EP4262759A1

EP4262759A1 - Immediate release solid dosage form comprising teriflunomide and method of preparation thereof

Info

Publication number: EP4262759A1
Application number: EP21824289.9A
Authority: EP
Inventors: Evangelos Karavas; Efthymios Koutris; Vasiliki SAMARA; Ioanna Koutri; Anastasia Kalaskani; Andreas KAKOURIS; Manolis FOUSTERIS
Original assignee: Pharmathen SA
Current assignee: Pharmathen SA
Priority date: 2020-12-15
Filing date: 2023-07-13
Publication date: 2023-10-25
Also published as: WO2022128156A1; GR1010137B

Abstract

The present invention relates to an immediate release stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of Teriflunomide or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof.

Description

IMMEDIATE RELEASE SOLID DOSAGE FORM COMPRISING TERIFLUNOMIDE AND METHOD OF PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable immediate release pharmaceutical formulation for oral administration containing a therapeutically effective quantity of an immunomodulatory agent such as Teriflunomide or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof.

B ACKROUND OF THE INVENTION

Teriflunomide 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. Consequently, Teriflunomide reduces the proliferation of dividing cells that need de novo synthesis of pyrimidine to expand.

Teriflunomide, has been approved as an oral treatment for patients with relapsing-remitting multiple sclerosis (MS) and has been launched by Sanofi as Aubagio®. The exact mechanism by which Teriflunomide exerts its therapeutic effect in MS is not fully understood, but this is mediated by a reduced number of lymphocytes.

Teriflunomide is the main active metabolite of Leflunomide, it is moderately metabolized and is the only component detected in plasma. The primary biotransformation pathway for Teriflunomide is hydrolysis with oxidation being a minor pathway. In terms of absorption, median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose following repeated oral administration of Teriflunomide, with high bioavailability (approximately 100%). Food does not have a clinically relevant effect on Teriflunomide pharmacokinetics. From the mean predicted pharmacokinetic parameters calculated from the population pharmacokinetic (PopPK) analysis using data from healthy volunteers and MS patients, there is a slow approach to steady state concentration.

The chemical name of Teriflunomide is (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4’- trifluoromethylphenyl)-amide. The molecular formula is C12H9F3N2O2 corresponding to a molecular weight of 270.2. Teriflunomide is sparingly soluble in ethyl acetate, methanol, acetone, slightly soluble in ethanol, very slightly soluble in isopropanol and polyethylene glycol-200 and practically insoluble in water. Teriflunomide is non-hygroscopic material and it has a strong acidic character as per pKa value. It exhibits a single polymorphic form and an absence of crystalline forms. Teriflunomide is a BCS Class II drug, consequently it exhibits poor water solubility and high permeability.

EP-B-1381356 discloses the use of Teriflunomide, for the manufacture of a medicament for the treatment of multiple sclerosis (MS).

WO 2007/118684 discloses Leflunomide containing solid pharmaceutical composition including an organic or inorganic acid characterized by improved stability. Said composition shows a slighter decomposition of Leflunomide to Teriflunomide, than in commercial Leflunomide tablets Arava® (Sanofi). Teriflunomide amounts are disclosed within the range 0.02mg-0.511mg per tablet containing lOmg leflunomide. These are less than 0.35% teriflunomide with respect to the total mass of the tablet.

EP-B-2477611 describes a solid dosage form of Teriflunomide comprising essentially of 1 %-30% by weight Teriflunomide or a pharmaceutically acceptable salt, 5-20% by weight disintegrant, 0- 40% by weight binder, 0.1-2% by weight lubricant and the remaining percentage comprising diluents provided that the solid pharmaceutical composition is essentially free of colloidal silicon dioxide.

Although each of the patents above represents an attempt to overcome stability and degradation problems associated with pharmaceutical compositions comprising Teriflunomide, there still remains the need in the art for alternative formulations with enhanced dissolution and adequate chemical and physical characteristics that overcome known problems.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a stable solid pharmaceutical composition containing Teriflunomide or pharmaceutical acceptable salt thereof, as an active ingredient that not only matches the physical and chemical attributes of the reference product but also overcomes the disadvantages associated with the prior art compositions in particular the formation of degradation products with toxic effects and the poor aqueous solubility of Teriflunomide. Further object of the present invention is to provide an immediate release film-coated tablet comprising Terifllunomide as an active ingredient, which is bioavailable and with sufficient selflife.

A major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients and method of preparation to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form affords predictable and reproducible drug release rates to achieve better treatment and patient compliance.

Another aspect of the present invention is to provide immediate release film-coated tablets comprising Teriflunomide or a pharmaceutically acceptable salt thereof comprising an appropriate amount of a binder in the internal phase and an appropriate amount of a glidant in the external phase of the tablet core. The internal phase be the part of the granule that is wet granulated, while the external phase is that after drying of the wetted granular mass.

A further approach of the present invention is to provide a tablet composition for oral administration comprising Teriflunomide which is manufactured through a fast, simple and cost- effective process.

According to another embodiment of the present invention, a process for the preparation of a stable, solid dosage form for oral administration, containing Teriflunomide or pharmaceutical acceptable salt thereof, and an effective amount of a diluent and a binder in the internal phase and an effective amount of a disintegrating agent and a glidant in the external phase is provided, which comprises the following steps:

-premixing diluents with Teriflunomide;

-preparing binder solution;

-mixing binder solution with the diluent/Teriflunomide mix to form a granular mass

-drying and sizing the granular mass

-mixing the granular mass with disintegrant and glidant;

-compressing the final blend

-optionally coating of compressed tablets.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description. DET AILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.

The primary goal of the present invention is to develop an immediate release film-coated tablet formulation comprising Teriflunomide or a pharmaceutical acceptable salt thereof as the single drug substance that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacotechnical properties.

One of the major challenges in formulating the present pharmaceutical composition lies in the poor aqueous solubility of Teriflunomide which is linked to the molecules’ bioavailability. Solubility is one of the most important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water-soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption.

In addition to the active ingredient, the tablet composition also contains one or more inert materials known as excipients. The primary composition includes diluents, disintegrants, binders, glidants and lubricants. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets. Typically, excipients are selected to impart good flow and compression characteristics to the material being compressed. Excipients are also selected with the perspective to enhance dissolution, physicochemical characteristics, and stability of the drug substance in the final dosage form. In the case of Teriflunomide, the stability of the drug substance in the final form is of especially important as known disintegrants have been shown to have a toxic effect.

Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug.

Pharmaceutical manufacturers would prefer to use direct compression techniques over wet or dry granulation methods because of quick processing time and cost advantages. However, direct compression is usually limited to those situations where the drug or active ingredient has physical characteristics required to form pharmaceutically acceptable tablets. However, the poor solubility of Teriflunomide requires wet granulation for increasing the solubility, absorption, and therapeutic efficacy of the drug in dosage form. Therefore, wet granulation process is chosen for the current development.

Lubricant is an essential component of the tablet formulation. Some pharmaceutical scientists believe that the manner of which a lubricant is added to a formulation must be carefully controlled. Accordingly, lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulate can materially affect hardness and disintegration time for the resulting tablets. For these reasons, composition of the tablet core is divided into two phases, an internal and an external phase. Lubricants are to be used in the external phase of the tablet core to avoid prolonged blending with the excipients used in the internal phase.

The preferred formulation of the present invention comprises Teriflunomide as the active ingredient, and the manufacturing process includes a combination of a disintegrant and a diluent in the internal phase of the tablet core and a combination of a disintegrant, glidant and a lubricant in the external phase of the tablet core. The incorporation of those excipients in the external phase of the alternative formulation the speed & ease of manufacture according to the present invention.

More particularly, one aspect of the present invention includes a pharmaceutical formulation comprising Teriflunomide in the granules formulated in the internal phase during wet granulation process and colloidal silicon dioxide at the external phase. Surprisingly, the addition of colloidal silicone dioxide in the external phase of the formulation showed unexpected results in the minimization of toxic degradation products such as 2-cyano-N-(4-trifluoromethyl-phenyl)- acetamide and also provided better dissolution profiles.

Teriflunomide or a pharmaceutically acceptable salt thereof is comprised in the present invention in an amount of 1 to 20% w/w of the total weight of the tablet, more preferably from 5 to 10% w/w of the total weight of the tablet.

A suitable binder and disintegrant are enclosed in the formulation to regulate the drug release rate and disintegration of film coated tablets. The preferred binder in the present invention is hydroxypropyl cellulose, a water-miscible, “hydrophilic” polymer which modifies the drug release profile by forming a polymer gel layer in aqueous medium. In the present context, the term “hydrophilic” describes that something is familiar to water: a molecule or portion of a molecule is electrically polarized and capable of forming hydrogen bonds with water molecules, enabling it to dissolve more readily in water than in oil or other “non-polar” solvents.

Wet granulation process using hydroxypropyl cellulose as binder is used to the current formulation to adjust the drug release from the granules. The preferred concentration of hydroxypropyl cellulose in the present invention is from 1 to 8% w/w of the total weight of the tablet, more preferably from 2 to 7% w/w of the total weight of the tablet and most preferably from 4 to 6% w/w of the total weight of the tablet.

The preferred glidant in the present invention is colloidal silicon dioxide, it is 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. The particles are non-porous and have a surface from 50 m²/g to 600 m²/g. It can be obtained for example under the trade name Aeorsil 200 Pharma from Evonik Industries.

The preferred concentration of colloidal silicon dioxide in the present invention is from 0 to 1.0% w/w of the total weight of the tablet, more preferably from 0.1 to 0.8% w/w of the total weight of the tablet and most preferably from 0.2 to 0.5 % of the total weight of the tablet.

Diluents are added to solid pharmaceutical dosage forms to make the product large enough for swallowing and handling, and more stable. Examples of diluents are microcrystalline cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, 1-O-a-D-Glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose monohydrate, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.

The preferred diluent in the present invention is microcrystalline cellulose and is preferably used in a concentration from 6 to 15% w/w of the total weight of the tablet. Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation Another preferred diluent for the present invention is starch maize. The preferred concentration of starch maize is from 25 to 50% w/w of the total weight of the tablet.

Also, lactose monohydrate is a preferred diluent in the present invention and is used preferably in a concentration from 40 to 70% w/w of the total weight of the tablet.

Different combinations of diluents were also tested in the present invention. A combination of microcrystalline cellulose, starch maize and lactose monohydrate showed the best results for the present invention in a total concentration from 60 to 90% w/w of the total weight of the tablet.

Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium); soy polysaccharides; and guar gum, sodium starch glycolate. Sodium starch glycolate is the preferred disintegrant in the present invention and is preferably used in concentration from 1 to 10% w/w of the total weight of the tablet.

Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose. The lubricant component may be hydrophobic or hydrophilic. Magnesium stearate is the preferred lubricant in the present invention and is preferably used in a concentration from 0 1 to 1% w/w of the total weight of the tablet. It aids the flow of the powder in the hopper and into the die. It is stable and does not polymerize within the tableting mix.

A further aspect of the invention relates to a process for preparing a pharmaceutical formulation comprising Teriflunomide according to the following manufacturing steps: a) pre-mixing diluents (microcrystalline cellulose, starch maize, lactose monohydrate) with Teriflunomide, b) dissolving appropriate quantity of hydroxypropyl cellulose in an aqueous solvent to form a binder solution, c) mixing the binder solution of step (b) with the premixed blend of the Teriflunomide mixture of step (a) to form granular mass d) drying the granular mass of step (c) until the water content level is well below acceptable limits e) sizing the granular mass of step (d) through a sieve of appropriate mesh size, f) mixing granular mass of step (e) with sodium starch glycolate and colloidal silicon dioxide, g) adding lubricant and blending to form a final blend, h) compression of final blend, i) optionally coating of compressed tablets with appropriate coloring agent.

The final formulation is formed as film coated tablets for oral use. The product strengths are prepared into final dosage of 14mg film coated tablets compressed in biconvex pentagonal punch.

EXAMPLES

Example 1

The scope of present invention is the preparation of a stable pharmaceutical dosage form for oral administration comprising Teriflunomide and exhibiting an immediate drug release profile. Also, the pharmaceutical composition shall be bioequivalent to reference product as per acceptance criteria indicated for generic products and must be stable under different storage conditions. Table 1 shows the qualitative and quantitative formulation of Trial (example 1).

Table 1: Qualitative/Quantitative Formulation Trial 1 The manufacturing process for the formulation of Trial 1 is the following: a) pre-mixing diluents (microcrystalline cellulose, starch maize, lactose monohydrate) with Teriflunomide, b) dissolving an appropriate quantity of hydroxypropyl cellulose in an aqueous solvent to form a binder solution, c) mixing the binder solution of step (b) with the premixed blend of Teriflunomide of step (a) to form a granular mass d) drying the granular mass of step (c) until the water content level is well below acceptable limits, e) sizing the granular mass of step (d) through a sieve of appropriate mesh size, f) mixing granular mass of step (e) with sodium starch glycolate and colloidal silicon dioxide, g) adding magnesium stearate and blending to form a final blend, h) compression of final blend, i) optionally coating of compressed tablets with appropriate coloring agent.

The in-vitro dissolution profile of Formulation Trial 1 was recorded in Buffer pH 6.8, 50RPM, lOOOmL, USP II in comparison to reference product as shown in Table 2.

Table 2: Dissolution results for Formulation Trial 1 compared to Aubagio® 14mg film coated tablets by Sanofi.

The data from the dissolution analysis shows an increased dissolution rate recorded for formulation Trial 1 at early time intervals of dissolution profile against reference product. Thus, further trials are needed for optimization of the dissolution profile. A range of alternative compositions were prepared applying alternative formulations. Primarily, the binder and disintegrant levels were evaluated with a Design of Experiment (DoE) series. A 22 full factorial DoE was performed to evaluate the impact of amount of hydroxypropyl cellulose dissolved in aqueous solution and sodium starch glycolate dispensed in external phase in product formula on CQAs of drug product.

Based on the results, the significant factors affecting the drug release at 5 min are A: hydroxypropyl cellulose (HPC) amount & B: sodium starch glycolate amount and the significant factors affecting the drug release at 45min are A: hydroxypropyl cellulose amount & B: the interaction between HPC and sodium starch glycolate.

It is obvious that when higher HPC amount levels were dispensed within the product formula the dissolution results at 45min were suppressed. On the contrary, higher dissolution results (burst effect) were recorded when lower HPC amount was used as binder within product formula. The binding properties endorsed on tablet matrix by hydroxypropyl cellulose are the primary factor of this pattern. Sodium starch glycolate also affected the drug release, however on a lower effect than HPC material.

Overall, considering the analytical results recorded along current Design of Experiments (DoE), the burst effect along the early time intervals of in-vitro dissolution was counterfeited at medium/low level of hydroxypropyl cellulose content at either disintegrant level. Also, the high hydroxypropyl cellulose content suppressed significantly the % of drug dissolved at 45min. Similar disintegration results to reference product were recorded at medium level for both formulation variables.

To further optimize different levels of diluents, a range of alternative compositions were prepared as per following series of experiments. A 2² full factorial DoE was performed to evaluate the impact of amount of lactose monohydrate and microcrystalline cellulose dispensed in product formula on CQAs of drug product.

Based on the results, the significant factors affecting the drug release at 5min are A: microcrystalline cellulose (MCC) amount & B: lactose monohydrate amount and C: their interaction and the significant factors affecting the drug release at 45min are A: lactose monohydrate amount & B: interaction between lactose and MCC.

The results show that when lower lactose amount levels were dispensed within the product formula, for both microcrystalline cellulose amounts, the dissolution results at 5 min were significantly enhanced. Suppressed drug release results were recorded at higher/medium lactose monohydrate levels in combination with low/medium microcrystalline cellulose content. Overall, it can be stated that lactose monohydrate significantly affects the drug release from one level to the other.

Furthermore, the results showed that microcrystalline cellulose does not significantly impact the drug release at later time interval (45min). The high dissolution may be attributed to the hydrophilicity of the tablet matrix which could be due to the high amount of lactose monohydrate.

Considering the current experiment dissolution results, the inventors concluded that lactose monohydrate must be applied at high level and microcrystalline cellulose must be applied at low level. Minor adjustment on both diluents level was performed to achieve an acceptable dissolution profile.

The qualitative/quantitative formula of optimized formulation trial is stated below in Table 3.

Table 3: Qualitative/Quantitative Formulation of Trial 2. The manufacturing process for preparing the pharmaceutical formulation of Trial 2 is the same as in Trial 1.

For further optimization of the formulation of Trial 2 different levels of starch maize as a diluent were also evaluated within the context of current invention. Based on formulation trials, starch maize content impacts the drug release rate. More particularly, higher dissolution results at early time interval of dissolution testing (5min) where obtained when higher diluent content was applied to the formula. However, similar results were recorded at either low or medium level. Additionally, similar flow properties of granular mass were recorded at either content level (medium and low) whereas poor flowability was recorded when high diluent amount was applied. At last, the risk of impact on assay of finished product was found to be low.

Additionally, the impact of colloidal silicon dioxide on finished product was also evaluated. The flow properties of finished product blend were evaluated, and the results show that the addition of colloidal silicon dioxide does in fact enhance the flow properties of finished product blend whereas the risk on assay is low. Thus, a medium level of colloidal silicon dioxide was selected for finished product formula.

The formulation of Trial 2 was optimum and further changes were not needed Therefore, the disintegration, hardness as well as the dissolution profile of formulation Trial 2 were tested and are shown in Table 4 and 5 below. Furthermore, the formulation of Trial 2 shows good physicochemical characteristics.

Table 4: Disintegration and Hardness for formulation of Trial 2

Table 5: Dissolution results for formulation Trial 2 Since the scope of current pharmaceutical preparations was to investigate the bioavailability of a generic drug product, a bioequivalence study was conducted on healthy fasted subjects to determine the bioavailability of the test product (Formulation Trial 2) versus Augabio® 14mg film coated tablets (Sanofi). The results indicated that the 90% Confidence Interval (CI) for AUCO-t, based on log-transformed data, was 102.9% (geometric mean value) and 108.7% for Cmax. Based on in-vivo studies results, it seems that generic product meets the bioequivalence criteria. Thus, both in-vivo and in-vitro results confirmed the bioequivalence to the marketed product.

Finally, the formulation of the current invention was investigated for stability under different conditions. For the evaluation of stability of the finished product of Teriflunomide, 14mg film coated tablets according to Trial 2 were loaded into stability chambers and monitored with a fit- for-purpose HPLC analytical method. Stability data (related substances and assay analysis) upon storage at zero time and 6 months under long term (25°C ± 2°C/60%±5%RH) and accelerated storage conditions (40°C±2°C/75%±5%RH) are summarized in Table 6. The in-vitro dissolution results under stability conditions are summarized in Table 7.

Based on the stability results from table 6 and 7 it is shown that the formulation of Trial 2 is stable since no significant shift of dissolution rate was recorded even in accelerated storage conditions for 6 months. Also, the related substances after 6 months of stability at long-term and accelerated storage conditions are well within the acceptance criteria.

Table 6: Stability data for Trial 2 at zero time and 6 months Table 7: Dissolution profile for Trial 2 at zero time and 6 months under different conditions

Finally, the stability of the crystalline form of Teriflunomide in the final product was also evaluated through X-Ray diffraction analysis. This is especially important since the degradation products of Teriflunomide have been known to have toxic effects. The results for the X-Ray diffraction analysis of Teriflunomide API and Teriflunomide in the final product are shown in Table 8.

Based on X-Ray analysis of Terilfunomide API, the material matches the crystalline polymoph Form I claimed in international application WO 2012/110911. The results show that the crystalline form of Teriflunomide API remains stable in the finished product even under storage of 6m at accelerated conditions.

Table 8: XRD results of Teriflunomide 14mg film coated tablets and Teriflunomide API. Overall, the pharmaceutical preparation of current invention is considered stable since no significant change on drug release, assay, related substances and API crystalline form were recorded under 6-month stability at long-term and accelerated storage conditions. While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and the scope of it.

Claims

1. An immediate release solid pharmaceutical composition for oral administration comprising Teriflunomide or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient and an amount of colloidal silicon dioxide incorporated into the external phase of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the amount of colloidal silicon dioxide is from 0.1% to 1% w/w of the total weight of the composition.

3. The pharmaceutical composition according to any of the preceding claims, wherein it further comprises a binder incorporated into the internal phase of the pharmaceutical composition.

4. The pharmaceutical composition according to any of the preceding claims, wherein Teriflunomide is comprised in an amount of 1 to 20% w/w of the total weight of the composition.

5. The pharmaceutical composition according to any of the preceding claims, wherein the binder is hydroxypropyl cellulose in an amount of from 1% to 8% w/w of the total weight of the composition.

6. The pharmaceutical composition according to any of the preceding claim, wherein it further comprises a diluent incorporated into the internal phase of the pharmaceutical composition at an amount from 1% by weight to 85% w/w of the total weight of the composition.

7. The pharmaceutical composition according to claim 6, wherein the diluent can be selected from microcrystalline cellulose, starch maize and lactose monohydrate or a combination thereof.

8. The pharmaceutical composition according to any preceding claim, wherein it further comprises a disintegrant incorporated into the external phase of the composition at an amount from 1% to 5% w/w of the total weight of the composition.

9. The pharmaceutical composition according to claim 8, wherein the disintegrant is sodium starch glycolate.

10. A method of treatment of adult patient with relapsing remitting multiple sclerosis through orally administering once daily an immediate release pharmaceutical composition comprising Teriflunomide, wherein no more than 40% of the drug substance is released after 5 minutes in an in-vitro dissolution testing using USP II (paddle method) at a rotation speed of 50rpm in a lOOOmL aqueous dissolution medium at pH 6.8. A process for the preparation of an immediate release stable, solid pharmaceutical composition for oral administration, comprising Teriflunomide or pharmaceutical acceptable salt thereof, which comprises the following steps: a) pre-mixing microcrystalline cellulose, starch maize and lactose monohydrate with Teriflunomide, b) dissolving an appropriate quantity of hydroxypropyl cellulose in an aqueous solvent to form a binder solution, c) mixing the binder solution of step (b) with the premixed blend of Teriflunomide of step (a) to form a granular mass d) drying the granular mass of step (c) until the water content level is well below acceptable limits, e) sizing the granular mass of step (d) through a sieve of appropriate mesh size, f) mixing granular mass of step (e) with sodium starch glycolate and colloidal silicon dioxide, g) adding magnesium stearate and blending to form a final blend, h) compressing of final blend, i) optionally coating of compressed tablets. The process according to claim 11, wherein it comprises colloidal silicon dioxide from 0.1% to 1% w/w of the total weight of the composition. The process according to claim 11, wherein it comprises 1 to 8% w/w of hydroxypropylcellulose of the total weight of the composition.