 40°C and 75% RH.

We Claim:
1. A Pharmaceutical composition comprising teriflunomide or salts thereof and colloidal silicon dioxide.
2. The pharmaceutical composition according to claim 1, wherein the amount of colloidal silicon dioxide is 0.1 to 10% by total weight of the composition.
3. The pharmaceutical composition according to claim 2, wherein the amount of colloidal silicon dioxide is 0.5% to 3% by total weight of the composition.
4. The pharmaceutical composition according to claim 1, wherein the composition is solid oral dosage form.
5. The pharmaceutical composition according to claim 1, wherein the amount of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide is no more than about 0.5% after being stored at about 40°C.and about 75% relative humidity for about 6 months.
6. The pharmaceutical composition according to claim 1, wherein the amount of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide is no more than about 0.3% after being stored at about 40°C.and about 75% relative humidity for about 6 months.
7. The pharmaceutical composition according to claim 1, wherein the composition is packed with moisture absorber.
8. The pharmaceutical composition according to claim 1, wherein the pH of the composition is more than 5.0.
9. The pharmaceutical composition according to claim 1, wherein the composition contains an alkalizer.

10. The pharmaceutical composition according to claim 1, wherein the process includes the steps of admixing, granulating and/or coating.