EP3813822A2 - Compositions pharmaceutiques solides d'administration par voie orale comprenant du tériflunomide - Google Patents

Compositions pharmaceutiques solides d'administration par voie orale comprenant du tériflunomide

Info

Publication number
EP3813822A2
EP3813822A2 EP19824639.9A EP19824639A EP3813822A2 EP 3813822 A2 EP3813822 A2 EP 3813822A2 EP 19824639 A EP19824639 A EP 19824639A EP 3813822 A2 EP3813822 A2 EP 3813822A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
solid oral
oral pharmaceutical
composition according
tablet
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
EP19824639.9A
Other languages
German (de)
English (en)
Other versions
EP3813822A4 (fr
Inventor
Ali Turkyilmaz
Ediz Yildirim
Bulent DEMIR
Ibrahim ATMACA
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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 Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP3813822A2 publication Critical patent/EP3813822A2/fr
Publication of EP3813822A4 publication Critical patent/EP3813822A4/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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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.
  • MS 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the amount of disintegrant is higher than 20% by weight in the total composition.
  • 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.
  • 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.
  • 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, hydroxy
  • the binder comprises corn starch and/or hydroxypropyl cellulose or a mixture thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition is preferably in the form of a tablet, most preferably in the form of a film- coated tablet.
  • 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.
  • 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.
  • the total composition comprises the following:
  • microcrystalline cellulose by weight
  • a production method of the pharmaceutical composition comprises the following steps,
  • 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,

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques comprenant du tériflunomide et un ou plusieurs excipient pharmaceutiquement acceptables et sont utilisées dans le traitement de maladies auto-immunes telles que notamment le lupus érythémateux disséminé ou la maladie du greffon contre l'hôte chronique, la sclérose en plaques ou la polyarthrite rhumatoïde.
EP19824639.9A 2018-06-27 2019-06-24 Compositions pharmaceutiques solides d'administration par voie orale comprenant du tériflunomide Pending EP3813822A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201809045 2018-06-27
PCT/TR2019/050497 WO2020005189A2 (fr) 2018-06-27 2019-06-24 Compositions pharmaceutiques solides d'administration par voie orale comprenant du tériflunomide

Publications (2)

Publication Number Publication Date
EP3813822A2 true EP3813822A2 (fr) 2021-05-05
EP3813822A4 EP3813822A4 (fr) 2022-03-16

Family

ID=68987306

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19824639.9A Pending EP3813822A4 (fr) 2018-06-27 2019-06-24 Compositions pharmaceutiques solides d'administration par voie orale comprenant du tériflunomide

Country Status (2)

Country Link
EP (1) EP3813822A4 (fr)
WO (1) WO2020005189A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022085015A1 (fr) * 2020-10-24 2022-04-28 V-Ensure Pharma Technologies Private Limited Composition orale solide de tériflunomide
TR202022336A2 (tr) * 2020-12-30 2022-07-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A film coated tablet comprising teriflunomide
EP4382097A1 (fr) * 2022-11-25 2024-06-12 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du tériflunomide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2496486C1 (ru) * 2012-07-11 2013-10-27 Александр Васильевич Иващенко Фармацевтическая композиция с улучшенной сыпучестью, лекарственное средство, способ получения и применение
WO2015077535A2 (fr) * 2013-11-22 2015-05-28 Genzyme Corporation Nouvelles méthodes pour traiter des maladies neurodégénératives
WO2016079687A1 (fr) * 2014-11-18 2016-05-26 Lupin Limited Composition pharmaceutique orale de tériflunomide
US20180147148A1 (en) * 2015-05-23 2018-05-31 Ftf Pharma Private Limited Pharmaceutical composition of teriflunomide
WO2017037645A1 (fr) * 2015-09-02 2017-03-09 Leiutis Pharmaceuticals Pvt Ltd Formulations pharmaceutiques stables de tériflunomide

Also Published As

Publication number Publication date
WO2020005189A3 (fr) 2020-03-12
EP3813822A4 (fr) 2022-03-16
WO2020005189A2 (fr) 2020-01-02

Similar Documents

Publication Publication Date Title
EP3813822A2 (fr) Compositions pharmaceutiques solides d'administration par voie orale comprenant du tériflunomide
US20230277506A1 (en) Novel preparation containing benzimidazole derivative
WO2022146354A1 (fr) Comprimé pelliculé de film comprenant du tériflunomide
EP2722034B1 (fr) Formulations pharmaceutiques orales comprenant du dabigatran
WO2014060545A1 (fr) Compositions pharmaceutiques de dabigatran sous forme de base libre
WO2019142207A1 (fr) Compositions pharmaceutiques comprenant de l'ibrutinib
WO2016079687A1 (fr) Composition pharmaceutique orale de tériflunomide
CN116133646A (zh) 普拉替尼药物组合物
US10583087B2 (en) Pharmaceutical composition for oral administration
WO2013109225A1 (fr) Formulations pharmaceutiques en comprimés comprenant du ceftibutène
WO2020009675A2 (fr) Compositoins pharmaceutiques solides d'administration par voie orale comprenant de la linagliptine
JP2019019112A (ja) ４−［５−（ピリジン−４−イル）−１ｈ−１，２，４−トリアゾール−３−イル］ピリジン−２−カルボニトリル、又はその塩を含む徐放製剤。
WO2019004980A2 (fr) Compositions pharmaceutiques orales solides d'étéxilate de dabigatran
CA3085455C (fr) Forme pharmaceutique orale solide comprenant de la linagliptine
WO2021091510A1 (fr) Capsule comprenant de l'eltrombopag olamine
KR20210071242A (ko) 제약 조성물
WO2019203751A2 (fr) Combinaisons de tolpérisone et d'inhibiteurs de la cox-2 sélectif
JP7407364B2 (ja) ラメルテオン含有固形製剤
US20240122857A1 (en) Pharmaceutical formulations of indoleamine 2, 3-dioxygenase inhibitors
EP3677254B1 (fr) Compositions pharmaceutiques orales solides de desvenlafaxine
EP4282415A1 (fr) Composition de comprimé stable d'axitinib
WO2023128900A1 (fr) Compositions pharmaceutiques comprenant de la pimavansérine comme principe actif et excipients appropriés
WO2022119542A1 (fr) Formulations pharmaceutiques solides de dapagliflozine amorphe
EA045272B1 (ru) Твердая фармацевтическая композиция на основе гидрохлорида луразидона для перорального применения
JP2020189824A (ja) レベチラセタムを含有する錠剤とその製造方法

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20201225

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20220216

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/20 20060101ALI20220210BHEP

Ipc: A61K 9/28 20060101ALI20220210BHEP

Ipc: A61K 47/10 20170101ALI20220210BHEP

Ipc: A61K 31/277 20060101AFI20220210BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230708

17Q First examination report despatched

Effective date: 20230725