WO2018153925A1 - Compositions pharmaceutiques stables comprenant du macitentan - Google Patents

Compositions pharmaceutiques stables comprenant du macitentan Download PDF

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Publication number
WO2018153925A1
WO2018153925A1 PCT/EP2018/054290 EP2018054290W WO2018153925A1 WO 2018153925 A1 WO2018153925 A1 WO 2018153925A1 EP 2018054290 W EP2018054290 W EP 2018054290W WO 2018153925 A1 WO2018153925 A1 WO 2018153925A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
macitentan
composition according
pharmaceutically acceptable
minutes
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PCT/EP2018/054290
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English (en)
Inventor
Jatin GAJJAR
Shreejit MENON
Dhruv SHAH
Nikunj Patel
Jalashri PATADIA
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Amneal Pharmaceuticals Company Gmbh
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Publication of WO2018153925A1 publication Critical patent/WO2018153925A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2022—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
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the present disclosure relates to a stable pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Specifically, the present disclosure relates to a pharmaceutical composition of macitentan or a pharmaceutically acceptable salt thereof is surfactant-free.
  • Macitentan is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.
  • the chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5- bromo-2-pyrimidinyl) oxy]ethoxy]-4- pyrimidinyl]-N'-propylsulfarnide. It has a molecular formula of C 19 H 20 Br 2 N 6 O 4 S and a molecular weight of 588.27.
  • Macitentan is a crystalline powder that is insoluble in water and possess achiral group with following structural Formula -I.
  • Macitentan is a BCS class II drug substance characterized by low solubility and high permeability.
  • the poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability.
  • rate limiting step is drug release from the dosage form and solubility in the gastric fluid and not the absorption, so increasing the solubility in turn increases the bioavailability for BCS class II drugs.
  • Macitentan is the active ingredient in a product being sold as OPSUMIT® for the long-term treatment of pulmonary arterial hypertension.
  • Inactive ingredients are: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A, polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.
  • Polysorbate 80 is a commonly known surfactant.
  • US Patent 8,367,685 B2 describes pharmaceutical compositions comprising macitentan or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof and additionally, a filler, a disintegrant, a surfactant, and a lubricant.
  • the '685 patent specifically requires use of surfactant to prepare pharmaceutical composition.
  • the '685 patent teaches that the pharmaceutical composition would have altered properties if certain components in formulation were missing or replaced by other components even though one skilled in the art would understand this as equivalent substitution. Moreover, the alteration would make the composition less stable and/or unsuitable for certain types of preparations.
  • the recited experiments emphasize that only a particular combination of excipients are suitable for the preparation of storage-stable pharmaceutical compositions of macitentan having a satisfactory dissolution profiles.
  • PCT Patent Application WO 2014/173805 describes a pharmaceutical composition comprising crystalline macitentan free base and at least one excipient.
  • the '805 patent application discloses a pharmaceutical composition that preferably comprises at least one excipient selected from the group consisting of fillers, disintegrants, lubricants, and surfactants and a method for the preparation thereof.
  • non-ionic surfactants are less toxic than ionic surfactants, non-ionic surfactants may change the permeability of the intestinal lumen, which can cause absorption of toxins that leads to serious medical conditions.
  • the present invention is directed to a stable surfactant-free pharmaceutical composition of macitentan.
  • the present invention relates to a stable surfactant-free pharmaceutical composition
  • a stable surfactant-free pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the present invention further relates to a process of preparing a stable surfactant- free pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • embodiments of the pharmaceutical composition are used in the treatment of a disease selected from the group consisting of: pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease and angina.
  • Methods of treatment include: administering a pharmaceutical formulation comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the formulation does not comprise a surfactant.
  • the pharmaceutical formulation is formulated to deliver an amount of macitentan or a pharmaceutically acceptable salt thereof effective to treat one or more of: pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease, and angina.
  • compositions comprise macitentan or a pharmaceutically acceptable salt thereof in the absence of a surfactant. Processes of preparing the pharmaceutical compositions are provided.
  • surfactant means a surface-active agent, a substance such as a detergent that, when added to a liquid, reduces its surface tension, thereby increasing its spreading and wetting properties, and include the following: sodium lauryl sulphate, polysorbates (commercially available as Tween®), polyethylene polyoxypropylene polymers (Pluronic F65), polyoxylethylene stearates (MYRJ), dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters (commercial available from Nikko Chemicals), polyoxyethylene Cl-4-alkyl ethers, sucrose monoesters and lanolin esters and ethers.
  • a pharmaceutical composition is considered “stable” if, during a certain period of time, 70%, preferably 80% and most preferably 95% of the initial content of a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, is maintained over said period of time.
  • the pharmaceutical compositions are surfactant-free, which excludes any functional (e.g., noncontaminating) amount of surfactant, including any amount that contributes to or has any effect on the stability of the macitentan. Stated differently, the composition may in some embodiments contain surfactant in an amount that is functionally negligible.
  • a first aspect is a surfactant-free pharmaceutical composition
  • a surfactant-free pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the present invention addresses major problems associated with the use of surfactants in an oral formulation, specifically gastric irritation and toxicity.
  • gastric irritation and toxicity When a higher amount of a surfactant is used in a formulation to solubilize a poorly soluble drug, it may cause toxicity and lead to gastric irritation.
  • Non-ionic surfactants are less toxic than ionic surfactants but they may lead to reversible changes in the permeability of the intestinal lumen. The change in the permeability of the membrane may lead to absorption of toxins leading to serious medical conditions.
  • the present invention has found an approach for solving this problem by formulating a surfactant-free pharmaceutical composition comprising of macitentan, wherein the pharmaceutical composition is free of surfactant without having a substantial impact on stability.
  • the surfactant-free macitentan composition may be formulated with one or more pharmaceutically acceptable excipients, representative examples of which include diluents, binders, disintegrants and glidants.
  • diluents include but are not limited to: inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof.
  • diluents may be one or more of: lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomalt, or celluloses like microcrystalline cellulose (MCC) or powdered celluloses.
  • the diluents may present in an amount from about 10% to about 80% by weight of the composition, preferably from about 40% to about 80% by weight of the composition.
  • the pharmaceutical composition may further include binders.
  • suitable binders include but are not limited to: polyvinylpyrrolidone (PVP), starch, cellulose derivatives like hydroxypropylmethyl cellulose, sucrose, lactose, xylitol, sorbitol, maltitol, water, alcohol, and the like.
  • a preferred binder includes polyvinylpyrrolidone, which is commercially available as Povidone K30.
  • the binders may present in an amount from about 0.5% to about 5.0% by weight of the composition, preferably from about 1.0% to about 3.0% by weight of the composition.
  • Disintegrants in the pharmaceutical composition may be selected from the group consisting of: sodium starch glycolate (SSG), alginates, pregelatinized starch, croscarmellose, and the like.
  • Preferable disintegrants include sodium starch glycolate.
  • the disintegrants may present in an amount from about 1.0% to about 10% by weight of the composition, preferably from about 3.0% to about 7.0% by weight of the composition.
  • the pharmaceutical composition may further include lubricants.
  • suitable lubricants include: fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid.
  • a preferred lubricant is magnesium stearate and may present in amount from about 0.1% to about 10% by weight of the composition.
  • Glidants present in a pharmaceutical dosage form include but are not limited to: silicon dioxide, talc, magnesium stearate, and the like.
  • a preferred glidant is talc and may present in amount from about 0.1% to about 10% by weight of the composition.
  • the pharmaceutical composition may be obtained by known conventional methods including but not limited to: dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion, and the like.
  • a pharmaceutical composition comprises: from about 1% to about 40% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 10% to about 80% w/w of one or more diluents, about 0.5% to about 5% w/w of one or more binders, about 1% to about 10% w/w of one or more disintegrants, about 0.1% to about 10% w/w of one or more lubricants, about 0.0% to about 10% w/w of one or more glidants, and optionally about 1.0% to about 10% w/w of one or more film coating materials.
  • the amounts of macitentan or a pharmaceutically acceptable salt thereof, diluents, binders, disintegrants, lubricants, glidants, and film coating material total 100% in the pharmaceutical composition.
  • the pharmaceutical composition consists of: from about 1% to about 40% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 10% to about 80% w/w of one or more diluents, about 0.5% to about 5% w/w of one or more binders, about 1% to about 10% w/w of one or more disintegrants, about 0.1% to about 10% w/w of one or more lubricants, about 0.0% to about 10% w/w of one or more glidants, and optionally about 1.0% to about 10% w/w of one or more film coating materials.
  • the pharmaceutical composition comprises: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.0 to 2.0% w/w of talc, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material.
  • talc is present in an amount in the range of 0.1 to 2.0% w/w.
  • the amounts of macitentan or a pharmaceutically acceptable salt thereof, lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone, sodium starch glycolate, talc, magnesium stearate, and film coating material total 100% in the pharmaceutical composition.
  • the pharmaceutical composition consists of: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0 to 2.0% w/w of talc, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material.
  • the pharmaceutical composition comprises: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material, preferably a PVA- based film coating material.
  • the pharmaceutical composition consists of: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material, preferably a PVA-based film coating material.
  • the pharmaceutical composition is prepared by a process comprising: (i) preparing a dry mixture comprising macitentan and one or more pharmaceutical excipients; (ii) granulating the dry mixture by addition of binder solution; (iii) sifting and milling of dried granules; (iv) blending of dried and milled granules with one or more pharmaceutical excipients and lubricants; (v) compressing or filling the lubricated blend to form a composition; and (vi) optionally coating the composition.
  • the dry mixture of (i) is prepared in the absence of a surfactant.
  • the blend of dried and milled granules with one or more pharmaceutical excipients and lubricants is in the absence of a surfactant. In one or more embodiments, the process is conducted in the absence of a surfactant.
  • a second aspect provides a process for the preparation of a pharmaceutical composition, wherein the process comprises: blending macitentan and one or more pharmaceutically acceptable excipients; further lubricating the blend; and directly compressing the lubricated blend into tablets or filling the lubricated blend into capsule dosage form.
  • blending of macitentan and one or more pharmaceutically acceptable excipients is done in the absence of a surfactant.
  • the process is conducted in the absence of a surfactant.
  • a third aspect provides a process for the preparation of the pharmaceutical composition, wherein the process comprises: blending macitentan and one or more diluents, binders, and disintegrants; compacting the blend to obtain granules or flakes; lubricating the granules/flakes using the additional lubricants; and compressing the lubricated granules into tablets or filling into capsules.
  • blending of macitentan and one or more diluents, binders, and disintegrants is done in the absence of a surfactant.
  • the process is conducted in the absence of a surfactant.
  • a fourth aspect provides a process for the preparation of a pharmaceutical composition, wherein the process comprises: blending macitentan and one or more hydrophilic polymers in a rapid mixer granulator; loading the granules obtained into a hot melt extruder to form a solid dispersion in the form of extrudates; milling the extrudates and adding one or more diluents, binders, disintegrants, and lubricants; and compressing the granules into tablets or filling into capsules.
  • hydrophilic polymers include: poly(ethylene glycol) (PEG), polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and polyacrylic acid (PAA).
  • blending of macitentan and one or more hydrophilic polymers is done in the absence of a surfactant. In one or more embodiments, the process is conducted in the absence of a surfactant.
  • the pharmaceutical composition may be in a dosage form of minitablets, granules, pellets, tablets, and/or capsules.
  • the pharmaceutical composition may further be film-coated using techniques known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using the hot melt technique.
  • the film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents.
  • film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; waxes; fat substances; or mixtures thereof.
  • cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose
  • OPADRY® commercially available coating compositions comprising film forming polymers marketed under various trade names, such as OPADRY®, may be used for coating.
  • solvents used for preparing the coating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
  • the pharmaceutical composition may be used in the treatment of a disease selected from the group consisting of, pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease and angina.
  • step 4 Perform granulation of step 3 by addition of binder solution of step 2.
  • Example 2 The dissolution profile for Example 1 is depicted in Table 2. USP dissolution studies were performed for both reference and test products. Table 2
  • Example 1 shows more than 95% drug release in 45 minutes in 900 ml of dissolution media containing mixture of pH Phosphate Buffer, pH 6.8 with 0.1% of cetrimonium bromide (CTAB) at 75 RPM using USP dissolution apparatus II.
  • CAB cetrimonium bromide
  • Example 1 the dissolution profile of pharmaceutical composition of Example 1 is comparable with marketed reference product of macitentan (Opsumit®), which contains surfactant polysorbate 80.
  • the pharmaceutical composition preferably the tablet, releases 80% or more of the macitentan after 10 minutes of USP dissolution testing; 90% or more of the macitentan after 20 minutes; and/or 95% or more of the macitentan after 45 minutes.
  • the pharmaceutical composition preferably the tablet, releases 93% or more of the macitentan after 10 minutes of USP dissolution testing; 97% or more of the macitentan after 15 minutes; 98% or more of the macitentan after 20 minutes; 99% or more of the macitentan after 30 minutes; and/or 99% or more of the macitentan after 45 minutes.
  • a percentage of the macitentan released after dissolution testing for a time of an inventive tablet that is surfactant-free is within (e.g., ⁇ ) 5% (absolute) of a percentage released by a reference tablet comprising macitentan and a surfactant (e.g., polysorbate 80) after dissolution testing for the same time.
  • the amount of the macitentan released at one or more time points after dissolution testing of an inventive tablet that is surfactant- free in a USP dissolution apparatus 2 (paddle) with 900 mL of phosphate buffer and 0.1% of cetrimonium bromide at pH 6.8 and 75 rpm stirring is within X% of the amount released at the same time points after dissolution testing of a reference tablet comprising macitentan and a surfactant (e.g., polysorbate 80), wherein X% and time points are as follows: about 1% after 10 minutes; about 3% after 15 minutes; about 3% after 20 minutes; about 4% after 30 minutes; and about 4% after 45 minutes.
  • a surfactant e.g., polysorbate 80
  • the stability of the pharmaceutical composition may be tested in a conventional manner, e.g. by measurement of compound of formula I and its degradation or other impurity products, dissolution, friability, disintegration time, appearance and/or microscopy, e.g. after storage at 25° C. and 60% relative humidity, and/or storage at 40° C. and 75% relative humidity for defined periods of time.
  • the pharmaceutical composition remains stable for longer periods of time in different thermo-hygrostats 25° C/60%+5% RH, 30° C/65%+5% RH, and 40° C/75%+5% RH as per ICH guidelines.
  • the solid compositions will be stable for at least 6 or 12 months when kept at a temperature of 5° to 50° C. More preferably, they will be stable for at least 6 or 12 months when kept at a temperature of 15° to 45° C. Most preferred, they will be stable for at least 6 or 12 months when kept at a temperature of 25° to 40° C.
  • the pharmaceutical compositions are stable over a certain period of time such as 1 year, and preferably 2 years. More preferably, the pharmaceutical compositions are stable for 3 years.
  • the content of compound of formula I and its degradation products in the capsules or tablets can be evaluated via high performance liquid chromatography (HPLC).
  • Amounts of impurity products in the pharmaceutical compositions should be as follows:
  • Stage-II-Dimer impurity NMT 0.15 % Any unspecified impurity: NMT 0.20 % Total Impurities: NMT 2.0 %
  • Table 3 shows results of an accelerated stability study of a pharmaceutical composition with identical makeup and dissolution profile to that of Example 1. The result indicates that the pharmaceutical composition remains stable for at least for 6 months in 40°C/75% RH condition with purity greater than 99% or more preferably greater than 99.5%.
  • the amino impurity increases by no more than a factor of about 5 or no more than about 0.1% (absolute) after 6 months of storage at 40°C and 75% relative humidity.
  • the percentage of dirtier impurity is substantially unchanged relative to the initial percentage of dimer impurity after 6 months of storage at 40°C and 75% relative humidity.
  • the percentage of any unspecified impurity is substantially unchanged relative to the initial percentage of unspecified impurity after 6 months of storage at 40°C and 75% relative humidity.
  • the percentage of total impurity increases no more than a factor of about 2 or no more than about 0.01% (absolute) of the initial percentage of total impurity after 6 months of storage at 40°C and 75% relative humidity.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du macitentan ou un sel pharmaceutiquement acceptable de celui-ci et au moins un excipient acceptable pharmaceutiquement. La présente invention concerne spécifiquement une composition pharmaceutique, sans tensioactif, de macitentan ou d'un sel pharmaceutiquement acceptable de celle-ci. De plus, la présente invention concerne une composition pharmaceutique, sans tensioactif, de macitentan, ou un sel pharmaceutiquement acceptable de celui-ci, qui est utilisée dans le traitement d'une maladie choisie dans le groupe constitué par l'hypertension artérielle pulmonaire, l'infarctus du myocarde, l'accident vasculaire cérébral, l'accident ischémique transitoire, la vasculopathie périphérique et l'angine de poitrine.
PCT/EP2018/054290 2017-02-22 2018-02-21 Compositions pharmaceutiques stables comprenant du macitentan WO2018153925A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021005478A1 (fr) 2019-07-05 2021-01-14 TECNIMEDE - Sociedade Técnico-medicinal, SA Compositions de macitentan comprimées, procédés et utilisations de celles-ci
CN113194953A (zh) * 2018-12-21 2021-07-30 埃科特莱茵药品有限公司 用于治疗肺动脉高血压的药物组合物
WO2021154027A1 (fr) * 2020-01-30 2021-08-05 삼성바이오에피스 주식회사 Préparation pharmaceutique d'anticorps anti-pd-1 stable
CN113329751A (zh) * 2019-01-25 2021-08-31 埃科特莱茵药品有限公司 包含用于治疗慢性栓塞性肺动脉高压的马西替坦的药物组合物
WO2022045991A1 (fr) * 2020-08-26 2022-03-03 Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş. Compositions pharmaceutiques comprenant du macitentan et des excipients appropriés
WO2023038600A1 (fr) * 2021-09-07 2023-03-16 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de capsule comprenant du macitentan

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Publication number Priority date Publication date Assignee Title
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