GB2491205A - Composition comprising bosentan and diluents - Google Patents
Composition comprising bosentan and diluents Download PDFInfo
- Publication number
- GB2491205A GB2491205A GB1109231.9A GB201109231A GB2491205A GB 2491205 A GB2491205 A GB 2491205A GB 201109231 A GB201109231 A GB 201109231A GB 2491205 A GB2491205 A GB 2491205A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pharmaceutical composition
- diluent
- solid pharmaceutical
- composition according
- bosentan
- 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- Withdrawn
Links
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- 239000003085 diluting agent Substances 0.000 title claims abstract description 48
- 229960003065 bosentan Drugs 0.000 title claims abstract description 45
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 54
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- 229960003988 indigo carmine Drugs 0.000 description 1
- 239000004179 indigotine Substances 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000007912 modified release tablet Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 201000003086 pulmonary systemic sclerosis Diseases 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000012776 robust process Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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
- A61K9/28—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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
A stable solid pharmaceutical composition comprises: - bosentan or a pharmaceutically acceptable salt thereof; - a first diluent or filler which is a cellulose derivative; - a second diluent or filler which is different from the first diluent. Preferably the second diluents is starch or lactose. Also disclosed is a process for manufacturing the inventive pharmaceutical composition, wherein a granulate is prepared from a powder mixture of the ingredients, compressing the mixture and applying a coating thereto.
Description
I
Pharmaceutical 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-te#butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) -pyrimidifl-4-yljbenzenesUlfOnamide.
is a dual endothelin receptor antagonist with affinity for both endothelin ETA and ETa recep-tors thereby preventing the deleterious effects of ET-l. 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 Al. 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.
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 (SrnPC) of Tracleer®, available in the S internet from the website of the European Medicines Agency (EMA): LJRL: http:llwww.ema.europa.eu/docs/enj3B/documentjibrarylEPAR_-....Product_ lnfon-nation/human/000401 /WC500041 597.pdf). According to the Sm PC, these tablets have a shelf life of 4 years, but they also exhibit a storage condition that it is not allowed to store the tablets above 30°C.
The 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/documentJibrary!EPAt-Scientific_Discussion/humani00040 11WC500041457.pdf).
According to the Sm PC, 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 I 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.
Therefore there is a need for alternative pharmaceutical compositions comprising or consisting of bosentan or a pharmaceutically acceptable salt thereof with increased stability.
According to relevant pharmaceutical regulatory guidelines, like the guidelines from the International Conference on Harmonisation (ICH) (e.g. QIA(R2) -Stability Testing of New Drug Substances and Products) or the European Medicines Agency (EMA) (e.g. CPMP/QWP/609/96/Rev 2 -Guideline on Declaration of Storage Conditions), 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 riot stable. The major attributes which affect the properties or the physical and chemical stability of a pharmaceutical composition are e.g. appearance, hardness (or resistance to crushing), disintegration time, dissolution (profile), friability, water content, chemical stability (degradation products, so-called related substances), and uniformity of dosage units or mass. A significant change of at least one of these attributes over the time under controlled storage conditions could lead to the requirement of storage conditions.
Therefore there it was an object of the present invention to provide a stable solid phamiaceutical 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.
In this context 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.
The object of the present invention has been solved by the subject matter as defined in the claims.
It was surprisingly found that the stability of 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.
Accordingly, the first aspect of the present Invention is 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.
In the context of the present invention 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. Preferably, 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.
In context of the present invention 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. Furthermore, bosentan can be used in anhydrous or in hydrate form, preferably bosentan is used in the monohydrate form. Furthermore, 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) c50 pm, and most preferably a D(v,O.9) <30 pm. Preferably, 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. In a preferred embodiment 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 %. In particular the amount of bosentan as active ingredient is about 50 %. in a most preferred embodiment of the present invention, the amount of bosentan in the inventive dosage form is 32 mg, 62.5 mg or 125 rrig calculated on the free base.
Examples of 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 exciplent. In a preferred embodiment the first diluent is microcrystalline cellulose.
As 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, rnaltitol, 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 niix) and/or in the extragranular phase. In a preferred embodiment of the invention 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.
Examples of the binder contained in the solid pharmaceutical composition according to the invention 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. In a preferred embodiment the binder is povidone or HPMC, Examples of the disintegrant, which may be contained in the granulate andlor as an extragranular component, are croscarmellose sodium, sodium starch glycolate, poly-vinylpolypyrrolidone (crospovidone), low-substituted hydroxypropyl cellulose (L-HPC), and the like. Preferably the disintegrant is sodium starch glycolate or low-substituted hydroxypropyl cellulose. As glidants, 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. Preferably 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. In addition, such a multi-stage process may lead to insufficient physical parameters and it may also affect the final quality of the pharmaceutical composition. When following the disclosed process, the present inventors observed indeed sticking during tablet compression, i.e. the tabletting mixture sticked to the punches.
On the other hand, the direct compression process disclosed in WO 2006/123285: mixing six different excipients of phase II for 10-20 minutes; adding this mixture to phase I, which is a mixture of bosentan and two further excipients, and re-mixing again for 10-20 minutes; adding of phase Ill and mixing 2-5 minutes; and subsequent compression into tablets; is also a quite complex and time consuming process.
Accordingly, 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 lactose1 and phamiaceutically 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).
In a particularly preferred form, 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. Moreover, the granulation liquid may optionally contain a binder, e.g. polyvinylpyrrolidone, copovidone, hydroxypropylmethyl cellulose or hydroxypropyl cellulose. Preferably wet granulation is conducted in a rapid mixer granulator or a fluid bed processor.
In an alternative embodiment, the granulate in step (I) is produced by means of dry granulation technique readily known to a person skilled in the art. Preferably roller compactors, Fitzpatrick roller compactor mills and tabletting machines can be used.
In a particularly preferred form, 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. The reason for this is that it has been found that the dissolution rate of the active ingredient bosentan in an aqueous medium is increased if an extragranular disintegrant is present. Preferably 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 Ll-1-32 which are fine grades, and sodium starch glycolate.
Alternatively, the present invention relates to 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 lii) applying a film coating to the tablet core obtained in step (ii).
In both processes, namely granulation and direct compression, fillers or diluents, binders, disirtegrants, glidants, and lubricants as set out hereinbefore may be used as pharmaceutically acceptable excipients.
In a preferred embodiment of the invention, 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. Typically, 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.
Preferably, 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. As 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.
According to the present invention, 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 S 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 intermediate and/or accelerated conditions according to ICH guideline QIA(R2) (i.e. at 25°C! % relative humidity (RH.) and/or at 40 °C / 75 % RH). These tests shall be performed -is according to applicable pharmaceutical regulatory standards as described e.g. in ICH or EMA guidelines and/or the European Pharmacopeia (EP).
At least some of these attributes, i.e. properties or physical and chemical stability, preferably most of these attributes and most preferably all of theses attributes of the inventive composition are stable over time and different controlled storage conditions. In a preferred embodiment 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 intermediate or long-term storage conditions. i.e. 25 °C /60 % RH or 40 °C /75 % RH. More preferably, 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 intermediate or long-term storage conditions. By "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 Pharmacopeia.
The solid pharmaceutical composition of the present invention, for example, a tablet or film-coated tablet, 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 dimesion 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 110 N. Furthermore the 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. The use of 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, polypropyrene or polyethylene (e.g. HDPE, high density polyethylene) containers or glass bottles. Preferably the composition is packed in a blister known in the art, e.g. sealed aluminium blister (Alu-Alu), Aluminium / Aluminium peel-push blisters or PVC/PEfPVDCIaluminium-blisters.
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 medicarnent for use in the treatment of pulmonary arterial hypertension. The invenvtive composition is preferably used in the treatment or prophylaxis of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, systemic sclerosis, and idiopathic pulmonary fibrosis.
In a preferred embodiment, 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.
In a more preferred embodiment 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 PAL-I associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology. Furthermore, in a preferred embodiment 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.
Examples:
Ingredients in (mgftablet) El E2 E3 E4 ES --E6 Stage A (Dry mix) Bosentanmonohydrate 133.88 133.52 12908 133.52 129.08 129.08 Microcrystalline cellulose 61.62 68.98 83.42 58.98 73.42 68.67 (Comprecele M 101 D+) Isomalt (Galen IQ 800) 28.00 -----Pregelatinized starch -20.00 ---- (Starch 1500@) Lactose monohydrate --20.00 40.00 -- (Granulac® 200) Maize starch ----20.00 18.00 -10.00 10.00 10.00 10.00 10.00 cellulose (L-HPC LFI-31) Sodium starch glycolate type -A 8 00 (Primojel) Stage B (BInder Solution) Povidone (PIasdone K-29/32) 10.00 5.00 5.00 5.00 5.00 10.00 Purified water q.s q.s q.s q.s q.s q.s Stage C (Blending and Lubrication) -10.00 --10.00 10.00 cellulose (L-HPC LH-31) Sodium starch9lycolate type-A 600 ---- (Primojele) Magnesium stearate 2.50 2.50 2.50 2.50 2.50 3.00 Colloidal anhydrous silica -----1.25 (Aerosil® 200) Corn tabiet weight (tng) 250.00 250.00 250.00 250.00 250.00 250.00 Stage D (Coating) lnstamoistshield Pink A21E00132 8.00 8.00 12.00 8.00 8.00 8.00 Isopropanol q. s. q. S. q. s. q. s. q. s. q. s.
Purified water q. s. q. s. -q. s. q. a q.s. q. s.
Coated tablet we;ght (mgi) 258.00 258.00 282.00 258.00 253.00 258.00 lnstamoistshield Pink A21 EO01 32 is composed of hypromellose. glycerine, ethyl cellulose, talc, titanium dioxide, iron oxide yellow and iron oxide red.
Process: 1) sift all the ingredients of stage A separately, 2) blend the sifted material in a rapid mixer granulator low impeller speed, 3) prepare binder solution of stage B by dissolving povidone in purified water, 4) granulate the dry mix in rapid mixer granulator using binder solution of stage B, 5) mill the wet mass, 6) load the wet mass in flu idized bed dryer and dry it, 7) sift the dried granules and all the stage C ingredients separately, 8) blend the extra-granular material with granules in blender, 9) compress the tablets on rotary tablet compression machine, 10) prepare coating solution of stage 0 by dispersing coating material in isopropanol and/or purified water, and 11) coat the tablets using perforated coating machine.
Ingredients in (mg/tablet) ---E7 Stage A (Dry mix) Bosentan monohydrate 133.88 Microcrystafline cellulose (Comprecel& M 102 D+) 39.37 Pregelatinized starch (Starch I 500) 37.00 Low-substituted hydroxypropyl cellulose (L-l-IPC LH-31) 25.00 Magnesium stearate 1.25 Stage B (Blending and Lubrication) Low-substituted hydroxypropyl cellulose (L-HPC LH-31) 11.00 Magnesium stearate 1.25 Colloidal anhydrous silica (Aerosil9 200) 1.25 Core tablet wei'ht (,ng) 250.00 Stage C (Coating) lnstamoistshield Pink A21E001 32 8.00 lsopropyl alcohol q. S. Purified water q. s.
Coated tablet we;ht (mg) -2.00 Instamoistshield Pink A21 E001 32 is composed of hyprornellose, glycerine, ethyl cellulose, talc, titanium dioxide, iron oxide yeflow and iron oxide red.
Process: 1) Sift all the ingredients of stage A separately, 2) blend all the sifted material in a blender, 3) compact the blend to form slugs, 4) mill the slugs to granules, 5) sift the granules and all the stage B ingredients separately, 6) blend the extra-granular material of stage B with granules in a blender, 7) compress the tablets on rotary tablet compression machine, 8) prepare coating solution of stage C by dispersing coating material in isopropanol and/or purified water, and 9) coat the tablets using perforated coating machine.
Claims (15)
- Claims: 1. Solid pharmaceutical composition comprising bosentan or a pharmaceutically acceptable salt thereof, a first diluent which is a cellulose derivative and a second diluent which is different from the first diluent and which is an organic diluent, such as lactose.
- 2. Solid pharmaceutical composition according to claim 1, wherein bosentan is in the monohydrate form.
- 3. Solid pharmaceutical composition according to claim I or 2, wherein the bosentan is contained in an pharmaceutical active amount, preferably 32 mg, 62.5 mg or 125 mg.
- 4. Solid pharmaceutical composition according to any one of claims I to 3, wherein 90 wt.- % of bosentan particles have a particle size of less than 150 pm.
- 5. Solid pharmaceutical composition according to any one of claims I to 4, wherein the solid pharmaceutical composition is a tablet.
- 6. Solid pharmaceutical composition according to any of the preceding claims obtainable by using the method of granulation.
- 7. Solid pharmaceutical composition according to claim 6 obtainable by using the method of wet granulation.
- 8. Solid pharmaceutical composition according to any one of claims 6 or 7, wherein the composition contains one or more disintegrants in the extragranular phase.
- 9. Solid pharmaceutical composition according to any of the preceding claims, wherein the first diluent is microcrystalline cellulose.
- 10. Solid pharmaceutical composition according to any of the preceding claims, wherein the second diluent is starch or lactose.
- II. Solid pharmaceutical composition according to any of the preceding claims, wherein the second diluent is maize starch or lactose monohydrate.
- 12. A process for manufacturing a solid pharmaceutical composition according to anyone of the preceding claims, comprising the steps of: 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 optional!y pharmaceutically acceptable excipients; iii) compressing the tabletting mixture; and optionally iv) applying a film coating to the tablet core obtained in step (iii).
- 13. Process according to claim 12, wherein the granules are prepared by granulation, preferably by wet granulation.
- 14. Process according to claim 13, wherein the tabletting mixture obtained in step (ii) contains one or more disintegrants in the extragranular phase.
- 15. Use of a solid pharmaceutical composition according of any one of claims I to 11 for the use in the manufacture of a medicament for use in the treatment of pulmonary arterial hypertension.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1109231.9A GB2491205A (en) | 2011-05-25 | 2011-05-25 | Composition comprising bosentan and diluents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1109231.9A GB2491205A (en) | 2011-05-25 | 2011-05-25 | Composition comprising bosentan and diluents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB201109231D0 GB201109231D0 (en) | 2011-07-13 |
| GB2491205A true GB2491205A (en) | 2012-11-28 |
Family
ID=44310740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1109231.9A Withdrawn GB2491205A (en) | 2011-05-25 | 2011-05-25 | Composition comprising bosentan and diluents |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2491205A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19743681A1 (en) * | 1997-10-02 | 1999-04-08 | Knoll Ag | Use of endothelin receptor antagonists to prevent transplant rejection |
| WO2007106494A2 (en) * | 2006-03-13 | 2007-09-20 | Encysive Pharmaceuticals, Inc. | Methods and compositions for treatment of diastolic heart failure |
-
2011
- 2011-05-25 GB GB1109231.9A patent/GB2491205A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19743681A1 (en) * | 1997-10-02 | 1999-04-08 | Knoll Ag | Use of endothelin receptor antagonists to prevent transplant rejection |
| WO2007106494A2 (en) * | 2006-03-13 | 2007-09-20 | Encysive Pharmaceuticals, Inc. | Methods and compositions for treatment of diastolic heart failure |
Non-Patent Citations (1)
| Title |
|---|
| http://www.tracleer.com/Content/Pdf/Tracleer-Full-Prescribing-Information-Mar11.pdf * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201109231D0 (en) | 2011-07-13 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |