WO2023195953A1 - Comprimé pelliculé comprenant du selexi̇pag - Google Patents

Comprimé pelliculé comprenant du selexi̇pag Download PDF

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Publication number
WO2023195953A1
WO2023195953A1 PCT/TR2023/050302 TR2023050302W WO2023195953A1 WO 2023195953 A1 WO2023195953 A1 WO 2023195953A1 TR 2023050302 W TR2023050302 W TR 2023050302W WO 2023195953 A1 WO2023195953 A1 WO 2023195953A1
Authority
WO
WIPO (PCT)
Prior art keywords
mixing
film coated
coated tablet
crospovidone
selexipag
Prior art date
Application number
PCT/TR2023/050302
Other languages
English (en)
Inventor
Fatih Sunel
Fadime Bilgehan ATAK
Nur PEHLIVAN AKALIN
Guldeniz TUNC
Busra ARI
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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 Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2023195953A1 publication Critical patent/WO2023195953A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the present invention relates to a film coated tablet comprising selexipag or crystalline polymorph thereof and D-mannitol as a filler, one more filler and crospovidone as disintegrant. Furthermore, the tablet is obtained using an effective process.
  • Selexipag is prostacyclin receptor agonist that causes vasodilation in pulmonary vasculature and is used in the therapy of pulmonary arterial hypertension (PAH).
  • Selexipag also known as 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)-N-(methylsulfonyl)acetamide can be represented by the following chemical structure according to Formula I:
  • each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of Selexipag.
  • the Uptravi® film-coated tablet is a standard immediate-release tablet that contains D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose and magnesium stearate.
  • the tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxide red, iron oxide yellow or iron oxide black.
  • Selexipag is considered to be a BCS (Biopharmaceutics Classification System) Class II drug, i.e. having high permeability and low solubility.
  • BCS Biopharmaceutics Classification System
  • EP3481807 discloses novel crystalline forms of selexipag and its process for the preparation thereof.
  • WO 2017/029594 describes the preparation of amorphous selexipag by dissolving the drug in a suitable solvent, e.g. acetone, and removing the solvent by, e.g., evaporation, spray-drying or freeze- drying.
  • the main object of the present invention is to provide a film coated tablet comprising selexipag or crystalline polymorph thereof with having desired level of dissolution rate and high stability and excellent physicochemical properties, such as flowability, compressibility and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
  • Another object of the present invention is to provides a process for a film coated tablet composition comprising selexipag or crystalline polymorph thereof.
  • the process is a simple, rapid, cost effective, time-saving and industrially convenient method.
  • selexipag or crystalline polymorph thereof is used small proportion that can lead to considerable problems during the manufacture of the composition with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity make an important role in the dissolution of the drug.
  • a film coated tablet comprises
  • D-mannitol as a filler and one more filler
  • Crospovidone as a disintegrant, wherein the amount of crospovidone is between 2.0% and 10.0% by weight of the total tablet.
  • the amount of selexipag or crystalline polymorph thereof is between 0.05% and 5.0%, preferably between 0.05% and 2.0% by weight of the total tablet.
  • selexipag is present in the form of amorph or form P or form 3 or form 1 or mixtures thereof.
  • selexipag is present in the form of amorph.
  • selexipag is present in the form of form P. It provides a tablet with high yields and purity.
  • selexipag is present in the form of form 3.
  • the amount of crospovidone is between 3.0% and 8.0% by weight of the total tablet.
  • the amount of D-mannitol is between 45.0% and 58.0%, between 50.0% and 56.0% by weight of the total tablet.
  • Suitable fillers are selected from the group comprising corn starch, microcrystalline cellulose, lactose monohydrate, cellulose, cellulose acetate, compressible sugar, ethylcellulose, lactitol, lactose, magnesium oxide, maltodextrin, maltose, sorbitol, sucrose, talc, or mixtures thereof.
  • another filler is corn starch.
  • D-mannitol and corn starch provides both the desired stability and excellent physicochemical properties.
  • the amount of filler is between 70.0% and 95.0%, between 78.0% and 90.0% by weight of the total tablet.
  • the amount of corn starch is between 25.0% and 45.0%, between 30.0% and 40.0% by weight of the total tablet.
  • the film coated tablet comprises at least one pharmaceutically acceptable excipient selected from the group comprising binders, lubricants or mixtures thereof.
  • Suitable binders are selected from the group comprising hydroxypropyl methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, polymethacrylates, methacrylate polymers, polysaccharides, carbomer, poloxamer, polydextrose, polyethylene oxide or mixtures thereof.
  • the binder is hydroxypropyl methyl cellulose.
  • HPMC hydroxypropyl methyl cellulose.
  • the amount of binder is between 1.0% and 8.0%, between 2.0% and 6.0% by weight of the total tablet.
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof.
  • the lubricant is magnesium stearate.
  • the amount of lubricant is between 0.5% and 3.5% by weight of the total tablet.
  • the film coated tablet further comprises at least one coloring agent.
  • Suitable coloring agents are selected from the group comprising indigo carmin aluminium lake, ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof. Coloring agent contributes positively to the shelf life of the product and so the desired stability.
  • the film coated tablet comprises;
  • the film coated tablet comprises;
  • the film coated tablet is obtained by wet granulation using solvent.
  • Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerine, cyclomethicone, glycerine triacetate, diethylene glycol monoethyl ether or mixtures thereof.
  • the solvent is water or dichloromethane or methanol or ethanol .
  • a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving a binder in solvent and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of a filler and mixing, then adding the remaining part of a filler and mixing again, d) Adding a half of D-mannitol and mixing, and then adding another half of D-mannitol and mixing,
  • This geometric dilution method provides the homogeneity and content uniformity of the active substance used in low amounts and the desired dissolution profile.
  • wet granulation with geometric dilution method is preferred in terms of pharmacotechnical properties, such as flowability, compressibility and content uniformity of selexipag.
  • suitable solvent also provides the desired stability.
  • a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving a binder in solvent and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding at least one lubricant and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.
  • a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving a binder in solvent and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding coloring agent and mixing, h) Adding at least one lubricant and then mixing, i) Compressing the mixture into tablets, j)
  • Example 2 A process for example 1 or 2; a) Dissolving a binder in water and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding at least one lubricant and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.
  • a process for example 3 a) Dissolving a binder in water and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding coloring agent and mixing, h) Adding at least one lubricant and then mixing, i) Compressing the mixture into tablets, j) Coating the tablets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un comprimé pelliculé comprenant du selexipag ou un polymorphe cristallin de celui-ci et du D-mannitol en tant que charge, une autre charge et de la crospovidone en tant que délitant. En outre, le comprimé est obtenu à l'aide d'un procédé efficace.
PCT/TR2023/050302 2022-04-05 2023-03-30 Comprimé pelliculé comprenant du selexi̇pag WO2023195953A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/005273 2022-04-05
TR2022005273 2022-04-05

Publications (1)

Publication Number Publication Date
WO2023195953A1 true WO2023195953A1 (fr) 2023-10-12

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PCT/TR2023/050302 WO2023195953A1 (fr) 2022-04-05 2023-03-30 Comprimé pelliculé comprenant du selexi̇pag

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4393475A1 (fr) * 2022-12-28 2024-07-03 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations comprenant du sélexipag
EP4393474A1 (fr) * 2022-12-28 2024-07-03 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulation comprenant du sélexipag

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112220770A (zh) * 2020-12-17 2021-01-15 上海翰森生物医药科技有限公司 司来帕格的药物组合物及其制备方法
US20210069187A1 (en) * 2019-05-11 2021-03-11 RK Pharma Solutions LLC Stable pharmaceutical composition of Selexipag
WO2021078835A1 (fr) * 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210069187A1 (en) * 2019-05-11 2021-03-11 RK Pharma Solutions LLC Stable pharmaceutical composition of Selexipag
WO2021078835A1 (fr) * 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
CN112220770A (zh) * 2020-12-17 2021-01-15 上海翰森生物医药科技有限公司 司来帕格的药物组合物及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4393475A1 (fr) * 2022-12-28 2024-07-03 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations comprenant du sélexipag
EP4393474A1 (fr) * 2022-12-28 2024-07-03 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulation comprenant du sélexipag

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