EP4262759A1 - Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation - Google Patents

Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation

Info

Publication number
EP4262759A1
EP4262759A1 EP21824289.9A EP21824289A EP4262759A1 EP 4262759 A1 EP4262759 A1 EP 4262759A1 EP 21824289 A EP21824289 A EP 21824289A EP 4262759 A1 EP4262759 A1 EP 4262759A1
Authority
EP
European Patent Office
Prior art keywords
teriflunomide
pharmaceutical composition
total weight
amount
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21824289.9A
Other languages
German (de)
English (en)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Andreas KAKOURIS
Manolis FOUSTERIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmathen SA
Original Assignee
Pharmathen SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmathen SA filed Critical Pharmathen SA
Publication of EP4262759A1 publication Critical patent/EP4262759A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • 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.
  • an immunomodulatory agent such as Teriflunomide or a pharmaceutically acceptable salt thereof
  • 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.
  • DHO-DH dihydroorotate dehydrogenase
  • Teriflunomide has been approved as an oral treatment for patients with relapsing-remitting multiple sclerosis (MS) and has been launched by Sanofi as Aubagio®.
  • MS relapsing-remitting multiple sclerosis
  • Aubagio® Sanofi as Aubagio®
  • 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.
  • 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.
  • PopPK population pharmacokinetic
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 m 2 /g to 600 m 2 /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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • Table 2 Dissolution results for Formulation Trial 1 compared to Aubagio® 14mg film coated tablets by Sanofi.
  • 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.
  • HPC hydroxypropyl cellulose
  • 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.
  • MCC microcrystalline cellulose
  • 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.
  • 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.
  • 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.
  • 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.
  • colloidal silicon dioxide 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.
  • a medium level of colloidal silicon dioxide was selected for finished product formula.
  • Trial 2 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.
  • Trial 2 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
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique stable à libération immédiate pour administration orale contenant une quantité thérapeutiquement efficace de tériflunomide ou un sel pharmaceutiquement acceptable de celui-ci, et son procédé de préparation.
EP21824289.9A 2020-12-15 2023-07-13 Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation Pending EP4262759A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20200100731A GR1010137B (el) 2020-12-15 2020-12-15 Στερεη φαρμακοτεχνικη μορφη αμεσης αποδεσμευσης περιεχουσα τεριφλουνομιδη και μεθοδος παρασκευης αυτης
PCT/EP2021/025498 WO2022128156A1 (fr) 2020-12-15 2021-12-14 Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation

Publications (1)

Publication Number Publication Date
EP4262759A1 true EP4262759A1 (fr) 2023-10-25

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ID=78851156

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21824289.9A Pending EP4262759A1 (fr) 2020-12-15 2023-07-13 Forme posologique solide à libération immédiate comprenant du tériflunomide et son procédé de préparation

Country Status (3)

Country Link
EP (1) EP4262759A1 (fr)
GR (1) GR1010137B (fr)
WO (1) WO2022128156A1 (fr)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1381356E (pt) 2001-04-05 2008-07-24 Aventis Pharma Inc Utilização de (4' -trifluorometilfenil) - amida do ácido (z) -2- ciano-3-hidroxi-but-2-enóico para tratamento da esclerose múltipla
DE102006017896A1 (de) 2006-04-13 2007-10-25 Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg Leflunomid enthaltende pharmazeutische Zusammensetzungen
US20120172427A1 (en) 2009-09-18 2012-07-05 Sanofi (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide tablet formulations with improved stability
WO2012110911A1 (fr) 2011-02-18 2012-08-23 Alembic Pharmaceuticals Limited Nouvelle forme polymorphe de tériflunomide
US20160058730A1 (en) * 2014-08-29 2016-03-03 Cadila Healthcare Limited Pharmaceutical compositions of teriflunomide
WO2017056104A1 (fr) * 2015-09-28 2017-04-06 Natco Pharma Limited Compositions pharmaceutiques stables de tériflunomide
WO2017125841A1 (fr) * 2016-01-20 2017-07-27 Emcure Pharmaceuticals Limited Compositions pharmaceutiques de tériflunomide

Also Published As

Publication number Publication date
GR1010137B (el) 2021-12-07
WO2022128156A1 (fr) 2022-06-23

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