Field of the Invention

The present invention relates to pharmaceutical compositions comprising teriflunomide and one or more pharmaceutically acceptable excipient and are used in the treatment of autoimmune diseases such as especially systemic lupus erythematosus or chronic graft- versus-host disease, multiple sclerosis or rheumatoid arthritis. More specifically, this composition is characterized in that it does not contain glidants.

Background of the Invention

Multiple Sclerosis (MS) is a demyelinating disease characterized by damage to insulating ends of neurons in the brain and spinal cord. This damage impairs the communication between the components of central nervous system and leads to a series of signs and symptoms including physical, mental, and sometimes, psychiatric problems. Specific symptoms include diplopia, blindness in one eye, muscle weakness, sensory impairment or coordination problems. MS presents with new symptoms either in isolated attacks (in relapsing-remitting forms) or over time (progressively). Symptoms may completely resolve in between attacks. In addition, the likelihood of having permanent neurological damage is high especially as the disease progresses.

Teriflunomide is a pyrimidine synthesis inhibitor. Teriflunomide acts via the mechanism of a dihydroorotate dehydrogenase inhibitor and it is an orally available immunomodulator used in the treatment of relapsing-remitting multiple sclerosis. Chemical name of teriflunomide is (Z)- 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2enamide and its chemical structure is shown in Formula I.

Formula I. Teriflunomide Teriflunomide inhibits rapidly dividing cells including activated T cells that are believed to drive the disease process in MS and it may decrease the risk of infection thanks to its more limited effects on the immune system compared to chemotherapeutic agents.

The document EP0527736B1 is the first molecule patent that describes teriflunomide in the prior art. It mentions the use of teriflunomide in the prophylaxis and/or treatment of rheumatic diseases and the possibility to administer the pharmaceuticals of the invention orally, topically, rectally and parenterally, if required.

The document EP1381356 in another state of the art mentions oral administration of teriflunomide and describes the use thereof in producing a drug for the treatment of multiple sclerosis. Document no. W02013062442 describes a composition comprising teriflunomide and colloidal silicone dioxide in an amount between 0.8-1.2% by weight.

The mentioned compositions show a slightly less degradation of teriflunomide but cannot shed a light on stability and solubility problems. According to the prior art as provided above, there is still a need for stable and highly soluble teriflunomide formulations.

Objectives and Brief Description of the Invention

The main object of the present invention is to obtain teriflunomide containing pharmaceutical compositions that eliminate the above-mentioned problems and provide additional advantages to the relevant prior art.

Another object of the present invention is to obtain solid pharmaceutical compositions of teriflunomide with high stability and solubility profile.

Another object of the present invention is to obtain more stable formulations of humidity- sensitive teriflunomide without using glidants.

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising at least one film coating that protects the composition against humidity in order to maintain stability.

Detailed Description of the Invention

For the purposes outlined above, detailed features of the present invention are provided herein. The present invention relates tosolid oral pharmaceutical compositions comprising teriflunomide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition does not comprise glidants.

The present invention particularly relates to solid oral pharmaceutical compositions comprising teriflunomide or a pharmaceutically acceptable salt thereof, wherein the composition does not comprise colloidal silicone dioxide.

Colloidal silicon dioxide is a fumed silica that is prepared with the hydrolysis of a silica compound. Its particle size is around 15nm and it is an amorphous powder that is odorless, tasteless and water-insoluble. Colloidal silicon dioxide can cause stability problems in pharmaceutical compositions depending on its amount therein due to its hygroscopic structure that enables absorbing a high amount of water. Colloidal silicon dioxide acts both as a lubricant and glidant in solid oral pharmaceutical compositions. Although it is frequently used in formulations due to its fluidity, the fact that it increases the rate of becoming unstable by promoting degradation and has highly humectant properties reveals the reasons for not preferring colloidal silicon dioxide especially in compositions that are sensitive to humidity.

In the main embodiment of the invention, the solid oral pharmaceutical composition comprises teriflunomide or a pharmaceutically acceptable salt thereof, at least one disintegrant, at least one binder, at least one lubricant and at least one filling material and does not contain a glidant.

The solid oral pharmaceutical composition of the invention comprises at least one disintegrant.

In the solid oral pharmaceutical composition of the invention, the amount of disintegrant is higher than 20% by weight in the total composition.

According to this embodiment of the invention, the disintegrant is selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), microcrystalline cellulose, cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycolate, starch, pregelatinized starch, alginic acid and alginates, ion exchange resins, magnesium aluminum silica, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, docusate sodium, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof. The mentioned solid oral pharmaceutical composition preferably comprises microcrystalline cellulose and/or sodium starch glycolate or a mixture thereof as a disintegrant.

In the mentioned solid oral pharmaceutical composition teriflunomide-disintegrant ratio is between 1 :35 and 1 :1 , preferably between 1 :5 and 1 :1 ,5, more preferably between 1 :4 and 1 :2.

The solid oral pharmaceutical composition of the invention comprises at least one binder.

According to this embodiment of the invention, the binder is selected from the group comprising copovidone, copolyvidone, polyvinylpyrrolidone (PVP), povidone, carnauba wax, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and copolymers thereof, gelatin, starch, pregelatinized starch, xanthan gum, guar gum, alginate, carrageenan, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, poloxamer, polyethylene glycol (PEG), sugars, glucose syrup, natural gums, tragacanth, polyacrylamide, aluminum hydroxide, bentonite, laponite, cetostearyl alcohol, polyethylene-alkyl ethers, acacia gum, and polydextrose or mixtures thereof.

Preferably, the binder comprises corn starch and/or hydroxypropyl cellulose or a mixture thereof.

It was also seen that the amount of the active ingredient, dispersant and lubricant in the composition is significantly important in order to obtain tablets that provide both high solubility and stability.

The solid oral pharmaceutical composition comprises at least one lubricant.

According to this embodiment of the invention, the lubricant is selected from the group comprising calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, magnesium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, stearic acid, hydrogenated natural oils, silica, and paraffin or mixtures thereof. The mentioned solid oral pharmaceutical composition preferably comprises polyethylene glycol and/or magnesium stearate or a mixture thereof as a lubricant. Considering the compression, chemical incompatibility and such properties of magnesium stearate especially in solid oral dosage forms, polyethylene glycol and preferably polyethylene glycol 6000 P is used as a lubricant in the present invention due to its non-hygroscopic, fluid and impermeable structure. It was also observed that polyethylene glycol used as a lubricant in the present invention due to the above-mentioned reasons surprisingly increased the stability of the solid oral pharmaceutical composition of the invention while also increasing solubility due to its surfactant properties.

In addition, polyethylene glycol is highly effective as a lubricant with considerably high concentration and small particle size, however it does not exhibit glidant properties and acts as an adhesion-preventing component in the composition.

In other preferred embodiments of the invention, polyethylene glycol base is soluble in water and it is used as a lubricant that increases water solubility for effervescent tablet formulations.

The solid oral pharmaceutical composition comprises teriflunomide or a pharmaceutically acceptable salt thereof in an amount between 1-20%, disintegrant in an amount between 20- 40%, binder in an amount between 2-40%, lubricant in an amount between 2-15% and filling material in an amount between 10-90% by weight and that does not contain any additional binders or colloidal silicon dioxide.

The solid oral pharmaceutical composition comprises teriflunomide or a pharmaceutically acceptable salt thereof in an amount between 1-20%, disintegrant in an amount preferably between 20-35%, binder in an amount between 2-30%, lubricant in an amount preferably between 2-10% and filling material in an amount between 70-90% by weight and that does not contain any additional binders or colloidal silicon dioxide.

In the solid oral pharmaceutical composition, the ratio of lubricant to a teriflunomide is in the range of between 1 :10 and 15:1 , preferably between 1 :7 and 1 :1.25, more preferably between 1 :5 and 1 :1.4. In the mentioned solid oral pharmaceutical composition, the ratio of lubricant to a disintegrant is in the range of between 1 :17.5 and 1 :1.33, preferably between 1 :10 and 1 :3, more preferably between 1 :10 and 1 :5.

According to another preferred embodiment of the invention, the composition is in the form of coated tablet, three-layered tablet, double-layered tablet, multi-layered tablet, orally disintegrating tablet, mini tablet, pellet, sugar pellet, buccal tablet, sublingual tablet, effervescent tablet, rapid release tablet, modified release tablet, film coated tablet, gastric disintegrating tablet, pill, capsule, oral granule, powder, coated bead system, microsphere, tablet-in-tablet, inlay tablet, sugar-coated tablet, sachet or orally-administrable film.

The composition is preferably in the form of a tablet, most preferably in the form of a film- coated tablet.

In one embodiment of the invention, the composition comprises a film coating. Suitable components of the coating can be selected from the group comprising polyvinyl alcohol, polyethylene glycol, polymethylmethacrylate derivatives, ethylcellulose dispersions (Surelease), Kerry-HPC, polyvinlypyrrolidone, vinyl acetate, pigments, dyes, titanium dioxide, iron oxide, talc and all Opadry types.

According to a preferred embodiment of the invention, the composition comprises a film coating such as hypromellose-based coatings, sugar, shellac or other enteric coating materials that form a barrier against humidity. Amount of the mentioned film coating is between 1-5% by weight in the total composition.

According to a preferred embodiment, the total composition comprises the following:

- 1-20% teriflunomide by weight

- 10-90% I Lactose monohydrate by weight

- 3-30% corn starch by weight

- 2-60% hydroxypropyl cellulose by weight

- 12-20% microcrystalline cellulose by weight

- 8-15% sodium starch glycolate by weight

- 1- 10% polyethylene glycol by weight

- 1- 5% magnesium stearate by weight

- 1-5% film coating These selected percentage values provide the effective doses required for treatment and enhance the stability and solubility profile of the film coated tablet of the invention.

In the main embodiment of the invention, a production method of the pharmaceutical composition comprises the following steps,

dissolving hydroxypropyl lcellulose in water,

mixing a half of microcrystalline cellulose, corn starch, lactose monohydrate, teriflunomide and a half of sodium starch glycolate and granulating with hydroxypropyl cellulose solution,

- drying the mentioned granules at 45 degrees and sieving,

adding the other half of microcrystalline cellulose, the other half of sodium starch glycolate and polyethylene glycol and mixing,

adding magnesium stearate and mixing, compressing into tablets,

dissolving film coating material in water and coating the tablets with this solution.

Table 1. Amounts in % according to the use in the tablet

Table 2. Unit formula

The present invention also relates to the production method of a pharmaceutical composition comprising teriflunomide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the mentioned method comprising the following steps; dissolving hydroxypropyl cellulose (HPC) in water,

mixing a half of microcrystalline cellulose, corn starch, lactose monohydrate, teriflunomide and a half of sodium starch glycolate and granulating with hydroxypropyl cellulose LF solution,

drying the mentioned granules at 45 degrees and sieving,

adding the other half of microcrystalline cellulose, the other half of sodium starch glycolate and polyethylene glycol 6000 P and mixing,

adding magnesium stearate and mixing, compressing into tablets,

dissolving film coating material in water and coating the tablets with this solution.