Claims:1. A solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate comprising
(a) 1 % to 30 % w/w of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate;
(b) less than 0.5% w/w of an alkalizing agent(s); and
(d) one or more pharmaceutical excipient(s);
wherein the composition is stable at 40°C and about 75% relative humidity for about 12 months & the weight % is on the weight of the composition.
2. A solid oral composition of teriflunomide as claimed in claim 1 wherein alkalizing agent is selected from oxides, hydroxides, carbonates, bicarbonates of alkali metals; oxides, hydroxides, carbonates, bicarbonates of alkaline earth metals ; organic amines, ammonium hydroxide and mixtures thereof.
3. A solid oral composition of teriflunomide as claimed in claim 1 wherein pharmaceutical excipient is selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.
4. A solid oral composition of teriflunomide as claimed in claim 1 wherein the composition is prepared by dry granulation, wet granulation or direct compression.
5. A solid oral composition of teriflunomide as claimed in claim 1 wherein the composition is film coated.
6. A solid oral composition of teriflunomide as claimed in claim 1 wherein the composition is packed in Polyamide/aluminum/poly(vinyl chloride)-aluminum blisters.
7. A solid oral composition of teriflunomide as claimed in claim 1 wherein the composition comprises not more than 1.5% by weight of total impurity at 40°C and about 75% relative humidity for about 6 months.

8. A process for the preparation of solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate comprising

(a) direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying or solution evaporation of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate optionally with one or more pharmaceutical excipient(s) and/or alkalizing agent(s);
(b) optionally drying;
(c) optionally mixing extragranular excipients and/or alkalizing agent(s);
(d) optionally compressing; and
(e) packaging in a blister such as polyamide/aluminum/poly(vinyl chloride)-aluminum blisters;
wherein when wet granulation is used the solvent is selected from water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof and alkalizing agent(s) is added to the solvent. , Description:A SOLID ORAL COMPOSITION OF TERIFLUNOMIDE

FIELD OF THE INVENTION

The present invention relates to a solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and the process of its preparation.

BACKGROUND OF THE INVENTION

Teriflunomide is chemically designated as (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl) -amide. Teriflunomide is indicated for the treatment of patients with relapsing forms of multiple sclerosis and is commercially available as film-coated tablets, AUBAGIO®, for oral administration.

United States Patent number 4965276 (assigned to M/s Hoechst AG, referred to herein as ‘276) teaches use of teriflunomide in the treatment of chronic graft-versus-host disease. The ‘276 patent suggests general possible compositions of teriflunomide. However, it does not exemplify any composition of teriflunomide.

European patent number EP2477611B1 (assigned to M/s Sanofi-Aventis, referred to herein as ‘611) discloses teriflunomide tablet formulations with improved stability, wherein the said tablet composition does not contain colloidal silicon dioxide. The ‘611 patent discourages use of colloidal silicon dioxide.

The ‘611 teaches that the following tablets display significantly reduced formation of impurity 2-cyano-N(4-trifluoromethylphenyl) acetamide as compared to tablets containing colloidal silicon dioxide :
(a) tablets comprising organic acids such as citric acid lubricated with or without colloidal silicon dioxide and
(b) tablets with no colloidal silicon dioxide;

The ‘611 further suggests use of acidic agents such as citric acid but does not teach use of alkalizing agents to reduce impurities in teriflunomide tablets on storage.

PCT publication WO2017056104A1 (assigned to M/s Natco, referred to herein as ‘104) teaches teriflunomide compositions with 0.1 to 10 weight % colloidal silicon dioxide. However, ‘104 does not disclose use of less than 0.5 weight % of an alkalizing agent to improve stability of teriflunomide tablets.

Prior art suggests teriflunomide was converted to degradant 2-cyano-N-(4-trifluromethyl-phenyl)-acetamide during storage period. At room temperature storage of solid compositions of teriflunomide, 2-cyano-N-(4-trifluromethyl-phenyl)-acetamide levels of upto 0.2% have been reported after 12 months of storage.

A need therefore exists to have stable pharmaceutical compositions comprising teriflunomide during storage period which are devoid of degradants.

The present invention intends to prepare stable solid oral compositions of teriflunomide or pharmaceutically acceptable salts thereof during storage period and the process for the preparation of stable solid oral compositions of teriflunomide or pharmaceutically acceptable salts thereof.

OBJECT OF THE INVENTION

The object of the present invention is to provide a solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate with an alkalizing agent.

Another object of the present invention is to provide a process for the preparation of a solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate with an alkalizing agent.

SUMMARY OF THE INVENTION

A solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate comprising
(a) 1 % to 30 % w/w of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate;
(b) less than 0.5% w/w of an alkalizing agent(s); and
(d) one or more pharmaceutical excipient(s);
wherein the composition is stable at 40°C and about 75% relative humidity for about 12 months & the weight % is on the weight of the composition.

A process for the preparation of solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate comprising

(a) direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying or solution evaporation of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate optionally with one or more pharmaceutical excipient(s) and/or alkalizing agent(s);
(b) optionally drying;
(c) optionally mixing extragranular excipients and/or alkalizing agent(s);
(d) optionally compressing; and
(e) packaging in a blister such as polyamide/aluminum/poly(vinyl chloride)-aluminum blisters;
wherein when wet granulation is used the solvent is selected from water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof and alkalizing agent(s) is added to the solvent.

DESCRIPTION OF THE INVENTION

Solid oral compositions of teriflunomide are found useful for treating autoimmune diseases in particular lupus erythematosus; proliferative effects on a wide variety of immune cells and cell lines and relapsing forms of multiple sclerosis.

Teriflunomide is known to be unstable and degrades under acidic and oxidative conditions. Forced degradation study suggests total impurities to increase up to 7.62% when teriflunomide was exposed to 1M Hydrochloric acid. However, under basic condition such as 1M NaOH, teriflunomide is stable. In view of this we have developed a composition with an alkalizing agent.

According to one embodiment of the present invention is a solid oral composition of teriflunomide
or pharmaceutically acceptable salts thereof and/or its solvate comprising
(a) 1 % to 30 % w/w of teriflunomide or pharmaceutically acceptable salts thereof;
(b) less than 0.5% w/w of an alkalizing agent; and
(d) one or more pharmaceutical excipient(s);
wherein the composition is stable at 40°C and about 75% relative humidity for about 12 months & the weight % is on the weight of the composition.

The composition may comprise teriflunomide or pharmaceutically acceptable salts thereof such as alkali metal salts such as sodium or potassium.

The amount of active ingredient teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate present in the composition according to the present invention can range from 1 % to 30 % w/w of the composition; preferably 5% to 25% and most preferably 5% to 20%.

The alkalizing agent as defined in the present invention is selected from oxides, hydroxides, carbonates, bicarbonates of alkali metals; oxides, hydroxides, carbonates, bicarbonates of alkaline earth metals ; organic amines, ammonium hydroxide and mixtures thereof. The alkali metals may be selected from sodium and potassium; and the alkaline earth metals may be selected form calcium, magnesium and barium.

The alkalizing agent is present in less than 0.5%w/w of the composition, preferably between 0.1 to 0.5% w/w of the composition.

The composition may be selected from beads, granules, tablets and capsules.

The pharmaceutical excipient used in the composition of the present invention may be selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.
The diluents may be selected from microcrystalline cellulose, lactose (anhydrous and monohydrate), combinations of crystalline cellulose with lactose (brand names - Cellactose, Tabletosse), guar gum, silicified cellulose, corn starch, maize starch, starch derivatives such as prege1atinized starch, calcium hydrogen phosphate in anhydrous and hydrated form, sugar, fructose, dextrates, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactiol, and/ or other sugars such as saccharose, raffinose, trehalose, fructose or mixtures thereof, calcium carbonate, calcium lactate and/or mixtures thereof.

The diluent may be in an amount of 10 to 99 weight%, preferably 25 to 90 weight% of the weight of the composition.

The pharmaceutical composition according to the invention preferably comprises one or more diluents selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol and mixtures thereof. Furthermore, it is preferred that the pharmaceutical composition according to the invention comprises 10 to 99 wt.-%, more preferably 25 to 90 wt.-%, most preferably 40 to 70 wt % of diluent, based on the total weight of the pharmaceutical composition.

The disintegrants may be selected from crospovidone, starch, starch derivatives such as pregelatinised starch and sodium starch glycolate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na, croscarmellose sodium) or calcium (CMC-Ca), cross-linked CMC-Na, polacrilin potassium, low substituted hydroxypropyl cellulose and/or mixtures thereof and can be present in an amount of 1 to 50 weight%. preferably 2 to 45 weight% based on the weight composition. Preferably, the composition of the present invention comprises croscarmellose sodium as disintegrant.

The binders may be selected from polyvinylpyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethy1 cellulose, hydroxypropy1 cellulose, hydroxypropy1 methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacry1ate, or mixtures thereof. The binder can be present in a range of 0.5 to 25 weight%, preferably 1 to 20 weight% on the weight of the
composition.

The lubricants may be selected from stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, magnesium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, glyceryl behanate, macrogols and/or mixtures thereof and can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of
the composition. Preferably, the pharmaceutical composition comprises a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate.

The surfactants may be selected from anionic surfactants such as sodium lauryl sulfate and docusate sodium, cationic surfactants such as cetrimide, ampholytic surfactants such as N-dodecyl-N,N-dimethylbetaine, non-ionic surfactants such as sorbitan fatty acid esters (e.g. Spans® ), polysorbates (e.g.polyoxyethylene alkyl ethers, poloxamers, mediumchain triglycerides, polyoxylglycerides, polyoxyethylene castor oil derivates (e. g. Cremophor ® ) and/or mixtures thereof & can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition.

The glidants may be selected from colloidal silicon dioxide, talc, stearic acid, palmitic acid, polyethylene glycol, carnauba wax and/ or mixtures thereof and can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition.

The sweetener can be selected from acesulfame K, sucralose, alitame, aspartame, saccharin sodium, dipotassium glycyrrhizinate, thaumatin and the like.

The coloring agents may be selected from natural pigments and inorganic materials.

The flavoring agents may be selected from natural or synthetic materials, such as orange, spearmint, strawberry and cream flavour and the like.

The solid oral composition of the present invention may be prepared by direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate & one or more pharmaceutical excipients. The wet granulation may be carried out using suitable solvent(s) selected from water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof.

The solid oral composition of the present invention is an immediate release composition.

The term “immediate release” as described herein refers to release of the active ingredient immediately on reaching the stomach. The immediate release composition of the present invention may be film coated which provides improved surface smoothness and color, increased chemical and physical stability of teriflunomide due to reduced permeability of oxygen and/ or water vapor, less disintegration of the solid composition in acidic medium resulting in decreased gastrointestinal side effects, and easier swallowing of tablet.

The film coating materials may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, povidone and copovidone, graft copolymers of polyethyleneglycol and polyvinyl alcohol (Kollicoat IR) , shellac, polymers of methacrylic acid or methacrylic acid esters, methacrylic acid-methyl acrylate copolymers, polyvinyl alcohol, plasticizers such as propylene glycol, polyethylene glycol, glycerol triacetate, triethyl citrate, antitacking agents such as talc, glycerol monostearate, magnesium stearate and colorants or pigments such as titanium dioxide or iron oxide.

The solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof of the present invention may optionally comprise active ingredients selected from dimethylfumarate, fingolimod, laquinimod, leflunomide, diroximel fumarate, siponimod, cadribine, ocrelizumab, natalizumab, alemtuzumab and their pharmaceutically acceptable salts, esters, isomers and mixtures thereof.

The invention also relates to a packaged pharmaceutical composition comprising the composition described above packaged in a blister made of single or multiple polymer and/or aluminum layers such as polyamide/aluminum/poly(vinyl chloride)-aluminum blisters. The packaging prevents moisture absorption. Typically the packaged composition is packaged with an atmosphere having a reduced oxygen concentration such as below 15 vol%, preferably below 10 vol%, more preferably below 5 vol% oxygen. The composition may be packaged with a nitrogen atmosphere.

The solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate is packaged in blister packaging and stored at 40°C / 75% relative humidity.

The solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate according to the present invention packaged in blister packaging do not degrade and are found to be stable as it prevents moisture absorption for 12 months at 40°C / 75% relative humidity.

The term stable defined herein is composition with weight % of total impurities of not more than 1.5% by weight of teriflunomide when tested in conventional manner after storage for 6 months at 40°C and 75% relative humidity. The content of teriflunomide and its degradation products in the composition was evaluated by HPLC.

The solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate of the present invention may preferably comprise
(a) 1 to 30 % w/w teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate;
(b) 0.1 to 0.5% w/w of an alkalizing agent;
(c) 70 to 99% w/w of one or more pharmaceutical excipients selected from disintegrants, binders, glidants, sweeteners, flavoring agents, coloring agents;
(d) optionally an active ingredient;
(e) optionally film coated; and
(f) packaged in polyamide/aluminum/poly(vinyl chloride)-aluminum blisters
wherein the % w/w is on the weight of the composition.

The solid oral composition of the present invention is bioequivalent to the reference product.

According to another embodiment of the present invention is a process for the preparation of solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate.

The solid oral composition of the present invention may be prepared by direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate & one or more pharmaceutical excipients; wherein the wet granulation may be carried out using suitable solvent(s).

Suitable solvent(s) may be selected from water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof.

The process of direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation may be conducted using standard techniques known in the art.

The wet granulation process may be carried out with suitable solvent(s) on
(a) teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate followed by addition of extragranular excipients; or
(b) mixture of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate and one or more excipients and/or alkalizing agent(s).

The granulated mass may be dried and used as granules or converted into beads or mixed with additional excipients and filled in sachets.

The granulated mass may be optionally dried and mixed with additional excipients prior to formation of beads or compression into tablets.

The composition prepared above may be packaged in a blister made of single or multiple polymer and/or aluminum layers such as polyamide/aluminum/poly(vinyl chloride)-aluminum blisters.

Typically, the process for the preparation of solid oral composition of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate comprises
(a) direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying or solution evaporation of teriflunomide or pharmaceutically acceptable salts thereof and/or its solvate optionally with one or more pharmaceutical excipient(s) and/or alkalizing agent(s);
(b) optionally drying;
(c) optionally mixing extragranular excipients and/or alkalizing agent(s);
(d) optionally compressing; and
(e) packaging in a blister such as polyamide/aluminum/poly(vinyl chloride)-aluminum blisters;
wherein when wet granulation is used the solvent is selected from water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof and alkalizing agent(s) is added to the solvent.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.

EXAMPLES

Example 1: Product of the present invention :
Sr. No. Ingredients %
1. Teriflunomide 7 – 12
2. Lactose monohydrate QS
3. Corn starch 7 – 12
4. Hydroxypropyl cellulose 3 – 8
5. Sodium starch glycolate 8 – 13
6. Sodium Hydroxide 0.1 – 0.5
7. Microcrystalline cellulose 5 – 15
8. Colloidal silicon dioxide 0.1 – 0.5
9. Magnesium stearate 0.5 – 2.0
10. Opadry Blue (03K505035) 2 - 5

Process:

1. Co-sift Teriflunomide, Lactose monohydrate, Corn starch, Hydroxypropyl cellulose and Sodium starch glycolate and charge to granulator
2. Prepare the binder solution by dissolving Sodium Hydroxide in water
3. Granulate step-1 by using step-2 and dry the wet granules
4. Blend the granules with pre-sifted Microcrystalline cellulose and Colloidal silicon dioxide
5. Lubricate the dried and sized granules with Magnesium stearate
6. Compress the blend to form tablets and coat using Opadry Blue (03K505035) dispersion.
Example 2 : Stability studies
Tests Limits Initial 1 M (40°C/75%RH) 2 M (40°C/75%RH) 3 M (40°C/75%RH) 6 M (40°C/75%RH)
Assay (%) 95.0%-105.0% 103.3 101.9 101.9 102.5 101.2
Dissolution NLT 80% in 30minutes 96 98 97 95 95
Related substances (by HPLC)
4-TFMA NMT 0.2% ND1 ND1 ND1 ND1 ND1
2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide NMT 0.5% 0.03 0.05 0.04 0.07 0.11
Any individual unspecified impurity NMT 0.2% ND1 0.01 0.01 0.01 0.02
Total impurities NMT 1.5% 0.03 0.06 0.05 0.08 0.13

1: not detected

Stability data of Teriflunomide Film Coated Tablets in Alu/Alu blisters at 40ºC/75% RH was found to be satisfactory up to 6 months