EP4398910A1 - A capsule formulation comprising macitentan - Google Patents

A capsule formulation comprising macitentan

Info

Publication number
EP4398910A1
EP4398910A1 EP22867824.9A EP22867824A EP4398910A1 EP 4398910 A1 EP4398910 A1 EP 4398910A1 EP 22867824 A EP22867824 A EP 22867824A EP 4398910 A1 EP4398910 A1 EP 4398910A1
Authority
EP
European Patent Office
Prior art keywords
macitentan
amount
formulation
weight
capsule according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22867824.9A
Other languages
German (de)
French (fr)
Other versions
EP4398910A4 (en
Inventor
Busra ARI
Akif ERDOGAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Priority claimed from PCT/TR2022/050945 external-priority patent/WO2023038600A1/en
Publication of EP4398910A1 publication Critical patent/EP4398910A1/en
Publication of EP4398910A4 publication Critical patent/EP4398910A4/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds

Definitions

  • Pulmonary arterial hypertension is a disease that accumulates pulmonary artery endothelial cells, muscle layer and adventitia, which restricts pulmonary artery blood flow, which leads to increased pulmonary vascular resistance, progressive increase in pulmonary artery pressure, and finally causes the right heart A malignant cardiovascular disease of failure or even death. Its main feature is the gradual increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) caused by pulmonary artery obstruction, accompanied by irreversible pulmonary vascular remodeling. Patients with severe symptoms can cause right heart failure and death, with poor prognosis and high mortality.
  • PVR pulmonary vascular resistance
  • PAP pulmonary arterial pressure
  • Macitentan is an endothelin receptor antagonist, which prevents endothelin (ET-1) from binding to ETA and ETB receptors, and exhibits high affinity and sustained occupancy in human pulmonary artery smooth muscle cells.
  • Macitentan is the active ingredient marketed under the brand OPSUMIT® for the long-term treatment of pulmonary arterial hypertension.
  • 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. It is known that for BCS class II drugs 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.
  • W02007031933 application discloses solid oral pharmaceutical compositions of macitentan comprising silicon dioxide or other incompatible excipients.
  • WO2014173805 application discloses macitentan compositions comprising a specific polymorphic form.
  • the document discloses the preparation of a pharmaceutical composition comprising crystalline macitentan free base.
  • WO 2018153925 application discloses macitentan compositions which does not contain surfactants.
  • Stability-related problems do occur in macitentan under the influence of ambient and physical conditions. Especially, macitentan is reactive against the excipients employed in developing formulations containing the same. This fact causes impurities to occur in the formulation and leads to the inclusion of undesired components into the formulation.
  • the main object of the present invention is to provide a capsule formulation comprising macitentan which is an easily applicable product, eliminating all problems and bringing additional advantages to the relevant prior art.
  • Another object of the present invention is to provide a capsule formulation comprising macitentan which has the desired stability, a short disintegration time, desired dissolution properties and enables a high bioavailability of macitentan in a patient.
  • the capsule form has advantages over other known forms. For examples; capsules tend to break down more quickly than tablets, they may offer faster relief from symptoms than tablets, capsules are less likely to have an unpleasant taste or odor. It protects the sensitive active ingredient. In addition to all of these, capsule form also increases patient compliance.
  • macitentan refers to macitentan in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • a capsule formulation comprises macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient wherein is free of silicon dioxide. So, this formulation does not cause any stability problems.
  • the capsule use in the treatment of pulmonary arterial hypertension.
  • the capsule formulation comprises macitentan in an amount of between 0.1 mg to 300 mg.
  • the capsule formulation comprises macitentan in an amount of between 0.1 mg to 100 mg.
  • the amount of macitentan is between 0.1% to 50.0% by weight of the total formulation.
  • the amount of macitentan is between 0.1% to 30.0% by weight or between 0.5% to 20.0% by weight of the total formulation.
  • the capsule formulation comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, dispersing agents, surfactant, modified release agents, lubricants, glidants or mixtures thereof.
  • Suitable fillers are selected from group comprising lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, mannitol, ammonium alginate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, fructose, glyceryl palmitostearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.
  • the filler is lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch or mixtures thereof. Selected the filler provides the desired dissolution profile.
  • the filler is lactose monohydrate.
  • the filler is microcrystalline cellulose.
  • the filler is mannitol.
  • the filler is lactose.
  • the filler is pregelatinized starch.
  • the amount of filler is between 35.0% to 85.0% by weight, preferably between 40.0 to 80.0% by weight of the total formulation.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sugars, cellulose acetate phthalate, chitosan, corn starch, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, polydextrose, polyethylene oxide, polymethacrylates, aluminum hydroxide, stearic acid, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
  • the binder is polyvinylpyrrolidone, hydroxypropyl methylcellulose or mixtures thereof.
  • the amount of binder is between 0.1% to 25.0% by weight of the total formulation.
  • the amount of binder is between 0.1% to 20.0% by weight, preferably between 1.0% to 15.0% by weight of the total formulation.
  • Suitable disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, sodium starch glycolate, magnesium aluminium silica, sodium glycine carbonate or mixtures thereof.
  • the amount of disintegrants is between 0.1% to 25.0% by weight of the total formulation.
  • the amount of disintegrants is between 1.0% to 15.0% by weight, preferably between 1.0% to 10.0% by weight of the total formulation.
  • Suitable dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
  • Suitable surfactants are selected from the group comprising polysorbates, sodium lauryl sulphate, benzalconium chloride, docusate sodium, glyceryl esters, glyceryl monoleate, poloxamer, polyethylene alkyl ethers, polyglyceryl esters, polyoxyetylene esters, polyoxyetylene stearates, sodium stearate, hexadecyl pyridinium chloride or mixtures thereof.
  • Modified release formulations can be preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.
  • Suitable modified release agents are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, polygalacturonic acid, chondroitic sulfate, xanthan gum, galactomannan, glucomannan, glyceryl behenate, nitrocellulose, methylcellulose, proteoglycan, glycerol, propylene glycol, macrogols, dibutyl sebacetate, citrate esters, triacetin, castor oil,
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, sodium chlorate, magnesium lauryl sulfate, sodium acetate, sodium benzoate, polyethylene glycol, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • Suitable glidants are selected from the group comprising talc, aluminium silicate, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
  • the amount of glidants is between 0.5% to 5.0% by weight of the total formulation. This ratio provides good flowability and content uniformity in the formulation.
  • the capsule formulation comprising macitentan is in the form of enteric coated capsules which are capsules that have an acid resistant coating to prevent them from dissolving when they pass through the stomach.
  • the enteric capsules are activated only when they pass through an alkaline environment that is with a pH factor of 5.5 or higher which is usually when they reach the small intestine.
  • capsule comprises of different type of particles are selected from the group comprising mini-capsules, mini-tablets, pellets, granules, powders or mixtures thereof.
  • pellets refers to small particles with approximately uniform shapes and sizes produced by an extrusion process.
  • a “small particle” refers to a particle of which diameter, length, height, and width is at most 10 mm (e.g., at most 2, 3, 4, 5, 6, 7, 8, or 9 mm).
  • mini tablet refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm.
  • the mini tablets have round shape and smooth surface to ease coating process.
  • the form of formulation is minicapsule in capsule wherein the mini capsule comprises at least one active agent.
  • Minicapsules is located within a capsule.
  • the form of formulation is mini-tablets in capsule wherein a mini-tablet comprises at least one active agent. Mini-tablets is located within a capsule.
  • the form of formulation is pellet in capsule wherein pellet comprises at least one active agent. Pellet is located within a capsule.
  • the form of formulation is powder in capsule. Powder is located within a capsule.
  • the capsule formulation of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • the capsule formulation are produced by wet granulation or dry granulation process therefore, a simple and low-cost production method was employed.
  • solvents are used in the process.
  • the solvent is selected from the group comprising water, acetone, ethanol, isopropanol or mixtures thereof.
  • the capsule formulation comprises;
  • the amount of filler is between 20.0% to 90.0% by weight
  • the amount of binder is between 0.1% to 25.0% by weight of the total formulation.
  • the capsule formulation comprises;
  • the amount of macitentan is between 7.0% to 30.0% by weight
  • the amount of filler is between 35.0% to 85.0% by weight of the total formulation.
  • the capsule formulation comprises;
  • the amount of macitentan is between 7.0% to 30.0% by weight
  • Example 1 A capsule formulation comprising macitentan
  • Example 2 A capsule formulation comprising macitentan
  • Example 3 A capsule formulation comprising macitentan

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Abstract

The present invention relates to a capsule formulation comprising macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient.

Description

A CAPSULE FORMULATION COMPRISING MACITENTAN
Field of the Invention
The present invention relates to a capsule formulation comprising macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient.
Background of the Invention
Pulmonary arterial hypertension (PAH) is a disease that accumulates pulmonary artery endothelial cells, muscle layer and adventitia, which restricts pulmonary artery blood flow, which leads to increased pulmonary vascular resistance, progressive increase in pulmonary artery pressure, and finally causes the right heart A malignant cardiovascular disease of failure or even death. Its main feature is the gradual increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) caused by pulmonary artery obstruction, accompanied by irreversible pulmonary vascular remodeling. Patients with severe symptoms can cause right heart failure and death, with poor prognosis and high mortality.
Macitentan is an endothelin receptor antagonist, which prevents endothelin (ET-1) from binding to ETA and ETB receptors, and exhibits high affinity and sustained occupancy in human pulmonary artery smooth muscle cells.
The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2- pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide and its chemical structure is shown in the Formula 1.
Formula I: Macitentan
Macitentan is the active ingredient marketed under the brand OPSUMIT® for the long-term treatment of pulmonary arterial hypertension. 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. It is known that for BCS class II drugs 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.
W02007031933 application discloses solid oral pharmaceutical compositions of macitentan comprising silicon dioxide or other incompatible excipients.
WO2014173805 application discloses macitentan compositions comprising a specific polymorphic form. In particular, the document discloses the preparation of a pharmaceutical composition comprising crystalline macitentan free base.
WO 2018153925 application discloses macitentan compositions which does not contain surfactants.
Stability-related problems do occur in macitentan under the influence of ambient and physical conditions. Especially, macitentan is reactive against the excipients employed in developing formulations containing the same. This fact causes impurities to occur in the formulation and leads to the inclusion of undesired components into the formulation.
Accordingly, there is still a need for stable solid pharmaceutical formulations eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
Consequently, it is clear that there is no teaching, suggestion or motivation in the prior art about how to develop a stable capsule formulation enabling a simple manufacturing process and ensuring the release of the active agent at the specified site of delivery at the same time.
Detailed Description of the Invention
The main object of the present invention is to provide a capsule formulation comprising macitentan which is an easily applicable product, eliminating all problems and bringing additional advantages to the relevant prior art.
Another object of the present invention is to provide a capsule formulation comprising macitentan which has the desired stability, a short disintegration time, desired dissolution properties and enables a high bioavailability of macitentan in a patient. The capsule form has advantages over other known forms. For examples; capsules tend to break down more quickly than tablets, they may offer faster relief from symptoms than tablets, capsules are less likely to have an unpleasant taste or odor. It protects the sensitive active ingredient. In addition to all of these, capsule form also increases patient compliance.
The term “macitentan” as used herein refers to macitentan in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
We found that macitentan has incompatibility problem and stability problem when it is combined with silicone dioxide. By keeping this excipient away from our formulation, we prevented macitentan from having a stability problem besides its dissolution disadvantage.
According to this embodiment of the present invention, a capsule formulation comprises macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient wherein is free of silicon dioxide. So, this formulation does not cause any stability problems. The capsule use in the treatment of pulmonary arterial hypertension.
According to this embodiment of the present invention, the capsule formulation comprises macitentan in an amount of between 0.1 mg to 300 mg.
According to this embodiment of the present invention, the capsule formulation comprises macitentan in an amount of between 0.1 mg to 100 mg.
According to this embodiment of the present invention, the amount of macitentan is between 0.1% to 50.0% by weight of the total formulation.
According to this embodiment of the present invention, the amount of macitentan is between 0.1% to 30.0% by weight or between 0.5% to 20.0% by weight of the total formulation.
An embodiment of this present invention, the capsule formulation comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, dispersing agents, surfactant, modified release agents, lubricants, glidants or mixtures thereof.
Suitable fillers are selected from group comprising lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, mannitol, ammonium alginate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, fructose, glyceryl palmitostearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.
According to this embodiment of the present invention, the filler is lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch or mixtures thereof. Selected the filler provides the desired dissolution profile.
According to this embodiment of the present invention, the filler is lactose monohydrate.
According to this embodiment of the present invention, the filler is microcrystalline cellulose.
According to this embodiment of the present invention, the filler is mannitol.
According to this embodiment of the present invention, the filler is lactose.
According to this embodiment of the present invention, the filler is pregelatinized starch.
According to this embodiment of the present invention, the amount of filler is between 20.0% to 90.0% by weight of the total formulation.
According to this embodiment of the present invention, the amount of filler is between 35.0% to 85.0% by weight, preferably between 40.0 to 80.0% by weight of the total formulation.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sugars, cellulose acetate phthalate, chitosan, corn starch, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, polydextrose, polyethylene oxide, polymethacrylates, aluminum hydroxide, stearic acid, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
According to this embodiment of the present invention, the binder is polyvinylpyrrolidone, hydroxypropyl methylcellulose or mixtures thereof.
According to this embodiment of the present invention, the amount of binder is between 0.1% to 25.0% by weight of the total formulation.
According to this embodiment of the present invention, the amount of binder is between 0.1% to 20.0% by weight, preferably between 1.0% to 15.0% by weight of the total formulation. Suitable disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, sodium starch glycolate, magnesium aluminium silica, sodium glycine carbonate or mixtures thereof.
According to this embodiment of the present invention, the amount of disintegrants is between 0.1% to 25.0% by weight of the total formulation.
According to this embodiment of the present invention, the amount of disintegrants is between 1.0% to 15.0% by weight, preferably between 1.0% to 10.0% by weight of the total formulation.
Suitable dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
Suitable surfactants are selected from the group comprising polysorbates, sodium lauryl sulphate, benzalconium chloride, docusate sodium, glyceryl esters, glyceryl monoleate, poloxamer, polyethylene alkyl ethers, polyglyceryl esters, polyoxyetylene esters, polyoxyetylene stearates, sodium stearate, hexadecyl pyridinium chloride or mixtures thereof.
Modified release formulations can be preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.
Suitable modified release agents are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, polygalacturonic acid, chondroitic sulfate, xanthan gum, galactomannan, glucomannan, glyceryl behenate, nitrocellulose, methylcellulose, proteoglycan, glycerol, propylene glycol, macrogols, dibutyl sebacetate, citrate esters, triacetin, castor oil, acetylated monoglycerides, stearic acid, cetyl alcohol, cetostearyl alcohol, gelucire (stearyl macrogolglyceride) or a mixtures thereof. Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, sodium chlorate, magnesium lauryl sulfate, sodium acetate, sodium benzoate, polyethylene glycol, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
Suitable glidants are selected from the group comprising talc, aluminium silicate, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
According to this embodiment of the present invention, the amount of glidants is between 0.5% to 5.0% by weight of the total formulation. This ratio provides good flowability and content uniformity in the formulation.
According to this embodiment of the present invention, the capsule formulation comprising macitentan is in the form of enteric coated capsules which are capsules that have an acid resistant coating to prevent them from dissolving when they pass through the stomach. The enteric capsules are activated only when they pass through an alkaline environment that is with a pH factor of 5.5 or higher which is usually when they reach the small intestine.
According to this embodiment of the present invention, capsule comprises of different type of particles are selected from the group comprising mini-capsules, mini-tablets, pellets, granules, powders or mixtures thereof.
The term “pellets” refers to small particles with approximately uniform shapes and sizes produced by an extrusion process. A “small particle” refers to a particle of which diameter, length, height, and width is at most 10 mm (e.g., at most 2, 3, 4, 5, 6, 7, 8, or 9 mm).
The term “mini tablet”, as used herein, refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm. The mini tablets have round shape and smooth surface to ease coating process.
According to this embodiment of the present invention, the form of formulation is minicapsule in capsule wherein the mini capsule comprises at least one active agent. Minicapsules is located within a capsule.
According to this embodiment of the present invention, the form of formulation is mini-tablets in capsule wherein a mini-tablet comprises at least one active agent. Mini-tablets is located within a capsule. According to this embodiment of the present invention, the form of formulation is pellet in capsule wherein pellet comprises at least one active agent. Pellet is located within a capsule.
According to this embodiment of the present invention, the form of formulation is powder in capsule. Powder is located within a capsule.
The capsule formulation of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
According to this embodiment of the present invention, the capsule formulation are produced by wet granulation or dry granulation process therefore, a simple and low-cost production method was employed.
During wet granulation, solvents are used in the process. The solvent is selected from the group comprising water, acetone, ethanol, isopropanol or mixtures thereof.
According to this embodiment of the present invention, the capsule formulation comprises;
-the amount of macitentan is between 3.0% to 50.0% by weight,
- the amount of filler is between 20.0% to 90.0% by weight,
- the amount of binder is between 0.1% to 25.0% by weight of the total formulation.
According to this embodiment of the present invention, the capsule formulation comprises;
-the amount of macitentan is between 7.0% to 30.0% by weight,
- the amount of filler is between 35.0% to 85.0% by weight of the total formulation.
According to this embodiment of the present invention, the capsule formulation comprises;
-the amount of macitentan is between 7.0% to 30.0% by weight,
- the amount of glidants is between 0.5% to 5.0% by weight of the total formulation. Example 1 : A capsule formulation comprising macitentan Example 2: A capsule formulation comprising macitentan Example 3: A capsule formulation comprising macitentan

Claims

1. A capsule formulation comprising macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient wherein is free of silicon dioxide.
2. The capsule according to claim 1 , wherein the formulation comprising macitentan in an amount of between 0.1 mg to 300 mg.
3. The capsule according to claim 1, wherein the formulation comprises macitentan in an amount of between 0.1 mg to 100 mg.
4. The capsule according to claim 1 , wherein the amount of macitentan is between 0.1% to 50.0% by weight of the total formulation.
5. The capsule according to claim 1 , wherein the amount of macitentan is between 0.1% to 30.0% by weight or between 0.5% to 20.0% by weight of the total formulation.
6. The capsule according to claim 1, wherein the capsule formulation comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, dispersing agents, surfactant, modified release agents, lubricants, glidants or mixtures thereof.
7. The capsule according to claim 6, wherein fillers are selected from group comprising lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, mannitol, ammonium alginate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, fructose, glyceryl palmitostearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.
8. The capsule according to claim 6, wherein binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sugars, cellulose acetate phthalate, chitosan, corn starch, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
9. The capsule according to claim 8, wherein the amount of binder is between 0.1% to 25.0% by weight of the total formulation.
10. The capsule according to claim 6, wherein disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, sodium starch glycolate, magnesium aluminium silica, sodium glycine carbonate or mixtures thereof.
11. The capsule according to claim 1, wherein the amount of glidants is between 0.5% to 5.0% by weight of the total formulation.
12. The capsule according to claim 1 , wherein capsule comprising different type of particles are selected from the group comprising mini-capsules, mini-tablets, pellets, granules, powders or mixtures thereof.
13. The capsule according to claim 1 , wherein the capsule formulation is produced by wet granulation or dry granulation process.
14. The capsule according to claim 1, wherein formulation comprising;
-the amount of macitentan is between 3.0% to 50.0% by weight,
- the amount of filler is between 20.0% to 90.0% by weight,
- the amount of binder is between 0.1% to 25.0% by weight of the total formulation.
15. The capsule according to claim 1 , wherein the formulation comprising;
-the amount of macitentan is between 7.0% to 30.0% by weight,
- the amount of glidants is between 0.5% to 5.0% by weight of the total formulation.
EP22867824.9A 2021-09-07 2022-09-05 CAPSULE FORMULA WITH MACITENTAN Pending EP4398910A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR202113983 2021-09-07
PCT/TR2022/050945 WO2023038600A1 (en) 2021-09-07 2022-09-05 A capsule formulation comprising macitentan

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EP4398910A1 true EP4398910A1 (en) 2024-07-17
EP4398910A4 EP4398910A4 (en) 2025-07-23

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Publication number Priority date Publication date Assignee Title
CN107913256A (en) * 2016-10-08 2018-04-17 郑州泰丰制药有限公司 A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof

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