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WO2025036941A1 - Forme posologique pharmaceutique à administrer par voie orale permettant une libération immédiate de vidofludimus - Google Patents

Forme posologique pharmaceutique à administrer par voie orale permettant une libération immédiate de vidofludimus Download PDF

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Publication number
WO2025036941A1
WO2025036941A1 PCT/EP2024/072924 EP2024072924W WO2025036941A1 WO 2025036941 A1 WO2025036941 A1 WO 2025036941A1 EP 2024072924 W EP2024072924 W EP 2024072924W WO 2025036941 A1 WO2025036941 A1 WO 2025036941A1
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WO
WIPO (PCT)
Prior art keywords
tablet
vol
tablet according
still
total weight
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
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PCT/EP2024/072924
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English (en)
Inventor
Daniel Vitt
Petra IGLICAR
Christian Gege
Andreas Mühler
Hella KOHLHOF
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Immunic AG
Original Assignee
Immunic AG
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Application filed by Immunic AG filed Critical Immunic AG
Publication of WO2025036941A1 publication Critical patent/WO2025036941A1/fr
Pending legal-status Critical Current
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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
    • A61K9/2022—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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

Definitions

  • Oral pharmaceutical dosage form providing immediate release of vidofludimus
  • the invention relates to a pharmaceutical tablet for oral administration, which comprises or essentially consists of vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof, one or more binders, and one or more disintegrants; and which under in vitro conditions in accordance with Ph. Eur. 2.9.3. at pH 7.5 dissolves within 45 minutes at least 80 wt.% of the vidofludimus free acid, physiologically acceptable salt and/or solvate thereof originally contained in the tablet.
  • Vidofludimus is a selective and potent second-generation dihydroorotate dehydrogenase (DHODH) oral immunomodulator being developed for the treatment of several chronic inflammatory diseases, including relapsing -remitting Multiple Sclerosis (RRMS).
  • DHODH dihydroorotate dehydrogenase
  • WO 2003/006424 and WO 2003/006425 relate to compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents.
  • WO 2012/001148 relates to calcium salts of compound as anti-inflammatory, immunomodulatory and anti-proliferatory agents.
  • WO 2012/001151 relates to salts as anti-inflammatory, immunomodulatory and anti-proliferatory agents.
  • WO 2016/200778 relates to methods for treatment of melanoma.
  • WO 2018/177151 relates to compounds modulating activity of famesoid x receptor and methods for the use thereof.
  • WO 2019/101888 relates to a dosage regimen of vidofludimus for use in the prevention or treatment of chronic inflammatory and/or autoimmune diseases.
  • WO 2019/175396 relates to calcium salt polymorphs as anti-inflammatory, immunomodulatory and anti-proliferatory agent.
  • WO 2021/214033 relates to vidofludimus for use in the treatment or prevention of viral diseases.
  • US 2023/051911 relates to methods of treating or ameliorating multiple sclerosis by the DHODH inhibitor vidofludimus or a pharmaceutically acceptable salt and/or a solvate, in particular a hydrate, thereof or a solvate, in particular a hydrate, of a pharmaceutically acceptable salt thereof, by administering to a human patient a therapeutically effective amount of the DHODH inhibitor, more specifically a daily dose of about 10 mg to about 45 mg.
  • oral dosage forms can be prepared that provide immediate release of vidofludimus and that are easy to manufacture.
  • the oral dosage forms according to the invention require a minimum number of pharmaceutical excipients.
  • oral dosage forms can be prepared from comparatively simple pharmaceutical compositions. These pharmaceutical compositions allow for preparing oral dosage forms having different dose strength of vidofludimus at the same total weight, wherein only the amount of excipients needs to be altered relative to one another in order to compensate the different amount of vidofludimus (i.e. the different dose strength). It has been found that only the amount of a single excipient (diluent) needs to be altered in order to compensate the different amount of vidofludimus (i.e. the different dose strength), whereas the content of all other excipients (e.g. binder, disintegrant and lubricant) can remain the same.
  • excipients e.g. binder, disintegrant and lubricant
  • fast disintegrating tablets can be prepared that provide immediate release of vidofludimus free acid in vitro.
  • the solubility of the non-salt form of vidofludimus strongly depends on the pH value and it is practically insoluble in water. Nevertheless, with the oral dosage forms according to the invention dissolution profiles can be achieved where at least 75%, at least 90%, or even more of the vidofludimus free acid that was originally contained in the dosage form have been released within 45 minutes at pH 7.5.
  • tablets containing vidofludimus can be advantageously prepared by wet granulation.
  • coarse granules are formed by wet granulation, tablets containing vidofludimus with higher resistance to crushing can be provided.
  • tablets containing vidofludimus with relatively high resistance to crushing and at the same time relatively low disintegration time can be provided, when a first portion of the diluent is contained in the intragranular phase and a second portion of diluent is contained in the extragranular phase.
  • the content of diluent in the extragranular phase can remain the same, while the content of diluent in the intragranular phase can be altered in order to compensate the different amount of vidofludimus (i.e. the different dose strength). Still further, it has been found that at least a portion of the binder can be dissolved in the granulation liquid thereby reducing the overage by about 10%.
  • vidofludimus is very well compatible with microcrystalline cellulose.
  • Microcrystalline cellulose can be used as predominant excipient, i.e. the excipient having the greatest content of all excipients, e.g. 70 wt.-% and above.
  • fast disintegrating tablets providing immediate release can be manufactured by wet granulation wherein the sum of the content of vidofludimus and the content of microcrystalline cellulose amounts to more than 80 wt.-% and even about 85 wt.-%.
  • vidofludimus in particular vidofludimus calcium present as polymorph A
  • vidofludimus calcium present as polymorph A is particularly stable in tablets. Such tablets can be produced by dry or wet granulation. The color of vidofludimus calcium present as polymorph A is white to off-white (see e.g. WO 2019/175396). Therefore, tablets containing vidofludimus calcium present as polymorph A do not need a coating for blinding in clinical studies.
  • a first aspect of the invention relates to a pharmaceutical tablet for oral administration, which comprises or essentially consists of
  • vidofludimus free acid a physiologically acceptable salt and/or a solvate thereof; preferably vidofludimus free acid or vidofludimus calcium;
  • the tablet according to the invention comprises vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof; preferably vidofludimus free acid.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is amorphous; preferably amorphous vidofludimus free acid or vidofludimus calcium.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is crystalline; preferably crystalline vidofludimus free acid or vidofludimus calcium.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is micronized.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof preferably has a particle size distribution such that the value for Dv 0, determined by laser light diffraction in accordance with Ph. Eur. 2.9.31, is at most 70 pm, preferably at most 60 pm, more preferably at most 50 pm, yet more preferably at most 40 pm, even more preferably at most 30 pm, most preferably at most 20 pm, and in particular at most 10 pm.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is not micronized.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof has a particle size distribution such that the value for Dv50, determined by laser light diffraction in accordance with Ph. Eur. 2.9.31, is at least 80 pm, preferably at least 90 pm, more preferably at least 100 pm, yet more preferably at least 110 pm, even more preferably at least 120 pm, most preferably at least 130 pm, and in particular at least 140 pm.
  • the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is both, crystalline and micronized.
  • a preferred physiologically acceptable salt of vidofludimus is vidofludimus calcium.
  • vidofludimus is present as free acid, preferably as ansolvate:
  • the vidofludimus free acid has characteristic XRPD peaks (Cu2 « irradiation at room temperature) at 10.6 ⁇ 0.2 20, 11.3 ⁇ 0.2 20, 14.2 ⁇ 0.2 20, 21.3 ⁇ 0.2 20, 21.6 ⁇ 0.2 20, and 26.1 ⁇ 0.2 20.
  • the vidofludimus free acid additionally has one or more characteristic XRPD peaks (Cm,, irradiation at room temperature) selected from 14.5 ⁇ 0.2 20, 19.8 ⁇ 0.2 20, 20.7 ⁇ 0.2 20, 22.6 ⁇ 0.2 20, 23.5 ⁇ 0.2 20, 28.0 ⁇ 0.2 20, 28.4 ⁇ 0.2 20, and 28.7 ⁇ 0.2 20.
  • vidofludimus is present as calcium salt, preferably as hemicalcium monohydrate:
  • vidofludimus calcium is present as polymorph A in accordance with WO 2019/175396 (sometimes also referred to as "polymorph I").
  • polymorph I a polymorph of vidofludimus calcium polymorph A
  • the total weight content of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is at least 1.0 wt.%, preferably at least 1.5 wt.%, more preferably at least 2.0 wt.%, still more preferably at least 2.5 wt.%, yet more preferably at least 3.0 wt.%, even more preferably at least 3.5 wt.%, most preferably at least 4.0 wt.%, and in particular at least 4.5 wt.%, relative to the total weight of the tablet.
  • the total weight content of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is at most 35 wt.%, preferably at most 32.5 wt.%, more preferably at most 30 wt.%, still more preferably at most 27.5 wt.%, yet more preferably at most 25 wt.%, even more preferably at most 22.5 wt.%, most preferably at most 20 wt.%, and in particular at most 17.5 wt.%, relative to the total weight of the tablet.
  • the pharmaceutical tablet comprises vidofludimus free acid, physiologically acceptable salt and/or solvate thereof in the range of from 1.0 wt.% to 35 wt.%, more preferably from 1.5 wt.% to 30 wt.%, yet more preferably 2.0 wt.% to 25 wt.%, in particular from 2.5 wt.% to 20 wt.%.
  • the dose of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is within the range of from 5.0 to 50 mg, relative to the equivalent weight of the free acid ansolvate of vidofludimus.
  • the dose of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof is 5.0 mg, 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg, relative to the equivalent weight of the free acid ansolvate of vidofludimus.
  • Excipients such as binders, disintegrants, diluents, lubricants, dispersants, glidants and the like have the generally acknowledged meaning.
  • the tablet according to the invention comprises one or more binders.
  • the total weight content of the one or more binders is at least 0.5 wt.%, preferably at least 1.0 wt.%, more preferably at least 1.5 wt.%, still more preferably at least 2.0 wt.%, yet more preferably at least 2.5 wt.%, even more preferably at least 3.0 wt.%, most preferably at least 3.5 wt.%, and in particular at least 4.0 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the one or more binders is at most 15 wt.%, preferably at most 12.5 wt.%, more preferably at most 10 wt.%, still more preferably at most 7.5 wt.%, yet more preferably at most 6.0 wt.%, even more preferably at most 5.5 wt.%, most preferably at most 5.0 wt.%, and in particular at most 4.5 wt.%, relative to the total weight of the tablet.
  • the total weight content of the one or more binders is in the range of from 0.5 wt.% to 15 wt.%, more preferably from 1.0 wt.% to 12.5 wt.%, yet more preferably from 2.0 wt.% to 10 wt.%, even more preferably from 2.5 wt.% to 7.5 wt.%, even more preferably from 3.0 wt.% to 6.0 wt.%, in particular from 3.5 wt.% to 5.5 wt.%, relative to the total weight of the tablet.
  • the one or more binders comprise or essentially consist of a binder selected from
  • synthetic polymers preferably polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, ethyl cellulose, polyethylene glycol, poloxamers, methacrylic acid copolymers, ammonio methacrylic acid copolymers, polyvinyl alcohol, and combinations thereof; and
  • sugars and sugar alcohols preferably glucose, sucrose, sorbitol, and combinations thereof; and combinations thereof.
  • the one or more binders comprise or essentially consist of polyvinylpyrrolidone; preferably selected from povidone K-12, K-15, K-17, K-25, K-30, and K-90; more preferably from povidone K-25, K-30 and K-90; still more preferably povidone K-25.
  • the tablet according to the invention comprises one or more disintegrants.
  • the total weight content of the disintegrant is at least 0.5 wt.%, preferably at least 1.0 wt.%, more preferably at least 1.5 wt.%, still more preferably at least 2.0 wt.%, yet more preferably at least 2.5 wt.%, even more preferably at least 3.0 wt.%, most preferably at least 3.5 wt.%, and in particular at least 3.7 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the disintegrant is at most 15 wt.%, preferably at most 10 wt.%, more preferably at most 9.0 wt.%, still more preferably at most 8.0 wt.%, yet more preferably at most 7.0 wt.%, even more preferably at most 6.0 wt.%, most preferably at most 5.0 wt.%, and in particular at most 4.0 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the disintegrant is in the range of from 0.5 wt.% to 15 wt.%, more preferably from 1.0 wt.% to 10 wt.%, yet more preferably from 1.5 wt.% to 9 wt.%, even more preferably from 2.0 wt.% to 8.0 wt.%, even more preferably from 2.5 wt.% to 7.0 wt.%, even more preferably from 3.0 wt.% to 6.0 wt.%, in particular from 3.5 wt.% to 5.0 wt.%, relative to the total weight of the tablet.
  • the one or more disintegrants comprise or essentially consist of a disintegrant selected from crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl cellulose sodium, sodium starch glycolate, pregelatinized starch, and combinations thereof.
  • the one or more disintegrants comprise or essentially consist of crosslinked polyvinylpyrrolidone.
  • the tablet according to the invention comprises one or more diluents (fdlers).
  • the total weight content of the one or more diluents is at least 40 wt.%, preferably at least 45 wt.%, more preferably at least 50 wt.%, still more preferably at least 55 wt.%, yet more preferably at least 57.5 wt.%, even more preferably at least 60 wt.%, most preferably at least 62.5 wt.%, and in particular at least 65 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the one or more diluents is at most 92.5 wt.%, preferably at most 90 wt.%, more preferably at most 87.5 wt.%, still more preferably at most 85 wt.%, yet more preferably at most 82.5 wt.%, even more preferably at most 80 wt.%, most preferably at most 77.5 wt.%, and in particular at most 75 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the one or more diluents is in the range of from 40 wt.% to 90 wt.%, more preferably from 45 wt.% to 85 wt.%, in particular from 50 wt.% to 75 wt.%, relative to the total weight of the tablet.
  • the one or more diluents comprise or essentially consist of a diluent selected from microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, lactose, mannitol, and combinations thereof.
  • the one or more diluents comprise or essentially consist of microcrystalline cellulose.
  • the microcrystalline cellulose has an average particle size within the range of from 25 to 125 pm; preferably about 50 pm or about 100 pm.
  • the tablet according to the invention comprises one or more lubricants.
  • the total weight content of the lubricant is at least 0.4 wt.%, preferably at least 0.6 wt.%, more preferably at least 0.8 wt.%, still more preferably at least 1.0 wt.%, yet more preferably at least 1.2 wt.%, even more preferably at least 1.4 wt.%, most preferably at least 1.6 wt.%, and in particular at least 1.8 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the lubricant is at most 3.4 wt.%, preferably at most 3.2 wt.%, more preferably at most 3.0 wt.%, still more preferably at most 2.8 wt.%, yet more preferably at most 2.6 wt.%, even more preferably at most 2.4 wt.%, most preferably at most 2.2 wt.%, and in particular at most 2.0 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the lubricant is in the range of from 0.4 wt.% to 3.4 wt. %, more preferably from 0.6 wt.% to 3.2 wt.%, yet more preferably from 0.8 wt.% to 3.0 wt.%, even more preferably from 1.0 wt.% to 2.8 wt.%, even more preferably from 1.2 wt.% to 2.6 wt.%, even more preferably from 1.4 wt.% to 2.4 wt.%, in particular from 1.6 wt.% to 2.2 wt.%, relative to the total weight of the tablet.
  • the one or more lubricants comprise or essentially consist of magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, and combinations thereof.
  • the one or more lubricants comprise or essentially consist of magnesium stearate.
  • the tablet according to the invention comprises one or more glidants.
  • the total weight content of the glidant is at least 0.4 wt.%, preferably at least 0.6 wt.%, more preferably at least 0.8 wt.%, still more preferably at least 1.0 wt.%, yet more preferably at least 1.2 wt.%, even more preferably at least 1.4 wt.%, most preferably at least 1.6 wt.%, and in particular at least 1.8 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the glidant is at most 3.4 wt.%, preferably at most 3.2 wt.%, more preferably at most 3.0 wt.%, still more preferably at most 2.8 wt.%, yet more preferably at most 2.6 wt.%, even more preferably at most 2.4 wt.%, most preferably at most 2.2 wt.%, and in particular at most 2.0 wt.%, in each case relative to the total weight of the tablet.
  • the total weight content of the glidant is in the range of from 0.4 wt.% to 3.4 wt.%, more preferably from 0.6 wt.% to 3.2 wt.%, yet more preferably from 0.8 wt.% to 3.0 wt.%, even more preferably from 1.0 wt.% to 2.8 wt.%, even more preferably from 1.2 wt.% to 2.6 wt.%, even more preferably from 1.4 wt.% to 2.4 wt.%, in particular from 1.6 wt.% to 2.2 wt.%, relative to the total weight of the tablet.
  • the one or more glidants comprise or essentially consist of talc, silicon dioxide, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, and combinations thereof.
  • the one or more glidants comprise or essentially consist of talc.
  • the pharmaceutical tablet comprises vidofludimus free acid, physiologically acceptable salt and/or solvate thereof in the range of from 2.5 wt.% to 20 wt.%; binder, preferably polyvinylpyrrolidone, in the range of from 2.5 wt.% to 7.5 wt.%; and disintegrant, preferably crospovidone, in the range of from 2.5 wt.% to 17.5 wt.%, relative to the total weight of the tablet.
  • binder preferably polyvinylpyrrolidone
  • disintegrant preferably crospovidone
  • the pharmaceutical tablet comprises vidofludimus free acid, physiologically acceptable salt and/or solvate thereof in the range of from 2.5 wt.% to 20 wt.%; binder, preferably polyvinylpyrrolidone, in the range of from 2.5 wt.% to 7.5 wt.%; disintegrant, preferably crospovidone, in the range of from 2.5 wt.% to 17.5 wt.%; and diluent, preferably microcrystalline cellulose, in the range from 50 wt.-% to 75 wt.%, relative to the total weight of the tablet.
  • binder preferably polyvinylpyrrolidone
  • disintegrant preferably crospovidone
  • diluent preferably microcrystalline cellulose
  • the pharmaceutical tablet comprises vidofludimus free acid, physiologically acceptable salt and/or solvate thereof in the range of from 2.5 wt.% to 20 wt.%; binder, preferably polyvinylpyrrolidone, in the range of from 2.5 wt.% to 7.5 wt.%; disintegrant, preferably crospovidone, in the range of from 2.5 wt.% to 17.5 wt.%; diluent, preferably microcrystalline cellulose, in the range from 50 wt.-% to 75 wt.%; and lubricant, preferably magnesium stearate, in the range of from 1.5 wt.% to 2.5 wt.%, relative to the total weight of the tablet.
  • binder preferably polyvinylpyrrolidone
  • disintegrant preferably crospovidone
  • diluent preferably microcrystalline cellulose
  • lubricant preferably magnesium stearate
  • the pharmaceutical tablet comprises vidofludimus free acid, physiologically acceptable salt and/or solvate thereof in the range of from 2.5 wt.% to 20 wt.%; binder, preferably polyvinylpyrrolidone, in the range of from 2.5 wt.% to 7.5 wt.%; disintegrant, preferably crospovidone, in the range of from 2.5 wt.% to 17.5 wt.%; diluent, preferably microcrystalline cellulose, in the range from 50 wt.-% to 75 wt.%; lubricant, preferably magnesium stearate, in the range of from 1.5 wt.% to 2.5 wt.%; and glidant, preferably talc, in the range of from 1.5 wt.% to 2.5 wt.%, relative to the total weight of the tablet.
  • binder preferably polyvinylpyrrolidone
  • disintegrant preferably crospovidone
  • diluent preferably microcrystalline cellulose
  • the tablet according to the invention comprises a fdm coating, preferably a non-functional fdm coating that is neither enteric nor retards drug release.
  • the tablet according to the invention is uncoated.
  • the tablet according to the invention comprises an intragranular phase and optionally an extragranular phase.
  • the intragranular phase refers to material that is contained within granules
  • the extragranular phase refers to material that is not contained within granules but is outside the granules, e.g. fdls the space between granules.
  • the tablet according to the invention comprises an intragranular phase and an extragranular phase.
  • the intragranular phase comprises essentially the total amount of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof.
  • the intragranular phase comprises essentially the total amount of the one or more binders.
  • the intragranular phase comprises a first portion of the one or more diluents.
  • the intragranular phase comprises at most 95 wt.-% of the one or more diluents, preferably at most 90 wt.%, more preferably at most 85 wt.%, still more preferably at most 80 wt.%, yet more preferably at most 75 wt.%, even more preferably at most 70 wt.%, most preferably at most 65 wt.%, and in particular at most 60 wt.%, in each case relative to the total weight of the one or more diluents contained in the tablet.
  • the intragranular phase comprises at least 15 wt.-% of the one or more diluents, preferably at least 20 wt.%, more preferably at least 25 wt.%, still more preferably at least 30 wt.%, yet more preferably at least 35 wt.%, even more preferably at least 40 wt.%, most preferably at least 45 wt.%, and in particular at least 50 wt.%, in each case relative to the total weight of the one or more diluents contained in the tablet.
  • the extragranular phase comprises essentially the total amount of the one or more disintegrants.
  • the extragranular phase comprises essentially the total amount of the one or more lubricants.
  • the extragranular phase comprises essentially the total amount of the one or more glidants.
  • the tablet comprises an extragranular phase, wherein the extragranular phase comprises a second portion of the one or more diluents.
  • the extragranular phase comprises at most 95 wt.-% of the one or more diluents, preferably at most 90 wt.%, more preferably at most 85 wt.%, still more preferably at most 80 wt.%, yet more preferably at most 75 wt.%, even more preferably at most 70 wt.%, most preferably at most 65 wt.%, and in particular at most 60 wt.%, in each case relative to the total weight of the one or more diluents contained in the tablet.
  • the extragranular phase comprises at least 15 wt.-% of the one or more diluents, preferably at least 20 wt.%, more preferably at least 25 wt.%, still more preferably at least 30 wt.%, yet more preferably at least 35 wt.%, even more preferably at least 40 wt.%, most preferably at least 45 wt.%, and in particular at least 50 wt.%, in each case relative to the total weight of the one or more diluents contained in the tablet.
  • the intragranular phase essentially consists of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof, the one or more binders, and a first portion of the one or more diluents.
  • the extragranular phase essentially consists of the one or more disintegrants, the one or more lubricants, the one or more glidants, and a second portion of the one or more diluents.
  • the relative weight ratio of the first portion of the one or more diluents comprised in the intragranular phase to the second portion of the one or more diluents comprised in the extragranular phase is within the range of from 3.5: 1.0 to 1.0: 3.5, preferably 3.0: 1.0 to 1.0: 3.0, more preferably 2.5: 1.0 to 1.0:2.5, still more preferably 2.0: 1.0 to 1.0:2.0, yet more preferably 1.5: 1.0 to 1.0: 1.5, even more preferably 1.3: 1.0 to 1.0: 1.3, most preferably 1.2: 1.0 to 1.0: 1.2, and in particular 1.1: 1.0 to 1.0: 1.1.
  • the intragranular phase is wet granulated; preferably aqueous; more preferably wherein at least a first portion of the one or more binders is dissolved in the granulation liquid; still more preferably wherein at least 15 wt.-% of the one or more binders is dissolved in the granulation liquid, preferably at least 20 wt.%, more preferably at least 25 wt.%, still more preferably at least 30 wt.%, yet more preferably at least 35 wt.%, even more preferably at least 40 wt.%, most preferably at least 45 wt.%, and in particular at least 50 wt.%, in each case relative to the total weight of the one or more binders contained in the tablet; yet more preferably half of the one or more binders contained in the tablet.
  • At least 15 vol.-% of the granules have a particle size of at least 0.125 mm, preferably within the range from 0.125 to 0.5 mm; preferably at least 18 vol.-%, more preferably at least 21 vol.- %, still more preferably at least 24 vol.-%, yet more preferably at least 27 vol.-%, even more preferably at least 30 vol.-%, most preferably at least 35 vol.-%, and in particular at least 40 vol.-%; preferably determined by analytical sieving in accordance with Ph. Eur. 2.9.38.
  • At most 60 vol.-% of the granules have a particle size of at least 0.125 mm, preferably within the range from 0.125 to 0.5 mm; preferably at most 55 vol.-%, more preferably at most 50 vol.- %, still more preferably at most 45 vol.-%, yet more preferably at most 40 vol.-%, even more preferably at most 35 vol.-%, most preferably at most 30 vol.-%, and in particular at most 25 vol.-%; preferably determined by analytical sieving in accordance with Ph. Eur. 2.9.38.
  • At least 14 vol.-% of the granules have a particle size of at least 0.25 mm, preferably within the range from 0.25 to 1.0 mm; preferably at least 17 vol.-%, more preferably at least 20 vol.-%, still more preferably at least 23 vol.-%, yet more preferably at least 26 vol.-%, even more preferably at least 29 vol.-%, most preferably at least 32 vol.-%, and in particular at least 35 vol.-%; preferably determined by analytical sieving in accordance with Ph. Eur. 2.9.38.
  • At most 55 vol.-% of the granules have a particle size of at least 0.25 mm, preferably within the range from 0.25 to 1.0 mm; preferably at most 50 vol.-%, more preferably at most 45 vol.-%, still more preferably at most 40 vol.-%, yet more preferably at most 35 vol.-%, even more preferably at most 30 vol.-%, most preferably at most 25 vol.-%, and in particular at most 20 vol.-%; preferably determined by analytical sieving in accordance with Ph. Eur. 2.9.38.
  • At least 8.0 vol.-% of the granules have a particle size of at least 0.5 mm, preferably within the range from 0.5 to 1.0 mm; preferably at least 10 vol.-%, more preferably at least 14 vol.-%, still more preferably at least 18 vol.-%, yet more preferably at least 22 vol.-%, even more preferably at least 26 vol.-%, most preferably at least 30 vol.-%, and in particular at least 34 vol.-%; preferably determined by analytical sieving in accordance with Ph. Eur. 2.9.38.
  • At most 45 vol.-% of the granules have a particle size of at least 0.5 mm, preferably within the range from 0.5 to 1.0 mm; preferably at most 40 vol.-%, more preferably at most 35 vol.-%, still more preferably at most 30 vol.-%, yet more preferably at most 25 vol.-%, even more preferably at most 21 vol.-%, most preferably at most 18 vol.-%, and in particular at most 15 vol.-%; preferably determined by analytical sieving in accordance with Ph. Eur. 2.9.38.
  • the total weight of the tablet is at most 600 mg, preferably at most 550 mg, more preferably at most 500 mg, still more preferably at most 450 mg, yet more preferably at most 400 mg, even more preferably at most 350 mg, most preferably at most 300 mg, and in particular at most 250 mg.
  • the tablet according to the invention has a circular cross section with a diameter within the range of from 6 mm to 10 mm, preferably 7 mm to 9 mm.
  • the tablet according to the invention dissolves within 45 minutes at least 80 wt.% of the vidofludimus free acid, physiologically acceptable salt and/or solvate thereof originally contained in the tablet.
  • the tablet according to the invention dissolves within 45 minutes at least 82 wt.% of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof originally contained in the tablet; preferably at least 85 wt.%, more preferably at least 88 wt.%, still more preferably at least 90 wt.%, yet more preferably at least 93 wt.%, even more preferably at least 95 wt.%, most preferably at least 97 wt.%, and in particular at least 98 wt.%.
  • the tablet according to the invention dissolves within 45 minutes at least 80 wt.-% of the vidofludimus free acid, a physiologically acceptable salt and/or a solvate thereof originally contained in the tablet; preferably at least 85 wt.%, more preferably at least 88 wt.%, still more preferably at least 90 wt.%, yet more preferably at least 93 wt.%, even more preferably at least 95 wt.%, most preferably at least 97 wt.%, and in particular at least 98 wt.%.
  • the tablet according to the invention disintegrates within at most 15 minutes, preferably at most 14 minutes, more preferably at most 13 minutes, still more preferably at most 12 minutes, yet more preferably at most 11 minutes, even more preferably at most 10 minutes, and most preferably at most 9.0 minutes.
  • the tablet according to the invention disintegrates within at most 8.0 minutes, preferably at most 7.0 minutes, more preferably at most 6.0 minutes, still more preferably at most 5.0 minutes, yet more preferably at most 4.0 minutes, even more preferably at most 3.0 minutes, most preferably at most 2.0 minutes, and in particular at most 1.5 minutes.
  • the tablet according to the invention has a resistance to crushing of at least 25 N, preferably at least 30 N, more preferably at least 35 N, still more preferably at least 40 N, yet more preferably at least 45 N, even more preferably at least 50 N, most preferably at least 55 N, and in particular at least 60 N.
  • the tablet according to the invention has a resistance to crushing of at least 65 N, preferably at least 70 N, more preferably at least 75 N, still more preferably at least 80 N, yet more preferably at least 85 N, even more preferably at least 90 N, most preferably at least 95 N, and in particular at least 100 N.
  • the tablet according to the invention has a resistance to crushing of at most 155 N, preferably at most 150 N, more preferably at most 145 N, still more preferably at most 140 N, yet more preferably at most 135 N, even more preferably at most 130 N, most preferably at most 125 N, and in particular at most 120 N.
  • the tablet according to the invention has a resistance to crushing of at most 115 N, preferably at most 110 N, more preferably at most 105 N, still more preferably at most 100 N, yet more preferably at most 95 N, even more preferably at most 90 N, most preferably at most 85 N, and in particular at most 80 N.
  • Another aspect of the invention relates to a packaging comprising one or more of the tablets according to the invention as described above.
  • the packaging is a bottle having a closure and optionally containing a desiccant.
  • the packaging is a blister.
  • Another aspect of the invention relates to a tablet according to any of the above embodiments for use in the prevention and/or treatment of a disease or a medical condition in a subject in need thereof, wherein said disease is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis (including relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis), lupus erythematosus, inflammatory bowel disease (in particular ulcerative colitis and Crohn’s disease), long COVID syndrome, type 1 diabetes and psoriasis, preferably relapsing-remitting multiple sclerosis (RRMS).
  • RRMS relapsing-remitting multiple sclerosis
  • Another aspect of the invention relates to a method of prevention and/or treatment of a disease or a medical condition in a subject in need thereof comprising administering a tablet according to any of the above embodiments to said subject, wherein said disease is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis (including relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis), lupus erythematosus, inflammatory bowel disease (in particular ulcerative colitis and Crohn’s disease), long CO VID syndrome, type 1 diabetes and psoriasis, preferably relapsing-remitting multiple sclerosis (RRMS).
  • RRMS relapsing-remitting multiple sclerosis
  • Another aspect of the invention relates to a use of a tablet according to any of the above embodiments in a method of prevention and/or treatment of a disease or a medical condition in a subject in need thereof, wherein said disease is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis (including relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis), lupus erythematosus, inflammatory bowel disease (in particular ulcerative colitis and Crohn’s disease), long CO VID syndrome, type 1 diabetes and psoriasis, preferably relapsing -remitting multiple sclerosis (RRMS).
  • RRMS relapsing-remitting multiple sclerosis
  • Another aspect of the invention relates to a use of a tablet according to any of the above embodiments for production of a medicament for prevention and/or treatment of a disease or a medical condition in a subject in need thereof, wherein said disease is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis (including relapsingremitting multiple sclerosis (RRMS) and progressive multiple sclerosis), lupus erythematosus, inflammatory bowel disease (in particular ulcerative colitis and Crohn’s disease), long CO VID syndrome, type 1 diabetes and psoriasis, preferably relapsing -remitting multiple sclerosis (RRMS).
  • RRMS relapsingremitting multiple sclerosis
  • the term “subject” refers to any member of the animal kingdom including humans. In some embodiments, “subject” refers mammals. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient.
  • Another aspect of the invention relates to a process for the preparation of a pharmaceutical tablet according to the invention as described above, said process comprising the steps of
  • vidofludimus free acid a physiologically acceptable salt and/or a solvate thereof; preferably vidofludimus free acid or vidofludimus calcium;
  • step (b) drying the wet granulate obtained in step (a) thereby obtaining a dried granulate
  • step (c) blending the dried granulate obtained in step (b) with
  • step (d) compressing the blend obtained in step (c) to tablets
  • the granulation liquid comprises or essentially consists of water.
  • At least a first portion of the one or more binders is dissolved in the granulation liquid; preferably wherein at least 15 wt.-% of the one or more binders is dissolved in the granulation liquid, preferably at least 20 wt.%, more preferably at least 25 wt.%, still more preferably at least 30 wt.%, yet more preferably at least 35 wt.%, even more preferably at least 40 wt.%, most preferably at least 45 wt.%, and in particular at least 50 wt.%, in each case relative to the total weight of the one or more binders contained in the tablet; yet more preferably half of the one or more binders contained in the tablet.
  • step (b) is performed at elevated temperature.
  • step (b) is performed at a temperature within the range of 50 ⁇ 50°C, preferably 50 ⁇ 35°C, more preferably 50 ⁇ 30°C, still more preferably 50 ⁇ 25°C, yet more preferably 50 ⁇ 20°C, even more preferably 50 ⁇ 15°C, most preferably 50 ⁇ 10°C, and in particular 50 ⁇ 5°C.
  • step (b) is performed under reduced pressure; preferably at most 900 mbar, more preferably at most 800 mbar, still more preferably at most 700 mbar, yet more preferably at most 600 mbar, even more preferably at most 500 mbar, most preferably at most 400 mbar, and in particular at most 300 mbar.
  • step (b) is performed for at least 10 hours, preferably at least 12.5 hours, more preferably at least 15 hours, still more preferably at least 17.5 hours, yet more preferably at least 20 hours, even more preferably at least 22.5 hours, most preferably at least 25 hours, and in particular at least 27.5 hours.
  • step (d) is performed at a man pressure of at least 8.0 kN, preferably at least 9.0 kN, more preferably at least 10 kN, still more preferably at least 11 kN, yet more preferably at least 12 kN, even more preferably at least 13 kN, most preferably at least 14 kN, and in particular at least 15 kN.
  • the one or more binders comprise or essentially consist of a binder selected from
  • synthetic polymers preferably polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, ethyl cellulose, polyethylene glycol, poloxamers, methacrylic acid copolymers, ammonio methacrylic acid copolymers, polyvinyl alcohol, and combinations thereof; and
  • the one or more diluents comprise or essentially consist of a diluent selected from microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, lactose, mannitol, and combinations thereof.
  • the one or more disintegrants comprise or essentially consist of a disintegrant selected from crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl cellulose sodium, sodium starch glycolate, pregelatinized starch, and combinations thereof.
  • the one or more lubricants comprise or essentially consist of magnesium stearate, calcium stearate, stearic acid, poly-ethylene glycol, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, and combinations thereof.
  • Immediate release fdm -coated tablets were prepared containing 10 mg, 20 mg, or 35 mg of vidofludimus as free acid in essentially amorphous form.
  • the tablets were produced utilizing aqueous granulation, followed by tableting and film -coating.
  • compositions are compiled in the table here below:
  • the swelling/standing time of the granulating suspension was varied between 0.5 and 22 hours without any measurable effect on the product quality.
  • tableting pressure and hardness of the tablet cores e.g., tableting pressures of 18 kN and 7.8 kN (covering the range of tableting pressures used) both resulted in hardness of 51 N.
  • tableting pressure and disintegration time was observed. There is reasonable correlation between hardness and disintegration time.
  • AUCO-24, AUCo-tz and AUG,.. were proportional to the vidofludimus dose.
  • C max values deviated from dose proportionality at higher dose levels, i.e., the C max values were lower than expected under dose proportionality.
  • Peak plasma levels occurred at t max 4 h (median over all dose levels) after application.
  • the elimination half-life ti/2 (median over all dose levels) amounted to 30.4 h.
  • the renal clearance was small (8.45 mL/h). It was estimated that maximally 3% of the highest dose (350 mg) was excreted unchanged in urine.
  • Example 3 multiple dose pharmacokinetics of vidofludimus free acid:
  • Pharmacokinetic parameters for vidofludimus free acid were also determined in a clinical study for multiple doses. Pharmacokinetics were assessed after a single dosing on Day 1 and after 14 days of consecutive multiple dosing from Day 3 onwards with 35 or 70 mg vidofludimus.
  • Example 4 manufacture of vidofludimus calcium IR tablets by wet granulation:
  • Immediate release tablets were prepared containing 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg of vidofludimus calcium. The tablets were produced utilizing aqueous granulation, followed by tableting.
  • compositions are compiled in the table here below:
  • the tablets had the following properties:
  • Dissolution was determined in accordance with Ph. Eur. 2.9.3. using the paddle method in 50 mM citrate buffer pH 7.5 + 2% SDS at 37 ⁇ 1°C and at 100 rpm (500 mb for tablets having a strength below 15 mg, 750 mb for tablets having a strength of 15 mg, and 1000 mb for tablets having a strength greater than 15 mg). Resistance to crushing was determined in accordance with Ph. Eur. 2.9.8. Results are also contained in the above table.
  • Example 4- 4a showed relatively low resistance to crushing.
  • the granulation process was optimized, granulating intensively to form coarse granules (preferably having an average particle size within the range of from 0.25 to 1.0 mm).
  • the tablets of Examples 4-1, 4-2b, 4-3, 4-4b and 4-5 were prepared according to the optimized process forming coarse granules and had optimized resistance to crushing of > 40 N.
  • Example 5 manufacture of vidofludimus calcium IR tablets by wet granulation:
  • immediate release tablets were prepared containing 5 mg, 15 mg, or 22.5 mg of vidofludimus calcium.
  • the tablets were produced utilizing aqueous granulation, followed by tableting.
  • compositions are compiled in the table here below:
  • the tablets had the following properties :
  • Dissolution was determined in accordance with Ph. Eur. 2.9.3. using the paddle method in 50 mM citrate buffer pH 7.5 + 2% SDS at 37 ⁇ 1°C and at 100 rpm (500 mL for tablets having a strength below 15 mg, 750 mL for tablets having a strength of 15 mg, and 1000 mL for tablets having a strength greater than 15 mg). Resistance to crushing was determined in accordance with Ph. Eur. 2.9.8. Results are also contained in the above table.
  • Example 6 manufacture of vidofludimus calcium IR tablets by wet granulation:
  • Immediate release tablets were prepared containing vidofludimus calcium salt, wherein half the amount of the binder povidone was used in aqueous solution and half the amount was added to the intragranular phase as dry substance. The thus optimized process permits reduction of the overage from 21% to 10%. [0166] The appearance of the obtained tablets was identical with the appearance of tablets, wherein the total amount of binder was added to the intragranular phase as dry substance. In-process control results are compiled in the table here below:
  • the amount of water in the granulation liquid was 15 mg/tablet (Example 6-1) and 10 mg (Example 6-2), respectively, corresponding to 750 g and 500 g for 50,000 tablet batch size.

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Abstract

L'invention concerne un comprimé pharmaceutique pour administration par voie orale, qui comprend ou consiste essentiellement en un acide libre de vidofludimus, un sel physiologiquement acceptable et/ou un solvate de celui-ci, un ou plusieurs liants et un ou plusieurs agents désintégrants ; et qui, dans des conditions in vitro conformément à Ph. Eur. 2.9.3. à un pH de 7,5, dissout en 45 minutes au moins 80 % en poids de l'acide libre de vidofludimus, un sel physiologiquement acceptable et/ou un solvate de celui-ci contenu à l'origine dans le comprimé.
PCT/EP2024/072924 2023-08-15 2024-08-14 Forme posologique pharmaceutique à administrer par voie orale permettant une libération immédiate de vidofludimus Pending WO2025036941A1 (fr)

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