WO2023195956A1 - Comprimé revêtu d'un film comprenant du sélexi̇pag et au moins une charge - Google Patents

Comprimé revêtu d'un film comprenant du sélexi̇pag et au moins une charge Download PDF

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Publication number
WO2023195956A1
WO2023195956A1 PCT/TR2023/050305 TR2023050305W WO2023195956A1 WO 2023195956 A1 WO2023195956 A1 WO 2023195956A1 TR 2023050305 W TR2023050305 W TR 2023050305W WO 2023195956 A1 WO2023195956 A1 WO 2023195956A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
selexipag
film coated
tablet according
cellulose
Prior art date
Application number
PCT/TR2023/050305
Other languages
English (en)
Inventor
Fatih Sunel
Fadime Bilgehan ATAK
Nur PEHLIVAN AKALIN
Guldeniz TUNC
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 WO2023195956A1 publication Critical patent/WO2023195956A1/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
    • A61K9/205—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

Definitions

  • the present invention relates to a film coated tablet comprising a solid dispersion of selexipag or crystalline polymorph thereof, wherein tablet further comprising at least one filler which is free of mannitol. 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.
  • a suitable solvent e.g. acetone
  • EP3705115 discloses a solid unit dosage form for oral administration (tablet or granules) containing non-crystalline selexipag in a polymeric matrix and mannitol.
  • the solid dispersion is prepared by hot-melt extrusion, whereby the milled extrudate is subsequently subjected to a drygranulation process.
  • the main object of the present invention is to provide a film coated tablet comprises a solid dispersion of selexipag or crystalline polymorph thereof with having the desired level of dissolution rate and high stability and excellent physicochemical properties, such as flowability, compressibility, homogeneity, 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 provide a process for preparing 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 a solid dispersion of selexipag or crystalline polymorph thereof, wherein the tablet further comprising at least one filler which is free of mannitol and the amount of filler is between 70.0% and 95.0% by weight of the total tablet.
  • the use of the filler at the described amount helps to provide the uniformity of the content and so the desired dissolution profile.
  • 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.
  • fillers are lactose monohydrate and corn starch.
  • lactose monohydrate and corn starch together help to provide both the desired stability and excellent physicochemical properties. It is advantageous to use lactose monohydrate instead of mannitol in order to ensure proper homogeneity, prevent particle size differences and provide the appropriate mixture.
  • the amount of filler is 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 and the amount of lactose monohydrate is between 45.0% and 58.0%, between 48.0% and 56.0% 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. According to one embodiment of this invention, selexipag is present in the form of form 3.
  • the solid dispersion further comprising at least one binder and solvent.
  • 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 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 or isopropyl alcohol or mixtures thereof.
  • the film coated tablet further comprises at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, lubricants or mixtures thereof.
  • Suitable disintegrants are selected from the group comprising low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.
  • the disintegrant is low-substituted hydroxypropyl cellulose.
  • low-substituted hydroxypropyl cellulose has proven to offer substantial advantages as disintegrant because of its ability to turn low-soluble selexipag into fast-dissolving stable tablets. Also, its use in the specified range provided the desired dissolution profile.
  • the amount of low-substituted hydroxypropyl cellulose is between 2.0% and 10.0% 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 aluminum 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. Due to their nature, coloring agents show antioxidant properties and often prevent the active substance from being oxidized. It also provides photostability by preventing contact with light.
  • FD&C Drug & Cosmetic
  • the film coated tablet comprises;
  • a solid dispersion comprising Crystalline form-P or 1 or 3 or amorph of selexipag
  • the film coated tablet comprises;
  • a solid dispersion comprising crystalline form-P or 1 or 3 or amorph of selexipag and hydroxypropyl methyl Cellulose E3 LV Lactose monohydrate
  • the film coated tablet comprises;
  • a solid dispersion comprising crystalline form-P or 1 or 3 or amorph of selexipag and hydroxypropyl methyl Cellulose E3 LV
  • Magnesium stearate Magnesium stearate.
  • the film coated tablet is obtained by wet granulation using solvent with solid dispersion technique.
  • This solid dispersion technique provides the homogeneity and content uniformity of the active substance used in low amounts and the desired dissolution profile.
  • wet granulation with solid dispersion technique is preferred in terms of Physicochemical properties, such as flowability, compressibility and content uniformity of selexipag.
  • suitable solvent preferably water and alcohol mixture
  • a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving at least one binder in solvent and adjusting pH and obtained a binder solution, b) Adding selexipag or crystalline polymorph thereof in the binder solution, and dissolving, and obtained a solid dispersion, c) Mixing at least one disintegrant and at least one filler and then adding at least one filler and mixing, d) Granulating the powder mixture at step (c) with the binder solution at step (b), and obtained wet granule, e) Sieving the wet granule and then drying, f) Adding at least one lubricant and then mixing, g) Compressing the mixture into tablets, h) Coating the tablets.
  • a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving hydroxypropyl methyl cellulose in solvent and adjusting pH and obtained a binder solution, b) Adding selexipag or crystalline polymorph thereof in the binder solution, and dissolving, and obtained a solid dispersion, c) Mixing low substituted hydroxypropyl cellulose and corn starch and then adding lactose monohydrate and mixing, d) Granulating the powder mixture at step (c) with the binder solution at step (b), and obtained wet granule, e) Sieving the wet granule and then drying, f) Adding magnesium stearate and then mixing, g) Compressing the mixture into tablets, h) Coating the tablets.
  • a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving hydroxypropyl methyl cellulose in solvent and adjusting pH and obtained a binder solution, b) Adding selexipag or crystalline polymorph thereof in the binder solution, and dissolving, and obtained a solid dispersion, c) Mixing low substituted hydroxypropyl cellulose and corn starch and then adding lactose monohydrate and mixing, d) Granulating the powder mixture at step (c) with the binder solution at step (b), and obtained wet granule, e) Sieving the wet granule and then drying, f) Adding a coloring agent and mixing, g) Adding magnesium stearate and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.
  • Example 1 Example 1:
  • Example 2 A process for example 1 or 2; a) Dissolving hydroxypropyl methyl cellulose in solvent and adjusting pH and obtained a binder solution, b) Adding selexipag or crystalline polymorph thereof in the binder solution, and dissolving, and obtained a solid dispersion, c) Mixing low substituted hydroxypropyl cellulose and corn starch and then adding lactose monohydrate and mixing, d) Granulating the powder mixture at step (c) with the binder solution at step (b), and obtained wet granule, e) Sieving the wet granule and then drying, f) Adding magnesium stearate and then mixing, g) Compressing the mixture into tablets, h) Coating the tablets.
  • Example 3 A process for example 1 or 2; a) Dissolving hydroxypropyl methyl cellulose in solvent and adjusting pH and obtained a binder solution, b) Adding selexipag or crystalline polymorph thereof in the binder solution, and
  • a process for example 3 a) Dissolving hydroxypropyl methyl cellulose in water-alcohol mixture as solvent and adjusting pH and obtained a binder solution, b) Adding selexipag or crystalline polymorph thereof in the binder solution, and dissolving, and obtained a solid dispersion, c) Mixing low substituted hydroxypropyl cellulose and corn starch and then adding lactose monohydrate and mixing, d) Granulating the powder mixture at step (c) with the binder solution at step (b), and obtained wet granule, e) Sieving the wet granule and then drying, f) Adding at least one coloring agent and then mixing, g) Adding magnesium stearate and then mixing, h) Compressing the mixture into tablets, i) 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)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un comprimé pelliculé comprenant une dispersion solide de sélexipag ou d'un polymorphe cristallin de celui-ci, le comprimé comprenant en outre au moins une charge qui est exempte de mannitol. En outre, le comprimé est obtenu à l'aide d'un procédé efficace.
PCT/TR2023/050305 2022-04-05 2023-03-30 Comprimé revêtu d'un film comprenant du sélexi̇pag et au moins une charge WO2023195956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/005276 2022-04-05
TR2022005276 2022-04-05

Publications (1)

Publication Number Publication Date
WO2023195956A1 true WO2023195956A1 (fr) 2023-10-12

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PCT/TR2023/050305 WO2023195956A1 (fr) 2022-04-05 2023-03-30 Comprimé revêtu d'un film comprenant du sélexi̇pag et au moins une charge

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017121806A1 (fr) * 2016-01-15 2017-07-20 Sandoz Ag Composition pharmaceutique de selexipag
WO2018015975A1 (fr) * 2016-07-22 2018-01-25 Sun Pharmaceutical Industries Limited Dispersion solide amorphe de selxipag.
US20210069187A1 (en) * 2019-05-11 2021-03-11 RK Pharma Solutions LLC Stable pharmaceutical composition of Selexipag

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017121806A1 (fr) * 2016-01-15 2017-07-20 Sandoz Ag Composition pharmaceutique de selexipag
WO2018015975A1 (fr) * 2016-07-22 2018-01-25 Sun Pharmaceutical Industries Limited Dispersion solide amorphe de selxipag.
US20210069187A1 (en) * 2019-05-11 2021-03-11 RK Pharma Solutions LLC Stable pharmaceutical composition of Selexipag

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