EP2696857A1 - Composition pharmaceutique comprenant du bosentan - Google Patents

Composition pharmaceutique comprenant du bosentan

Info

Publication number
EP2696857A1
EP2696857A1 EP12716240.2A EP12716240A EP2696857A1 EP 2696857 A1 EP2696857 A1 EP 2696857A1 EP 12716240 A EP12716240 A EP 12716240A EP 2696857 A1 EP2696857 A1 EP 2696857A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
diluent
solid pharmaceutical
bosentan
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.)
Withdrawn
Application number
EP12716240.2A
Other languages
German (de)
English (en)
Inventor
Chaitanya Yogananda Gujjar
Bala Ramesha Chary RALLABANDI
Manohar Lal Pasahn
Thomas Rillmann
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.)
Alfred E Tiefenbacher GmbH and Co KG
Original Assignee
Alfred E Tiefenbacher GmbH and Co KG
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 Alfred E Tiefenbacher GmbH and Co KG filed Critical Alfred E Tiefenbacher GmbH and Co KG
Publication of EP2696857A1 publication Critical patent/EP2696857A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • composition comprising bosentan
  • the present invention relates to a solid pharmaceutical composition comprising bosentan or a pharmaceutically acceptable salt thereof, a process for manufacturing the inventive composition and use of the inventive pharmaceutical composition.
  • Bosentan represented by structural formula (I) and chemically named 4-tert-butyl-/V-[6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulfonamide, is a dual endothelin receptor antagonist with affinity for both endothelin ETA and ETB receptors thereby preventing the deleterious effects of ET-1. It is useful for the treatment of cardiovascular disorders such as hypertension, ischaemia, vasospasm and angina pectoris.
  • Bosentan and the preparation thereof is disclosed in EP 526 708 A1. It is marketed as Tracleer ® and it is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and it is indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Bosentan is commercial available as 62.5 mg or 125 mg film-coated tablets as well as 32 mg dispersible tablet.
  • PAH pulmonary arterial hypertension
  • the commercial available film-coated tablets have the following composition: bosentan (125 or 62.5 mg), maize starch, pregelatinized starch, sodium starch glycolate, povidone, glycerol dibehenate and magnesium stearate, while the coating is composed of hypromellose, glycerol triacetate, talc, titanium dioxide, yellow and red iron oxides, and ethyl cellulose (taken from the Summary of Products Characteristics (SmPC) of Tracleer ® , available in the internet from the website of the European Medicines Agency (EMA): URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_
  • EMA European Medicines Agency
  • bosentan tablets are manufactured using a typical wet granulation method which comprises (i) dry blending of bosentan monohydrate, maize starch, pregelatinized starch, sodium starch glycolate, and povidone; (ii) wet granulation with purified water in a high shear granulator to obtain granules; (iii) subsequent fluid bed drying, sieving, and mixing with glycerol dibehenate and magnesium stearate; and (iv) compressing into tablets and coating (taken from the EPAR - Scientific Discussion of Tracleer ® , available in the internet from the website of the EMA: URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Scientific_
  • the commercial dispersible bosentan tablet contains 32 mg bosentan, microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, anhydrous colloidal silica, tartaric acid, tutti frutti flavour, aspartame, acesulfame potassium and magnesium stearate.
  • the dispersible tablet has also a storage condition; it is prohibited to store it above 25°C.
  • WO 2006/123285 discloses in example 1 the composition of commercial Tracleer ® dispersible tablets and in example 2 and 3 further dispersible tables which comprise bosentan and suitable excipients, which are fillers, disintegrants, glidants, acidifying agents, flavouring agents, sweetening agents, and lubricants.
  • the pharmaceutical compositions comprising bosentan which are known in the state of the art are labelled with storage conditions. It is not allowed to store the film-coated bosentan tablets above 30°C and the dispersible bosentan tablets have to be stored below 25°C.
  • Such storage conditions are in general a great disadvantage for the commercialization of pharmaceutical compositions, e.g. tablets, as temperature controlled manufacturing, transport and storage is necessary. Furthermore the storage at a certain temperature is a burden for the patient in need of such pharmaceutical compositions, particularly in tropical or sub-tropical climate zones.
  • the present inventors have carried out stability studies with commercially available Tracleer ® 125 mg film-coated tablets for a period of up to 7.5 months.
  • Tracleer ® 125 mg film-coated tablets show a time dependent drop in drug dissolution (profile), i.e. a retarded drug release, over time.
  • profile time dependent drop in drug dissolution
  • the tested Tracleer ® tablets showed after 7.5 months of storage about 16 % (after 15 minutes), about 13 % (after 30 mins), and about 13 % (after 45 mins) less dissolution of bosentan in comparison to initial dissolution.
  • Such a time dependent drop in dissolution (profile) or retarded drug release is unfavourable from pharmaceutical point of view and leads according to the applicable pharmaceutical guidelines, at least, to the declaration of a storage condition (as occurred in case of the commercially available Tracleer ® tablets) or, in the worst case, to the restriction of the shelf life.
  • ICH International Conference on Harmonisation
  • EMA European Medicines Agency
  • storage conditions are necessary, when a deterioration of the properties of a pharmaceutical composition, e.g. a tablet, is noticeable during stability studies under controlled storage conditions, i.e. the pharmaceutical composition is not stable.
  • the major attributes which affect the properties or the physical and chemical stability of a pharmaceutical composition are e.g.
  • a stable solid pharmaceutical composition comprising bosentan or a pharmaceutically acceptable salt thereof, characterized in that the stable solid pharmaceutical composition having a less strict storage condition or no storage condition.
  • increased stability means that the inventive composition has a less strict storage condition or no storage condition. Accordingly, it was an object of the present invention to provide such a stable pharmaceutical composition comprising bosentan.
  • a stable pharmaceutical composition comprising bosentan which does not show after storage, e.g. at accelerated conditions for up to 6 months, an increased amount of degradation products, a deterioration of the disintegration time of the tablet and/or a deteriorated dissolution profile of the drug bosentan.
  • a stable pharmaceutical composition comprising bosentan or a pharmaceutically acceptable salt thereof with a stable dissolution profile over time; i.e. the tablets show after storage, e.g. at accelerated conditions for up to 6 months, no significant drop in dissolution (profile) or no significantly retarded release of bosentan.
  • a solid pharmaceutical composition comprising bosentan or a pharmaceutically acceptable salt thereof is increased, if the composition comprises a combination of two different diluents or fillers, whereby the first diluent or filler is a cellulose derivative.
  • the first aspect of the present invention is a solid pharmaceutical composition
  • a solid pharmaceutical composition comprises or consists of bosentan or a pharmaceutically acceptable salt thereof, a first diluent or filler which is a cellulose derivative and a second diluent or filler, which is different from the first diluent and which is an organic diluent, e.g. an organic diluent selected from carbohydrates, modified carbohydrates and starches.
  • the inventive pharmaceutical composition can be present in all solid dosage forms which are compressed, including optionally coated tablets as film-coated tablets, (oro)dispersible tablets, modified-release tablets and gastro-resistant tablets.
  • the inventive composition is suitable for oral administration and is coated with a suitable coating. Accordingly, the most preferred composition is a coated or film- coated tablet.
  • bosentan can be used as the free base or in form of a pharmaceutically acceptable salt (also commonly referred to as bosentan), preferably in form of the free base.
  • bosentan can be used in anhydrous or in hydrate form, preferably bosentan is used in the monohydrate form.
  • the particle size distribution of bosentan in the inventive composition is preferably such, that 90 wt.-% of bosentan particles have a particle size of less than 150 pm (D(v,0.9) ⁇ 150 pm). More preferably the particle size distribution has a D(v,0.9) ⁇ 100 pm, more preferably a D(v,0.9) ⁇ 50 ⁇ , and most preferably a D(v,0.9) ⁇ 30 pm.
  • the particle size distribution is further characterized in that 50 wt.-% of the bosentan particles have a particle size of less than 50 pm (D(v,0.5) ⁇ 50 pm). More preferably the particle size distribution has a D(v,0.5) ⁇ 30 pm, more preferably a D(v,0.5) ⁇ 15 pm, and most preferably a D(v,0.9) ⁇ 10 pm.
  • Bosentan is present in the inventive pharmaceutical composition in a therapeutically effective amount.
  • the amount of bosentan, calculated as the percentage of the content in weight of the free base, based on the total weight of the uncoated composition, e.g. tablet, is 15 % to 75 %, preferably between 30 % to 60 %, and more preferably 45 % to 55 %.
  • the amount of bosentan as active ingredient is about 50 %.
  • the amount of bosentan in the inventive dosage form is 32 mg, 62.5 mg or 125 mg calculated on the free base.
  • cellulose derivative as first diluent or filler contained in the inventive solid pharmaceutical composition are microcrystalline cellulose, powdered cellulose, silicified cellulose, cellulose acetate and celluloses which are co-processed with one or more pharmaceutical acceptable excipient.
  • the first diluent is microcrystalline cellulose.
  • second diluent which is different from the first diluent, preferably an organic diluent is used, e.g. an organic diluent selected from carbohydrates, modified carbohydrates and starches, but also inorganic diluents, like calcium or magnesium carbonate, calcium sulfate, kaolin, and magnesium oxide, are applicable.
  • Examples of the second diluent or filler contained in the inventive composition are glucose (synonym is dextrose), lactose (anhydrous or monohydrate), maltose, sucrose, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, starch (maize, potato, wheat), pregelatinized starch, dextrin, and the like.
  • the second diluent is preferably lactose (anhydrous or monohydrate) or starch (maize, potato, wheat).
  • the solid pharmaceutical composition according to the present invention e.g. a tablet or film- coated tablet, contains amongst bosentan or a pharmaceutically acceptable salt thereof, first diluent and second diluent further pharmaceutical excipients as diluent or filler, binder, disintegrant, glidant and lubricant. These pharmaceutical excipients may be contained in the powder mixture (dry mix) and/or in the extragranular phase.
  • the granulate contains bosentan, a cellulose derivative as first diluent, at least one additional diluent, at least one binder and optionally one disintegrant, while lubricants and optionally glidants and are contained as extragranular components only. More preferably at least one disintegrant is contained in addition as extragranular component.
  • binder contained in the solid pharmaceutical composition according to the invention examples include methyl cellulose (MC), hydroxypropylmethyl cellulose (hypromellose, HPMC), hydroxypropyl cellulose (hyprolose, HPC), carboxymethylcellulose sodium (CMC sodium), maltodextrin, polyethylene glycol (PEG), maltodextrin, polyvinylpyrrolidone (povidone, PVP), vinylpyrrolidone/vinyl acetate copolymer (copovidone), and polyvinyl alcohol/polyethylene glycol graft copolymer (Kollicoat ® IR), and the like.
  • the binder is povidone or HPMC.
  • disintegrant examples include croscarmellose sodium, sodium starch glycolate, poly- vinylpolypyrrolidone (crospovidone), low-substituted hydroxypropyl cellulose (L-HPC), and the like.
  • the disintegrant is sodium starch glycolate or low-substituted hydroxypropyl cellulose.
  • colloidal (anhydrous) silica, talc and the like may be used, while magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, magnesium silicate, magnesium trisilicate and hydrogenated vegetable oil are examples of suitable lubricants.
  • colloidal (anhydrous) silica is used as glidant.
  • the lubricant is preferably magnesium stearate or sodium stearyl fumarate.
  • a second aspect of the present invention relates to a process for manufacturing of the solid pharmaceutical composition according to the present invention.
  • the wet granulation process known form the prior art which is disclosed in the scientific discussion of Tracleer ® , is a fairly time-consuming and not quite efficient process, as bosentan and four additional excipients have to be sieved and blended.
  • such a multi-stage process may lead to insufficient physical parameters and it may also affect the final quality of the pharmaceutical composition.
  • the present inventors observed indeed sticking during tablet compression, i.e. the tabletting mixture sticked to the punches.
  • another object of the present invention was to provide a simple, (cost) efficient, and robust process for manufacturing a pharmaceutical composition, preferably an optionally coated tablet as film-coated tablet, comprising bosentan.
  • This object was solved by a process for manufacturing the solid pharmaceutical composition according to the present invention by granulation which comprises the following steps: i) preparing a granulate from a powder mixture (dry mix) comprising bosentan or a pharmaceutically acceptable salt thereof, a first diluent which is a cellulose derivative, a second diluent which is different from the first diluent and which is an organic diluent, such as lactose, and pharmaceutically acceptable excipients; ii) preparing a tabletting mixture comprising the granulate obtained in step (i) and optionally pharmaceutically acceptable excipients; iii) compressing the tabletting mixture; and optionally iv) applying a film coating to the tablet core obtained in step (iii).
  • the granulate in step (i) is produced by means of wet granulation, whereby water, an alcohol such as ethanol or isopropanol, and mixtures of the aforementioned solvents may be used as a granulation liquid.
  • the granulation liquid may optionally contain a binder, e.g. polyvinylpyrrolidone, copovidone, hydroxypropylmethyl cellulose or hydroxypropyl cellulose.
  • a binder e.g. polyvinylpyrrolidone, copovidone, hydroxypropylmethyl cellulose or hydroxypropyl cellulose.
  • wet granulation is conducted in a rapid mixer granulator or a fluid bed processor.
  • the granulate in step (i) is produced by means of dry granulation technique readily known to a person skilled in the art.
  • the inventive composition contains one or more disintegrants in the intragranular phase (step (i)) and/or extragranular phase (step (ii)), preferably in the intragranular and extragranular phase.
  • disintegrants in the intragranular phase (step (i)) and/or extragranular phase (step (ii)), preferably in the intragranular and extragranular phase.
  • the disintegrant is croscarmellose sodium, sodium starch glycolate, polyvinylpolypyrrolidone, or low-substituted hydroxypropyl cellulose.
  • the most preferred disintegrants are low-substituted hydroxypropyl cellulose, e.g. LH-31 or LH-32 which are fine grades, and sodium starch glycolate.
  • the present invention relates to a direct compression process for manufacturing the inventive solid pharmaceutical composition
  • a direct compression process for manufacturing the inventive solid pharmaceutical composition comprising the steps of: i) providing a powder mixture (dry mix) comprising bosentan or a pharmaceutically acceptable salt thereof, a first diluent which is a cellulose derivative, a second diluent which is different from the first diluent and which is an organic diluent, such as lactose, and pharmaceutically acceptable excipients; ii) compressing the powder mixture, and optionally iii) applying a film coating to the tablet core obtained in step (ii).
  • fillers or diluents, binders, disintegrants, glidants, and lubricants as set out hereinbefore may be used as pharmaceutically acceptable excipients.
  • the solid pharmaceutical composition additionally comprises a pharmaceutically acceptable coating.
  • Suitable inert coating agents and methods for coating particles or granules are well known in the art.
  • inert coating agents comprise an inert film-forming agent dispersed in a suitable solvent, and may further comprise other pharmaceutically acceptable excipients, such as colorants and/or plasticizers.
  • the coating of the inventive composition comprises one or more of the following film forming components: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol/polyethylene glycol graft copolymer, sugar, or mixtures thereof.
  • colorants aluminium lakes, such as indigo carmine aluminium lake, and/or iron oxides, such as red iron oxide, and/or titanium dioxide are preferably used in suitable amounts.
  • the amount of the first diluent or filler in the solid pharmaceutical composition may vary within a range of 10 to 60 %, in particular 20 to 40 % in weight based on the total weight of the uncoated composition.
  • the amount of second diluent may vary within a range of 2 to 35 %, in particular 8 to 20 % in weight based on the total weight of the uncoated composition.
  • the amount of binder may vary within a range of 0.5 to 15 %, in particular 1 to 5 % in weight based on the total weight of the uncoated composition.
  • the amount of disintegrant may vary within a range of from 0.5 to 20%, in particular 2 to 10 % in weight based on the total weight of the uncoated composition.
  • the amount of glidant may vary within ranges of from 0.1 to 5 %, in particular 0.5 to 2.5 % in weight based on the total weight of the uncoated composition.
  • the amount of lubricant may vary from 0.1 to 5 %, preferably from 0.1 to 3.0 %.
  • the properties or the physical and chemical stability of the solid pharmaceutical composition of the invention may be tested in conventional manner, e.g. by measurement of appearance, hardness (or resistance to crushing), disintegration time, dissolution, friability, water content, assay for bosentan and/or its degradation products (related substances), and/or uniformity of dosage units or mass after storage at controlled storage conditions; e.g. at long term and/or accelerated conditions according to ICH guideline Q1A(R2) (i.e. at 25 °C / 60 % relative humidity (RH) and/or at 40 °C / 75 % RH).
  • ICH guideline Q1A(R2) i.e. at 25 °C / 60 % relative humidity (RH) and/or at 40 °C / 75 % RH.
  • the dissolution (profile) of the solid pharmaceutical composition according to the present invention e.g. a tablet or film-coated tablet, is stable over at least 6 months when stored at long term or accelerated storage conditions, i.e. 25 °C / 60 % RH or 40 °C / 75 % RH.
  • a stable dissolution profiles over time does not show a significant, e.g. more than 5%, change or drop in drug dissolution after storage.
  • dissolution and further additional attributes such as, e.g., assay, related substances or uniformity of dosage units or mass are stable after storage over at least 6 months when stored at long term or accelerated storage conditions.
  • stable is meant that a measured value is within a narrow range of values which are set before in a specification according to a regulatory guideline, e.g. the European Pharmacopoeia or the ICH guideline. In most cases said narrow range of values is interpreted in accordance to the definition of a "significant change" and therefore it is a range of ⁇ 5 % from an intial value (i.e. a range from intial value minus 5 % to intial value plus 5 %).
  • the solid pharmaceutical composition of the present invention may vary in shape and be, e.g., round, oval, oblong, cylindrical, caplet shaped or any other suitable shape, preferably it is round or caplet shaped. Furthermore the composition according to the invention may be scored or engraved.
  • the solid pharmaceutical composition of the present invention for example, a tablet or film- coated tablet, has a diameter ranging between 3.5 and 15 mm and most preferably between 5.5 and 7.0 mm for round tablets and the dimension of a caplet is between 9.0 x 3.0 mm and 17.0 x 7.5 mm, preferably it is 12.7 x 5.9 mm. Thickness is ranging from 2.0 to 5.0 mm, preferably between 2.5 and 4.6 mm.
  • the solid pharmaceutical composition according to the present invention has a suitable hardness (or resistance to crushing), preferably the film-coated tablets may have a hardness (or resistance to crushing) from 50 N to 130 N, preferably 85 N to 1 0 N.
  • composition of the invention for example, a tablet or a film-coated tablet, may be coloured and/or marked so as to impart an individual appearance and to make them instantly recognizable.
  • dyes can serve to enhance the appearance as well as to identify the pharmaceutical composition.
  • Dyes suitable for use in pharmacy typically include carotinoids, iron oxides or chlorophyll.
  • the pharmaceutical composition of the invention for example, a tablet or a film-coated tablet, may be marked using an imprint code.
  • the inventive pharmaceutical composition may be packed in any conventional packaging known in the art, for example blisters, polypropylene or polyethylene (e.g. HDPE, high density polyethylene) containers or glass bottles.
  • the composition is packed in a blister known in the art, e.g.
  • a third aspect of the present invention relates to the use of the solid pharmaceutical composition according of the present invention in the manufacture of a medicament for use in the treatment of pulmonary arterial hypertension.
  • the inventive composition is preferably used in the treatment or prophylaxis of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, systemic sclerosis, and idiopathic pulmonary fibrosis.
  • PAH pulmonary arterial hypertension
  • chronic thromboembolic pulmonary hypertension chronic thromboembolic pulmonary hypertension
  • systemic sclerosis and idiopathic pulmonary fibrosis.
  • the solid pharmaceutical composition according to the present invention is used in the treatment or prophylaxis of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class II, III, and IV.
  • PAH pulmonary arterial hypertension
  • the solid pharmaceutical composition according to the present invention is used in the treatment or prophylaxis of primary (idiopathic and familial) PAH, secondary PAH associated with scleroderma without significant interstitial pulmonary disease, or PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology.
  • the solid pharmaceutical composition according to the present invention is used to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. The following examples are intended to further illustrate the present invention.
  • Coated tablet weight (mg) 258.00 258.00 262.00 258.00 258.00 258.00 258.00
  • Instamoistshield Pink A21 E00132 is composed of hypromellose, glycerine, ethyl cellulose, talc, titanium dioxide, iron oxide yellow and iron oxide red. Process:
  • Microcrystalline cellulose (Comprecel ® M 102 D+) 39.37
  • Colloidal anhydrous silica (Aerosil ® 200) 1.25
  • Instamoistshield Pink A21E00132 is composed of hypromeilose, glycerine, ethyl
  • E3a and E3b Two batches of the solid pharmaceutical compositions according to the present invention in form of film-coated tablets are produced according to formulation E3 (hereinafter referred to as E3a and E3b).
  • the film-coated tablets of formulations E3a and E3b as well as Tracleer ® 125 mg film-coated tablets (batch no. BW029A02; manufacturer: Actelion Pharmaceuticals Deutschland GmbH; packaging material: PVC/PE/PVDC/aluminium-blisters) are used to carry out stability studies under conditions of 40 °C and 75 % relative humidity (RH) for up to 7.5 months (accelerated storage conditions, ICH guideline Q1 A(R2)).

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Abstract

La présente invention concerne une composition pharmaceutique solide stable comprenant ou constituée de bosentan ou un sel pharmaceutiquement acceptable de celui-ci, un premier diluant ou charge qui est un dérivé de cellulose et un deuxième diluant ou charge qui est différent du premier diluant ainsi qu'un procédé pour fabriquer la composition pharmaceutique de l'invention.
EP12716240.2A 2011-04-11 2012-04-05 Composition pharmaceutique comprenant du bosentan Withdrawn EP2696857A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1056DE2011 2011-04-11
PCT/EP2012/001522 WO2012139736A1 (fr) 2011-04-11 2012-04-05 Composition pharmaceutique comprenant du bosentan

Publications (1)

Publication Number Publication Date
EP2696857A1 true EP2696857A1 (fr) 2014-02-19

Family

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Family Applications (1)

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EP12716240.2A Withdrawn EP2696857A1 (fr) 2011-04-11 2012-04-05 Composition pharmaceutique comprenant du bosentan

Country Status (2)

Country Link
EP (1) EP2696857A1 (fr)
WO (1) WO2012139736A1 (fr)

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GB201400034D0 (en) 2014-01-02 2014-02-19 Astrazeneca Ab Pharmaceutical Compositions comprising AZD9291
TR201915787A2 (tr) * 2019-10-14 2021-04-21 Yilmaz Usta Duygu Bosentan monohi̇drat yüklenmi̇ş sivi kendi̇li̇ği̇nden nanoemülsi̇fi̇ye i̇laç taşiyici si̇stem ve tablet formülasyonu
TR202018841A2 (tr) * 2020-11-23 2021-01-21 Yilmaz Usta Duygu Uzun zi̇nci̇rli̇ mono ve di̇gli̇seri̇t karişimlari i̇le hazirlanan bosentan monohi̇drat yüklü kendi̇li̇ği̇nden nanoemülsi̇fi̇ye i̇laç taşiyici si̇stemleri̇n (snedds) formülasyonu
WO2023128902A1 (fr) * 2021-12-30 2023-07-06 Pharmactive Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques comprenant du bosentan et des excipients pertinents

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