WO2024085821A1

WO2024085821A1 - Content uniformity of teriflunomid in pharmaceutical dosage forms

Info

Publication number: WO2024085821A1
Application number: PCT/TR2022/051170
Authority: WO
Inventors: Hatice ONCEL; Onur Pinarbasli; Feristah BILGIN; Hande GAYRETLI; Bahar KOKSEL OZGEN; Nurdan ATILGAN; Asuman AYBEY DOGANAY; Nagehan SARRACOGLU
Original assignee: Ilko Ilac Sanayi ve Ticaret AS
Current assignee: Ilko Ilac Sanayi ve Ticaret AS
Priority date: 2022-10-21
Filing date: 2022-10-21
Publication date: 2024-04-25
Anticipated expiration: 2025-04-21
Also published as: EP4604942A1; EP4604942A4

Abstract

The invention relates to develop a pharmaceutical tablet composition for oral administration, comprising Teriflunomide or а pharmaceutically ассерtаblе salt thereof, and а method for the preparation of said tablet with obtaining teriflunomide containing granules using wet granulation method and using a specific particle size distribution of Teriflunomide granules to provide content uniformity of tablets.

Description

CONTENT UNIFORMITY OF TERIFLUNOMID IN PHARMACEUTICAL

DOSAGE FORMS

Technical field:

The present invention relates to an immediate release pharmaceutical formulation for oral administration, comprising a therapeutically effective amount of Teriflunomide or a pharmaceutically acceptable salt thereof, and a wet granulation method for the preparation of said tablet by using a specific particle size distribution of Teriflunomide granules.

Prior Art:

Teriflunomide is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4 trifluoromethylphenyl)-amide. Its molecular weight is 270.21 gram/mol, and the empirical formula is C12H9F3N2O2 with the following chemical structure (Formula-1):

Formula-1

Teriflunomide is a white to almost white powder that is sparingly soluble in acetone, slightly soluble in polyethylene glycol and ethanol, very slightly soluble in isopropanol and practically insoluble in water. Teriflunomide is a BCS Class II drug, consequently it exhibits poor water solubility and high permeability. It 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.

Teriflunomide, has been approved by the FDA as an oral tablet of 7 mg or 14 mg administered once daily for the treatment of adults with relapsing-remitting multiple sclerosis (MS) and has been launched by Sanofi as Aubagio® (www.accessdata.f a.gov/drugsatfda_docs /label/2012 /202992s0001bl.pdf). Multiple Sclerosis (MS) is a neurological disease affecting more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on subjects and their families, friends and bodies responsible for health care. EP1381356B1 discloses the use of teriflunomide, for the manufacture of a medicament for treating multiple sclerosis wherein said medicament is administered orally.

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.

EP2477611B 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.

WO2022128156A1 relates to an immediate release stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of Teriflunomide or a pharmaceutically acceptable salt thereof, wherein the amount of colloidal silicon dioxide is from 0.1% to 1% w/w of the total weight of the composition incorporated into the external phase of the pharmaceutical composition.

Despite the advantages of the direct compression, such as reduced processing time and cost, wet granulation is widely used in the industry to prepare solid dosage forms. Wet granulation is often preferred over direct compression because wet granulation has a greater chance of overcoming any problems associated with the physical characteristics of various ingredients in the formulation. This provides material which has the required flow and cohesive properties necessary to obtain an acceptable solid dosage form.

The popularity of wet granulation compared to direct compression is based on at least three advantages. First, wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances. The addition of hydrophilic excipients makes the surface of the hydrophobic drug more hydrophilic, reducing disintegration and dissolution problems. Second, the content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug. Lastly, the segregation of drug(s) from excipients is avoided. However, for some pharmaceutical active substances wet granulation alone is not enough to solve the segregation problem. Especially in the products obtained as a result of commercial production method, the problem of content uniformity occurs in the tablets obtained as a result of segregation during tablet compressing. Segregation is a potential problem for tablets. To solve this problem, the size and shape of the particles that make up the granule to be compacted can be optimized.

When wet granulation method was preferred for the active substance in teriflunomide having a flowability problem, segregation problem was encountered during tablet compressing. In this direction, with the present invention, both the active substance flow is regulated by wet granulation and the segregation problem is solved by keeping the particle sizes of the obtained granules within a certain range.

Description of the Invention:

It is an object of the present invention to provide content uniformity of pharmaceutical tablet composition comprising teriflunomide or a pharmaceutically acceptable salt thereof, obtaining teriflunomide containing granules using wet granulation method, wherein particle size distribution (D90) of teriflunomide granules, measured by the method of laser diffraction in a dry method (Malvern Mastersizer, general purpose mode, refractive index: 1.55, air pressure: 0.5 atm- 1.5 atm, obscuration rate: 0.5%-10.0%, feed rate 30%-40%), is between 350 pm to 800 pm

In the main embodiment of the invention, the content uniformity of pharmaceutical composition comprises therapeutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof, at least one disintegrant, at least one binder, at least one filling material, at least one glidant and at least one lubricant, obtaining teriflunomide containing granules using wet granulation method, wherein particle size distribution (D90) of teriflunomide granules, measured by the method of laser diffraction in a dry method (Malvern Mastersizer, general purpose mode, refractive index: 1.55, air pressure: 0.5 atm- 1.5 atm, obscuration rate: 0.5%-10.0%, feed rate 30%-40%), is between 350 pm to 800 pm.

In the another embodiment of the invention, the pharmaceutical composition comprises teriflunomide or a pharmaceutically acceptable salt thereof in an amount between 3-15%, binder in an amount between 2-40%, disintegrant in an amount between 2-10%, glidant in an amount between 0-1%, lubricant in an amount between 0.1-2% and diluent in an amount between 40- 60% by weight. In the another embodiment of the invention, the pharmaceutical film tablet composition comprises therapeutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof, obtaining teriflunomide granules using wet granulation method, wherein the binder is a combination of corn starch and hydroxylpropyl cellulose, disintegrant is sodium starch glycolate, glidant is colloidal silicon dioxide, lubricant is sodium stearyl fumarate and diluent is lactose monohydrate.

One of the major difficulties in formulating the pharmaceutical composition comprising teriflunomide in the present invention is the poor aqueous solubility of teriflunomide, which also significantly affects the bioavailability of the molecules. Solubility is one of the most important parameters to achieve the desired drug concentration in the systemic circulation to achieve the required pharmacological response. In addition to solubility problems, teriflunomide is hygroscopic, presents stability problems, and is not inherently compressible. Consequently, there is a need to provide teriflunomide tablet compositions that provide content uniform tablet compositions having an acceptable in vitro dissolution profile and stable under stability conditions.

The prior art references disclose that Teriflunomide tablets without colloidal silicon dioxide result in a product with lesser degradants compared to Teriflunomide tablets containing colloidal silicon dioxide. However, the presence of colloidal silicon dioxide in the formulation is preferred, as it is used to improve flowability. The present invention is directed to formulations of Teriflunomide tablets comprising colloidal silicon dioxide without adversely affecting the stability.

From the studies, it has been revealed that formulations prepared with and without colloidal silicon dioxide exhibit a comparative dissolution profile. In the present invention, the use of colloidal silicon dioxide is preferred because of its ability to improve the flow properties of the active substance.

According to previous studies, it is known that there are stability and degradation problems of pharmaceutical compositions comprising teriflunomide. Another problem that arises when finding solutions for existing problems is the segregation that occurs during tablet compressing. However, there is not any study for content uniformity of Teriflunomide. Although some studies have been done to overcome stability and degradation problems, there is still a need in the art for stable formulations with improved dissolution and adequate chemical and physical properties that overcome segregation and degradation problems simultaneously. The most important and critical point of developing a pharmaceutical composition is to select and quantify the pharmaceutical excipients to obtain the appropriate dissolution profile and stability for the specified finished product dosage form, and to produce them with the appropriate production method. In the present invention, the selection of the optimal composition and method of preparation of pharmaceutical auxiliary excipients is an important object to obtain the content uniform tablets having appropriate stability for the finished dosage form.

The term "active ingredient" or "active pharmaceutical ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active ingredient is teriflunomid or its pharmaceutically acceptable salts, esters, and solvates thereof.

The term "therapeutically effective amount" refers to the amount of teriflunomid or its pharmaceutically acceptable salts, esters, and solvates thereof, that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.

As used herein, "stable" refers to a composition that substantially maintains its physical and chemical properties when stored. 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 term 'feedstock' refers to particulate material to be granulated.

The expression "comprising" means "including, but not limited to". Thus, other non-mentioned substances, additives, carriers, or steps may be present.

In addition to the active or therapeutic ingredients, tablets may contain a number of inert materials known as excipients. The pharmaceutical compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, which may be used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralizing agents, if necessary), penetration enhancers, solubilizing agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition. Any such excipients can be used in any dosage forms according to the present disclosure. The foregoing classes of excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types and combinations of excipients could be used to achieve the desired goals for release and stability of teriflunomid tablet composition.

The excipients may be classified according to the role they play in the final tablet. The primary composition includes a filler/ diluent, binder, lubricant, and glidant. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps, such as wet granulation, spray drying spheronization, or crystallization etc.

Filler/ diluents are added to increase the bulk weight of the blend resulting in a practical size for compression. In further aspect of the present invention filler/ diluents are selected from the group of cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, 1-0-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. In the present invention, lactose monohydrate is selected.

Binders are agents, which impart cohesive qualities to the powdered material. In further aspect of the present invention binders are selected from the group of 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. In the present invention, corn starch and hydroxypropylcellulose are selected.

Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the com pressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight. In further aspect of the present invention lubricants are selected from the group of 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. In the present invention, sodium stearyl fumarate is selected.

Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. In further aspect of the present invention disintegrants are selected from the group of carboxymethylcellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methyfcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate or a mixture of one or more of said disintegrants. In the present invention, sodium starch glycolate is selected.

Glidants are incorporated into solid dosage forms to improve the flow properties of powders or granulates. These are excipients adsorbing during mixing (preparation of tableting mixture) on the surface of the powders - particles of other excipients or active pharmaceutical substances. In the phase of pouring the tableting mixture from the hopper into the tableting press die glidants reduce friction between particles and between particles and the wall of the hopper. The consequence of friction reduction (i.e. improving of the mixture flowability) is the uniform die filling with the powder mixture, ensuring of required weight and content uniformity of produced tablets. Glidants also prevent sticking of pressed powders/ granules on compression thorns and tablets capping. In further aspect of the present invention glidants are selected from the group of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate and talc. In the present invention, colloidal silicon dioxide is selected.

The compressed tablets are further film coated by non-aqueous coating or aqueous coating or by hydroalcoholic coating. This coating composition contains film-forming substances such as hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol; solvents, colloidal silicon dioxide, optionally other excipients such as plasticizers, lubricants and colourants.

Solvents used for granulation and coating can be either aqueous or non-aqueous solvents. Suitable non-aqueous solvents include, but are not limited to isopropyl alcohol, ethanol, dichloromethane, acetone and the like. Aqueous solvent include water.

The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example 1. Production Methods

The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tabletting. The procedure consists of mixing the powders in a suitable blender to form feedstock followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is dried by tray drying or fluidized bed drying. The dried granules are milled and screened through a suitable screen. The overall process includes: weighing, dry powder blending, wet granulating, drying, milling, screening, blending lubrication and compression.

In order to examine the effect of the obtained granule particle size on segregation, tablet compression processes were carried out with sieved granules from different sieve sizes. When the content uniformity results of the obtained tablets are evaluated, the importance of the particle size determined in the present invention for the finished product emerges.

Table 1. Contents of excipients in compositions containing teriflunomide

The particle size distribution for used granules were measured by the method of laser diffraction in a dry method (Malvern Mastersizer, general purpose mode, refractive index: 1.55, air pressure: 0.5 atm- 1.5 atm, obscuration rate: 0.5%-10.0%, feed rate 30%-40%) are given below.

Table 2. Particle size distribution (D90) of granules fort he prepared formulations

Particle size distribution (D90) of granules

Formulation-1 D90 = higher than 900 pm

Formulation-2

D90 = between 800-900 pm

Formulation-3

Formulation-4

D90 = between 600-800 pm

Formulation-5

Formulation-6 D90 = between 350-600 pm

In the studies carried out to solve the teriflunomide content uniformity problem, the content uniformity results of the finished products obtained from the granules with different particle sizes specified in the examples were compared. Same unit formula and same mixing procedure are used with different particle size distribution of granules.

Table 3. Results of content uniformity of Teriflunomide

*'Form' means 'Formulation'. The results in the Table 3 showed that, screening the prepared granules through a suitable screen prevents segregation of powders in the hopper during tablet compression. As it is understood, the presence or absence of colloidal silicone in the formulation does not affect the results of content uniformity. The content uniformity of Form-4, 5 and 6 is better than Form-1, 2 and 3. These results showed the effect of sieving process, especially screened through a suitable screen to provide desired size of granules, particularly particle size distribution (D90) of teriflunomide granules, measured by the method of laser diffraction in a dry method (Malvern Mastersizer, general purpose mode, refractive index: 1.55, air pressure: 0.5 atm- 1.5 atm, obscuration rate: 0.5%-10.0%, feed rate 30%-40%), is between 350 pm to 800 pm.

In addition to the studies mentioned above, formulation studies were carried out with a particle size distribution (D90) of lower than 300 pm using the direct mixing method. However, in the process prepared with this particle size distribution, tablets could not be compressed due to agglomeration problem.

Example 2. Dissolution Profiles

Comparative dissolution tests were conducted based on the general dissolution test method. The analysis was performed according to FDA Dissolution Methods - Teriflunomide Tablet. The progress of dissolution is monitored for 45 minutes (recommended sampling times: 5, 10, 15, 20, 30 and 45 minutes). Dissolution test was performed at USP Apparatus II (paddle), speed 50 rpm, 1000 mL volume with 0.05 M Phosphate buffer pH 6.8 (FDA medium), pH 1.2 and pH 4.5 mediums. Dissolution testing measures the portion (%) of Teriflunomide that has been released from tablet and has dissolved in the dissolution medium. Dissolved teriflunomide content was determined spectrophotometrically by a validated HPLC method at 254 nm.

Comparative dissolution tests were conducted with test products (Formulation 1 to 6) and reference product of Aubagio® 14 mg Tablet. The conditional release profiles of the test products and reference product were plotted as the cumulative percent of drug dissolved vs. time. The dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (f₂) (Helmy & Bedaiwy, 2013). An f2 value between 50 and 100 suggests that the two dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010). The similarity factor (f₂) values of test products (Formulation 1 to 6) and reference product (R - Aubagio® 14 mg Tablet) for the different pH media are found between 50 and 100.

Example 3. Stability Studies

The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.

The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment.

It is known that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues, but even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable, as it make therapy with the drug less certain. Stability issues can be caused by environmental factors such as humidity, temperature and the like. However, degradation may result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients such as fillers, binders, lubricants, glidants and disintegrating agents or impurities contained in any of these excipients.

In the literature, one of the observations made during stability studies was a strong increase in one degradant, which is 2-cyano-N-(4-trifluoromethylphenyl)-acetamide, named as Impurity B.

Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions. The accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/Q.WP/122/02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months.

Thus, in the development of Teriflunomide Tablet form, the applicant carried out both accelerated and ambient stability studies for the test and reference products. The accelerated stability condition is temperature of 40°C ± 2°C and 75 % ± 5°C RH and ambient stability condition is temperature of 25°C±2°C and 60% ± 5% RH for up to 6 months.

Test product tablet formulations were packed in, Alu-Alu container, and they were charged on to the stability cabinets. Samples were taken out at each stability stage interval and submitted for analysis. The results are summarized in the following Table 4. Table 4. Stability results (degradation products) for Test products initially and after 6 months at 40°C±2°C/ 75%±5 %RH and 25°C±2°C/ 60±5% Relative Humidity, RH±5% storage conditions.

Degradation Product (%)

Claims

1. A pharmaceutical tablet composition comprising teriflunomide or a salt thereof, obtaining teriflunomide containing granules using wet granulation method, wherein particle size distribution (D90) of teriflunomide granules, measured by the method of laser diffraction in a dry method (Malvern Mastersizer, general purpose mode, refractive index: 1.55, air pressure: 0.5 atm- 1.5 atm, obscuration rate: 0.5%-10.0%, feed rate 30%-40%), is between 350 pm to 800 pm.

2. The tablet composition according to claim 1, wherein the formulation comprising therapeutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof, at least one disintegrant, at least one binder, at least one filling material, at least one glidant and at least one lubricant.

3. The tablet composition according to claim 2, wherein the said formulation comprises the following by weight;

3-15 % teriflunomide or a salt thereof,

2-40 % binder,

2-10 % disintegrant,

0-1 % glidant,

0.1-2% lubricant,

40-60 % diluent.

4. The tablet composition according to claim 3, wherein the binder is a combination of corn starch and hydroxylpropyl cellulose.

5. The tablet composition according to claim 3, wherein the disintegrant is sodium starch glycolate.

6. The tablet composition according to claim 3, wherein the glidant is colloidal silicon dioxide.

7. The tablet composition according to claim 3, wherein lubricant is sodium stearyl fumarate.

8. The tablet composition according to claim 3, wherein diluent is lactose monohydrate.

9. The tablet composition according to claim 1, wherein the tablet dosage form is film coated.