WO2024115680A1 - Sels de ribociclib et formulations de ceux-ci - Google Patents

Sels de ribociclib et formulations de ceux-ci Download PDF

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Publication number
WO2024115680A1
WO2024115680A1 PCT/EP2023/083781 EP2023083781W WO2024115680A1 WO 2024115680 A1 WO2024115680 A1 WO 2024115680A1 EP 2023083781 W EP2023083781 W EP 2023083781W WO 2024115680 A1 WO2024115680 A1 WO 2024115680A1
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WIPO (PCT)
Prior art keywords
ribociclib
hydrochloride
coating
signals
acid
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PCT/EP2023/083781
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English (en)
Inventor
David ZUPANCIC
Gasper VRHUNC
Bostjan JERMAN
Katja ZUPANCIC
Ana BERGANT SIMONCIC
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Krka, D.D., Novo Mesto
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Application filed by Krka, D.D., Novo Mesto filed Critical Krka, D.D., Novo Mesto
Publication of WO2024115680A1 publication Critical patent/WO2024115680A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to physiologically acceptable acid addition salts of Ribociclib and pharmaceutical compositions thereof.
  • the invention relates to tablet formulations containing Ribociclib malate monohydrate, Ribociclib hydrochloride dihydrate or Ribociclib hydrochloride anhy- drate.
  • Ribociclib has the systematic name 7-cyclopentyl-N,N-dimethyl-2-[[5-(l-piperazinyl)-2-pyri- dinyl]amino]-7H-pyrrolo-[2,3-d]pyrimidine-6-carboxamide (CAS Number: 1211441-98-3).
  • Ribociclib (LEE011; Novartis) is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6).
  • Ribociclib drug product (Kisqali®) was approved by FDA and EMA in 2017 and is commercially available as film coated, immediate release tablets containing 200 mg of Ribociclib. Each tablet contains 254.40 mg Ribociclib succinate (equivalent to 200 mg Ribociclib), microcrystalline cellulose, crospovidone type A, low-substituted hydroxypropyl cellulose, magnesium stearate and colloidal anhydrous silica as inactive ingredients, and is coated with PVA based film-coating composition.
  • Kisqali® is approved in combination with (i) an aromatase inhibitor for the treatment of pre/ perimenopausal or postmenopausal women with HR+/HER2- advanced or metastatic breast cancer, as initial endocrine-based therapy or (ii) Fulvestrant for the treatment of postmenopausal women with HR+/ HER2- advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy.
  • FDA expanded the use of Kisqali® in a co-package with Femara® (letrozole). Kisqali® Femara® Co-Pack is indicated for HR-positive, HER2 -negative advanced breast cancer in postmenopausal women.
  • WO 2012/064805 Al discloses hydrated and non-hydrated form of Ribociclib mono-succinate. Based on the EPAR (Kisqali) the active substance Ribociclib succinate is a slightly hygroscopic yellow to brown crystalline powder, soluble in acidic aqueous media, becoming less soluble as pH increases. Non-hydrated Ribociclib succinate form A has been demonstrated to be stable and not to convert into other polymorphic forms under long term and accelerated stability studies when stored in the proposed packaging.
  • WO 2016/166703 Al discloses coated tablet pharmaceutical composition compri sing active substance Ribociclib in the form of a succinate salt (at least 50% of tablet core) and PVA based advanced moisture barrier coating.
  • Exemplified pharmaceutical composition of tablets comprises microcrystalline cellulose, crospovidone type A, low-substituted hydroxypropyl cellulose, magnesium stearate and colloidal anhydrous silica as inactive ingredients.
  • PVA-based coating shows improved appearances and is essentially free of cracking defects.
  • WO 2010/020675 Al WO 2016/091221 Al (EP 3 231 805 Bl), WO 2018/051280 Al, WO 2019/040567 Al, WO 2019/062854 Al, WO 2019/082143 Al, WO 2019/130068 Al, WO 2019/167068 Al, WO 2020/152629 Al, WO 2020/222256 Al, WO 2022/207788 A2, CN 108 245 486 A, and CN 109 400 612 A.
  • Hydrochloric acid is added dropwise at room temperature and reacted for 1 hour.
  • the aqueous layer is separated from the organic layer, and acetone is added to the separated aqueous phase.
  • the temperature is raised to reflux, and then lowered to below 10°C to crystallize.
  • the suspension is stirred for 3 hours and the solid is fdtered off.
  • WO 2022/207788 A2 relates to a process for preparing Ribociclib and its protected intermediates and further to physiologically acceptable salts of Ribociclib having advantages compared to the prior art.
  • Ribociclib is an important aspect in pharmaceutical development, because the different solid forms affect the properties of the medicinal product such as thermodynamic stability, storage stability, solubility, bioavailability, tendency to form solvates, density, hygroscopicity, adhesiveness, electrical properties, mechanical properties (such as compressibility, friability, hardness, breaking strength, elasticity), optical properties (such as color, transparency, refraction), and the like.
  • the present disclosure relates to Ribociclib salts, more preferably to Ribociclib malate monohydrate, Ribociclib hydrochloride dihydrate, Ribociclib hydrochloride anhydrate, and Ribociclib succinate anhydrous.
  • Ribociclib salts more preferably to Ribociclib malate monohydrate, Ribociclib hydrochloride dihydrate, Ribociclib hydrochloride anhydrate, and Ribociclib succinate anhydrous.
  • Ribociclib salts more preferably to Ribociclib malate monohydrate, Ribociclib hydrochloride dihydrate, Ribociclib hydrochloride anhydrate, and Ribociclib succinate anhydrous.
  • Ribociclib salts more preferably to Ribociclib malate monohydrate, Ribociclib hydrochloride dihydrate, Ribociclib hydrochloride anhydrate, and Ribociclib succinate anhydrous.
  • These properties include, but are not limited to: (a) packing properties such as molar volume, bulk density and hygroscopicity, (b) thermodynamic properties such as melting temperature, vapor pressure and solubility, (c) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), (d) surface properties such as surface area, wettability, interfacial tension and shape, (e) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and (f) fdtration properties.
  • packing properties such as molar volume, bulk density and hygroscopicity
  • thermodynamic properties such as melting temperature, vapor pressure and solubility
  • kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions)
  • surface properties such as surface area, wettability, interfacial tension and shape
  • e mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend
  • Figures 1A to C show electron micrographs of Ribociclib malate monohydrate at different magnifications.
  • Figures 2 through 5 show IR spectrum, Raman spectrum, thermogravimetric analysis, and DSC analysis of Ribociclib malate monohydrate.
  • Figures 6 through 9 show IR spectrum, Raman spectrum, thermogravimetric analysis, and DSC analysis of Ribociclib hydrochloride dihydrate.
  • Figures 10 through 13 show IR spectrum, Raman spectrum, thermogravimetric analysis, and DSC analysis of Ribociclib hydrochloride anhydrate.
  • a first aspect of the invention relates to Ribociclib malate monohydrate.
  • the Ribociclib malate monohydrate according to the invention is at least partially crystalline, preferably essentially crystalline.
  • the Ribociclib malate monohydrate according to the invention is at least partially amorphous, preferably essentially amorphous.
  • the Ribociclib malate monohydrate according to the invention is characterized by one or more of the following:
  • thermogravimetric weight loss of about 3.4 % in the range of 30 - 155°C.
  • Ribociclib malate monohydrate does not form higher hydrate forms after exposure to humid atmosphere, i.e. 90% relative humidity. Further, it was surprisingly found that Ribociclib malate monohydrate is thermodynamically stable. Upon exposure of Ribociclib malate monohydrate to elevated humidity and temperature for 1 month, that is 40 °C and 75% RH, no polymorphic transition is observed.
  • the Ribociclib malate monohydrate according to the invention can be prepared e.g. as described in Example 1.
  • Ribociclib hydrochloride dihydrate Another aspect of the invention relates to Ribociclib hydrochloride dihydrate.
  • the Ribociclib hydrochloride dihydrate according to the invention is at least partially crystalline, preferably essentially crystalline.
  • the Ribociclib hydrochloride dihydrate according to the invention is at least partially amorphous, preferably essentially amorphous.
  • the Ribociclib hydrochloride dihydrate according to the invention is characterized by one or more of the following:
  • the Ribociclib hydrochloride dihydrate according to the invention can be prepared e.g. as described in Example 2.
  • Ribociclib hydrochloride dihydrate does not form higher hydrate forms after exposure to humid atmosphere, i.e. 90% relative humidity. Further, it was surprisingly found that Ribociclib hydrochloride dihydrate is thermodynamically stable. Upon exposure of Ribociclib hydrochloride dihydrate to elevated humidity and temperature for 1 month, that is 40 °C and 75% RH, no polymorphic transition is observed.
  • a further aspect of the invention relates to Ribociclib hydrochloride anhydrate.
  • the Ribociclib hydrochloride anhydrate according to the invention is at least partially crystalline, preferably essentially crystalline.
  • the Ribociclib hydrochloride anhydrate according to the invention is at least partially amorphous, preferably essentially amorphous.
  • the Ribociclib hydrochloride anhydrate according to the invention is characterized by one or more of the following:
  • thermogravimetric weight loss of about 0.4 % in the range of 30 - 120°C.
  • the Ribociclib hydrochloride anhydrate according to the invention can be prepared e.g. as described in Example 3.
  • Ribociclib malate monohydrate according to the invention as described above the Ribociclib hydrochloride dihydrate according to the invention as described above, and the Ribociclib hydrochloride anhydrate according to the invention as defined above are commonly referred to as "Ribociclib salt" according to the invention.
  • Ribociclib succinate preferably Ribociclib succinate anhydrous.
  • the hydrate and non-hydrate (i.e. anhydrous) of Ribociclib succinate are known from WO 2012/064805.
  • Polymorphic forms of Ribociclib succinate are known from WO 2019/167068 Al and WO 2020/152629 Al which are all contemplated according to the invention and incorporated by reference.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising
  • Ribociclib salt preferably selected from the group consisting of Ribociclib malate monohydrate, Ribociclib hydrochloride dihydrate, Ribociclib hydrochloride anhydrate, and Ribociclib succinate anhydrous; and
  • the Ribociclib salt according to the invention can be milled thereby reducing the size of the particles. Any process and equipment for milling of pharmaceutical substances known in the literature can be used.
  • the Ribociclib salt has an average particle size in the range of from 0.5 to 350 pm, preferably 1.0 to 300 pm, and most preferably from 10 and 10 pm. In a particularly preferred embodiment, the Ribociclib salt has an average particle size in the range of from 35 to 65 pm.
  • the average particle size is determined by laser diffraction and is expressed as volume based value D v 50 in accordance with Ph. Eur. 2.9.31 "Particle Size Analysis By Laser Light Diffraction" .
  • the physiologically acceptable carrier e.g. vehicle, diluent
  • other excipients useful in the pharmaceutical composition according to the invention e.g. binders, fillers, disintegrants, lubricants, and the like
  • the pharmaceutical composition according to the invention contains Ribociclib salt at a content within the range of from 1 to 90 wt.-%, more preferably 1 to 80 wt.-% by weight, still more preferably 1 to 60 wt.-%, based upon the actual molecular weight of the Ribociclib salt and relative to the total weight of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention contains Ribociclib salt at a content of at most 60 wt.-%, more preferably less than 60 wt.-%, still more preferably at most 55 wt.-%, yet more preferably less than 55 wt.-%, even more preferably at most 50 wt.-%, most preferably at most 45 wt.-%, and in particular at most 40 wt.-%, based upon the actual molecular weight of the Ribociclib salt and relative to the total weight of the pharmaceutical composition
  • the solid pharmaceutical compositions containing Ribociclib salt further comprise at least one more auxiliary agent, selected from the group of lubricant, glidant, binder, solubility enhancer, flavoring agent, coloring agent, and mixtures thereof.
  • Lubricant (which can be used as further pharmaceutical mixture excipient) can be, for instance, selected from stearic acid; calcium stearate; magnesium stearate; talc; colloid silica; a wax variety such as beads wax or spermaceti; boric acid; adipic acid, a sulphate such as sodium sulphate; glycol, fumaric acid, sodium stearyl fumarate; sucrose aliphatic acid ester, sodium benzoate, D,L-leucine; a lauryl sulphate such as sodium lauryl sulphate or magnesium lauryl sulphate; silicic anhydride; silicic acid hydrate; starch or a starch derivative, such as com starch, potato starch, a-starch; dextrin, and mixtures thereof.
  • a particularly preferred lubricant is magnesium stearate.
  • Glidant/dispersant (which can be used as further pharmaceutical mixture excipient) can be e.g. selected from talc, colloidal silica, and silicates.
  • a particularly preferred glidant/dispersant is silicon dioxide.
  • Binder (which can be used as further pharmaceutical mixture excipient) can be, for instance, selected from hydroxypropyl cellulose; hydroxypropyl methyl cellulose; polyvinyl pyrrolidone (povidone); polyvinylpyrrolidone-vinyl acetate copolymer (copovidone); polyethylene glycol; glucose; sorbitol; mannitol; polydextrose; maltodextrin; lactose; a starch derivative such as com starch, potato starch, a-starch or dextrin; a cellulose derivative such as crystalline cellulose or microcrystalline cellulose; gum arabic; dextran; silicic anhydride; aluminum silicate; calcium silicate; magnesium metasili- cate-aluminate; calcium hydrophosphate; calcium carbonate; calcium sulphate, and mixtures thereof.
  • polyvinyl pyrrolidone povidone
  • Particularly preferred binders include polyvinyl pyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, and combinations thereof.
  • Filler/diluent can be e.g. lactose (e.g. anhydrous or hydrate or amorphous (partially or completely)); polysaccharides, (e.g.
  • starches or celluloses may be selected from partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch and any mixture thereof; celluloses may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose co-processed with other excipients such as lactose, starch, silicon dioxide, mannitol, etc. and any mixture thereof; monosaccharides (e.g. glucose, fructose); disaccharides (e.g.
  • oligosaccharides e.g. raffinose, dextrates
  • compressible sugars e.g. mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol
  • inorganic salts of phosphoric acid e.g. mannitol, erythritol, sorbitol, maltitol
  • a particularly preferred filler/diluent is mannitol.
  • Disintegrant (which can be used as further pharmaceutical mixture excipient) can be e.g. cro- spovidone; starch, maize starch, pregelatinized starch, sodium starch gly collate, modified starch, hydroxypropyl starch, carboxymethyl starch; sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. sodium croscarmellose and/or calcium croscarmellose); po- lacrilin potassium; alginic acid or alginates, sodium and/or calcium alginate; polyacrylates; docusate sodium; methylcellulose; and agar, gums, guar gum, chitosan.
  • cro- spovidone starch, maize starch, pregelatinized starch, sodium starch gly collate, modified starch, hydroxypropyl starch, carboxymethyl starch; sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g.
  • Particularly preferred disintegrants include crospovidone, crosscarmellose sodium, and sodium starch glycolate.
  • Solubility enhancer/surfactant (which can be used as further pharmaceutical mixture excipient) can be, for instance, selected from anionic, cationic, ampholitic or nonionic surfactants, inorganic or organic acids such as (-)-(2S,3S)-tartaric acid, (+)-(2S,3S)-di-O-benzoyltartaric acid, (+)-(2S,3S)-di-O- (4-methylbenzoyl)tartaric acid, (-)-Z -phenylalanine, benzenesulfonic acid, cyclohexane sulfamic acid, naphthalene-2-sulfonic acid, sebacic acid, camphor- 10-sulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, methanesulfonic acid, adipic acid, pimelic acid, maleic acid, fumaric acid, citric acid
  • the pharmaceutical composition of the present invention is or comprises a mixture which is a compressed mixture, e.g. tablet or granule(s).
  • the pharmaceutical composition comprising a compressed mixture, which is preferably a tablet, can further comprise a coating, especially a film coating, applied on the compressed mixture, e.g. tablet.
  • Coating can be prepared employing conventional procedures, e.g. using, for instance, a film coating apparatus.
  • the coating, especially film coating can be e.g. a sugar coating, a water-soluble film coating, an intestinally soluble film coating.
  • pharmaceutical compositions of the present invention can be coated with conventional materials used for coating, in particular film coating, e.g. as described in Pharmaceutical Coating Technology (G. Cole (ed.), 1995).
  • Coating a compressed mixture can for example comprise contacting the compressed mixture with a film coating dispersion to obtain a coated compressed mixture, and optionally drying the coated compressed mixture (e.g. coated tablet or granule).
  • Film coating dispersions can be prepared by combining one or more solvents, such as water or organic solvent(s) such as alcohol(s) (e.g. methanol, ethanol, isopropanol), ketones (e.g. acetone), and mixtures thereof, with film-coating excipient(s).
  • solvents such as water or organic solvent(s) such as alcohol(s) (e.g. methanol, ethanol, isopropanol), ketones (e.g. acetone), and mixtures thereof, with film-coating excipient(s).
  • a coating can be a coating comprising a polymer e.g. selected from cellulose ethers such as hyprolose (hydroxypropyl cellulose) or hypromellose (hydroxypropyl methyl cellulose), block copolymer of polyvinyl alcohol and polyethylene glycol (commercially obtainable under trade name of Kol- licoat IR or Kollicoat protect), polyvinyl alcohol, aminoalkyl methacrylate copolymers (such as Eudragit E PO), methacrylic acid copolymers, salts of carboxymethylcellulose, and mixtures thereof.
  • cellulose ethers such as hyprolose (hydroxypropyl cellulose) or hypromellose (hydroxypropyl methyl cellulose)
  • block copolymer of polyvinyl alcohol and polyethylene glycol commercially obtainable under trade name of Kol- licoat IR or Kollicoat protect
  • polyvinyl alcohol aminoalkyl methacrylate copolymers (such as Eudragit E PO), methacrylic
  • Said coating can further comprise coating additive(s) selected from plasticizers, pigments, colorants, opacifying agents, preservatives, antitacking agents and mixtures thereof.
  • coating additive(s) selected from plasticizers, pigments, colorants, opacifying agents, preservatives, antitacking agents and mixtures thereof.
  • the thickness of the coating (in particular film coating) applied on the tablet can be in the range of from 10 to 100 pm, preferably from 15 to 50 pm.
  • the coating of the tablet can include from 10% to 95% of polymer, based on the weight of the coating.
  • the coating (especially film coating) of the tablet can comprise from 20% to 90% of polymer, optionally from 2% to 30% by weight of plasticizer, each based on the weight of the coating, optionally glidant, optionally opacifying agent and optionally colorant.
  • the film coating of the tablet can comprise from 20% to 90% of polyvinyl alcohol (PVA), from 2% to 30% by weight of plasticizer, each based on the weight of the coating, preferably the plasticizer being or including polyethylene glycol; the film coating can further comprise optionally glidant, optionally opacifying agent and optionally colorant.
  • PVA polyvinyl alcohol
  • plasticizer being or including polyethylene glycol
  • the film coating can further comprise optionally glidant, optionally opacifying agent and optionally colorant.
  • polymer for the coating include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, starch, and mixtures thereof.
  • the coating layer polymer can be preferably PVA. Presence of PVA in the coating allows for enhanced film adhesion, and facilitates faster coating of the drug.
  • Plasticizers can be selected from, but are not limited to, triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin, propylene glycol, polypropylene glycol, glycerol, sorbitol, acetyl triethyl citrate, and mixtures thereof.
  • the plasticizer can be advantageously polyethylene glycol.
  • the coating can also optionally comprise a glidant such as talc, fumed silica, magnesium stearate, or a combination thereof.
  • the coating can also optionally comprise an opacifying agent, such as titanium dioxide.
  • the coating layer may optionally comprise one or more colorants, for example, iron oxide based colorant(s). Examples of commercially available coating material include Opadry® HP, Opadry® II HP white. Examples of commercially available coating material include Opadry® HP, Opadry® II HP white. Examples of commercially available coating material include Opadry
  • compositions provided herein exhibit advantageous physical and/or pharmacological properties. Such properties include, but are not limited to, low friability, content uniformity, flow properties for manufacture, advantageous dissolution and bioavailability, and/or storage stability.
  • a pharmaceutical composition (especially in the form of a tablet or granule(s)) of the present invention can be prepared by any of the method known in the art.
  • the compositions can be prepared by uniformly admixing the active ingredient with excipients, and then, if necessary, shaping the product into the desired presentation (e.g., compaction such as roller-compaction). If desired, tablets can be coated by standard aqueous or non-aqueous techniques.
  • the pharmaceutical composition of the present invention can be prepared by a preparation method, preferably a solvent free preparation method, which can be a direct compression method or a (preferably solvent free) granulation method such as roller compaction, or slugging; the direct compression method being preferred.
  • a preparation method preferably a solvent free preparation method
  • a direct compression method or a (preferably solvent free) granulation method such as roller compaction, or slugging; the direct compression method being preferred.
  • the "direct compression method” is a method of formulation wherein a mixture comprising Ribociclib and excipients is subjected to direct compression molding, in particular without any preagglomeration processes.
  • the "dry granulation method” is a method which comprises that a mixture comprising Ribociclib and excipients is subjected to compression molding into comprimate or sheet, wherein granules are produced by crushing and division of comprimates and/or sheets by a suitable method.
  • Such methods are described in The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman et al., LEA & FEBIGER 1986) or Pharmaceutical Dosage Forms: Tablets Volume 1 (Second Edition) (Herbert A. Lieberman et al.: MARCEL DEKKER Inc. 1989).
  • Granules can be fdled into a capsule to prepare an encapsulated product or, after an optional addition of pharmaceutical additives selected from disintegrating agents and/or lubricants and/or other additives, formulated into tablets by means of compression molding, e.g. in a tableting machine.
  • Another aspect of the invention relates to a pharmaceutical dosage form comprising the Ribociclib salt according to the invention as described above or the pharmaceutical composition according to the invention as described above.
  • composition according to the invention can be prepared into any pharmaceutical dosage form, including tablet, powder, capsule, suppository, suspension, liposome, spray, and the like.
  • the pharmaceutical dosage form according to the invention form may provide immediate release (conventional release), delayed release, controlled release, modified release or any other type of release of Ribociclib or the Ribociclib salt.
  • the pharmaceutical dosage form according to the invention may be prepared by any conventional method including but not limited to direct blending and compression, dry granulation, wet granulation, melt granulation, extrusion, and the like.
  • the pharmaceutical dosage form is a tablet, preferably a fdm coated tablet essentially consisting of tablet core and fdm coating, wherein the tablet core has a content of Ribociclib or a physiologically acceptable salt thereof of at least 20 wt.-%, preferably at least 25 wt.-%, more preferably at least 30 wt.-%, still more preferably at least 35 wt.-%, yet more preferably at least 40 wt.-%, even more preferably at least 45 wt.-%, most preferably at least 50 wt.-%, and in particular at least 55 wt.-%, in each case based upon the weight of Ribociclib or physiologically acceptable salt thereof and relative to the total weight of the tablet core.
  • the pharmaceutical dosage form is a tablet, preferably a film coated tablet essentially consisting of tablet core and film coating, wherein the tablet core has a content of Ribociclib or a physiologically acceptable salt thereof of less than 70 wt.-%, preferably less than 65 wt.- %, more preferably less than 60 wt.-%, still more preferably less than 55 wt.-%, yet more preferably less than 50 wt.-%, even more preferably less than 45 wt.-%, most preferably less than 40 wt.-%, and in particular less than 35 wt.-%, in each case based upon the weight of Ribociclib or physiologically acceptable salt thereof and relative to the total weight of the tablet core.
  • the tablet cores according to the invention comprise the following ingredients at the following weight contents, relative to the total weight of the tablet cores (additional, not specified ingredients may be present such as intragranular lubricant (e.g. magnesium stearate) and/or intragranular dispersant (e.g. anhydrous colloidal silicon dioxide) and/or extragranular dispersant (e.g. anhydrous colloidal silicon dioxide):
  • intragranular lubricant e.g. magnesium stearate
  • intragranular dispersant e.g. anhydrous colloidal silicon dioxide
  • extragranular dispersant e.g. anhydrous colloidal silicon dioxide
  • the pharmaceutical dosage form according to the invention is preferably film coated, e.g. a film coated tablet.
  • Preferred coating compositions comprise film forming polymers such as polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethylene glycol such as Kollicoat® IR and/or Kollicoat® Protect, polyvinyl acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, acrylate polymers such as those commercially available under the trade name Eudragit® (e.g. Eudragit® RL, Eudragit® RS, Eudragit® NE, Eudragit® E, Eudragit® S), and combinations thereof.
  • Eudragit® e.g. Eudragit® RL, Eudragit® RS, Eudragit® NE, Eudragit® E, Eudragit® S
  • Preferred coating compositions further comprise plasticizers such as polyethylene glycol, propylene glycol, glycerin, acetylated monoglycerides, castor oil, propyl gallate, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin.
  • Plasticizers improve some drawbacks of polymers. Polymer (such as PVA) and plasticizer (such as PEG) are commercially available, sometimes as copolymer.
  • the fdm coating is non-functional.
  • the film coating does not contain polyvinyl alcohol (PVAL).
  • PVAL polyvinyl alcohol
  • the film coating is based upon hydroxypropyl methyl cellulose (HPMC).
  • Coating materials based upon hydroxypropyl methyl cellulose are commercially available under the trade designations Opadry® and Opadry II®, e.g. Opadry® WHITE 00F280002 (HPMC based).
  • the original Opadry formulations® comprise low viscosity hypromellose (HPMC), plasticizers, and pigments.
  • the Opadry® II family of products comprises HPMC and polysaccharides.
  • the film coating is based upon an acrylate polymer selected from poly(butyl methacrylate, (2 -dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2: 1 (e.g. Eudragit® E, Eudragit® E PO); poly(ethyl acrylate, methyl methacrylate) 2: 1 (e.g. Eudragit® NE, Eudragit® NM); poly(methacrylic acid, methyl methacrylate) 1: 1 (e.g. Eudragit® L); poly(methacrylic acid, ethyl acrylate) 1: 1 (e.g.
  • Eudragit® L 100-55 poly(ethyl acrylate, methyl methacrylate, trime- thylammonioethyl methacrylate chloride) l:2:0.2 (e.g. Eudragit® RL); and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS). More preferably, the fdm coating is based upon poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2: 1 (e.g., Eudragit® E).
  • the pharmaceutical dosage form is a fdm coated tablet comprising
  • a tablet core preferably according to any one of preferred embodiments A 1 to C 4 as compiled in the table above, and
  • an acrylate polymer preferably poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2: 1 (e.g., Eudragit® E).
  • the fdm coating may not influence release of Ribociclib or the physiologically acceptable salt thereof from the fdm coated dosage form. When the dosage form does not otherwise retard release, the dosage form may then provide immediate release. [0088] In preferred embodiments, the fdm coated pharmaceutical dosage form releases at least 75% of the Ribociclib or the physiologically acceptable salt thereof after 45 minutes when tested with the rotating basket at 100 rpm with 900 mb of dissolution medium pH 2 or pH 4.5, at 37°C, according to Ph. Eur.
  • the film coating alters the release profile, which may include e.g. sustained release, controlled release, modified release or delayed release. Enteric coating materials are also contemplated.
  • Preferred coating compositions further comprise pigments, colorants and/or opacifiers such as titanium dioxide, aluminum lakes, iron oxides, natural colors, and the like.
  • Preferred coating compositions further comprise amines such as glycine, lysine, histidine, arginine, ethanolamine, diethanolamine, triethanolamine, and the like.
  • amines such as glycine, lysine, histidine, arginine, ethanolamine, diethanolamine, triethanolamine, and the like.
  • Preferred coating compositions further comprise glidants such as talc, lecithin, magnesium stearate, calcium stearate, and the like.
  • Preferred coating compositions further comprise a surfactant such as a nonionic surfactant, anionic surfactant or cationic surfactant.
  • a surfactant such as a nonionic surfactant, anionic surfactant or cationic surfactant.
  • the pharmaceutical dosage form according to the invention contains Ribociclib salt in an amount corresponding to an equivalent dose of 200 mg Ribociclib in its non-salt ansolvate form.
  • the pharmaceutical dosage form according to the invention may be for use in combination therapy, e.g. as unit dosage form comprising the Ribociclib salt according to the invention in combination with a second pharmacologically active ingredient or a physiologically acceptable salt thereof; or for separate dosing, i.e. in therapy where a first dosage form is administered which contains the Ribociclib salt and a second, separate dosage form is administered which contains a second pharmacologically active ingredient or a physiologically acceptable salt thereof. If administered as a separate dosage form, the additional therapeutic agent may be administered either simultaneously with, or sequentially with the dosage form according to the invention.
  • the pharmaceutical dosage form according to the invention comprises the Ribociclib salt and additionally a second pharmacologically active ingredient or a physiologically acceptable salt thereof.
  • said second pharmacologically active ingredient or a physiologically acceptable salt thereof is selected from the group consisting of:
  • Another aspect of the invention relates to a Ribociclib salt according to the invention as described above, a pharmaceutical composition according to the invention as defined above, or a pharmaceutical dosage form according to the invention as described above for use in the treatment of a cancerous condition.
  • the invention relates to the use of a Ribociclib salt according to the invention as described above, a pharmaceutical composition according to the invention as defined above, or a pharmaceutical dosage form according to the invention as described above, for the manufacture of a medicament for treating a cancerous condition.
  • the invention relates to a method for treating a cancerous condition comprising administering a Ribociclib salt according to the invention as described above, a pharmaceutical composition according to the invention as defined above, or a pharmaceutical dosage form according to the invention as described above to a subject in need thereof.
  • the cancerous condition is selected from the group consisting of breast cancer, lung cancer, urinary and reproductive cancer, gastrointestinal cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, bone cancer, prostate cancer, small-cell lung carcinoma, glioblastoma, colorectal cancer, kidney cancer, epithelial cancer, liver cancer, esophageal cancer, leukemia, lymphoma, bone marrow cancer, fibrosarcoma, epithelioid sarcoma, and follicular thyroid carcinoma; more preferably for the treatment of breast cancer; still more preferably for the treatment of advanced or recurrent breast cancer; most preferably for the treatment of postmenopausal women with hormone receptor (HR)-posi- tive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • the pharmaceutical dosage form according to the invention is orally administered, preferably once daily, whereas the daily dose preferably corresponds to an equivalent dose of 600 mg Ribociclib in its non-salt ansolvate form.
  • the pharmaceutical dosage form contains an amount corresponding to an equivalent dose of 200 mg Ribociclib in its non-salt ansolvate form
  • 3 pharmaceutical dosage forms according to the invention are orally administered within a short period of time, e.g. a few seconds or up to 5 minutes.
  • Raman spectra were recorded using a RAMAN Senterra Bruker Raman microspectrometer, laser wavelength: 785 nm, laser power: 100 mW, objective magnification: 20x, integration time: 10 s, number of coadditions: 2, spectral range: 1800-440 cm 1 .
  • Thermogravimetry was performed using a Mettler Toledo TGA/DSC3+, din. 30-220°C, flow N2 40ml/min, approx. lOmg of weight, lOOul aluminum crucibles covered with aluminum perforated lid.
  • DSC Differential Scanning Calorimetry
  • Ribociclib base (15 g), 101.3 mb 50 % 2-propanol in water and 4.9 g malic acid charged into 400 mb overhead glass reactor with pitchblade stirrer. The reaction mass was heated to 65 °C and mixed until the clear solution was formed. The clear solution was cooled to 50°C and 101.3 mL 2-propanol was added dropwise. The obtained suspension was cooled to 25 °C in 2h, stirred for 15 hours and fdtered using vacuum fdtration. Wet cake was washed with 30 mL of 2-propanol and dried in a vacuum tray dryer for 18 hours at 50°C, p ⁇ 50 mbar, 16.7 g of Ribociclib malate monohydrate was obtained.
  • Ribociclib base (3.3 g), 20.3 mL 50 % 2-propanol in water and 0.98 g malic acid charged into 100 mL overhead glass reactor with pitchblade stirrer. The reaction mass was heated to 65 °C and mixed until the clear solution was formed. The clear solution was cooled to 50°C and 20.3 mL 2-propanol was added dropwise. The obtained suspension was cooled to 0°C in 3h and stirred for 15 hours. The obtained suspension was fdtered using vacuum fdtration. Wet cake was washed with 6 mL of precooled 2-propanol and dried in a vacuum tray dryer for 24 hours at 50°C, p ⁇ 50 mbar, 3.8 g of Ribociclib malate monohydrate was obtained.
  • Ribociclib base (20 g) and 100 mL 50 % 2-propanol in water was charged into 250 mL overhead glass reactor with pitchblade stirrer. The reaction mass was heated to 60°C. Into the reaction mass 48.3 mL of IM hydrochloric acid (1.05 eq) was added dropwise. The clear solution was cooled to 0°C in 2h and additionally stirred for 60 minutes at isolation temperature. The obtained suspension was filtered using vacuum filtration. Wet cake was washed with 40 mL of precooled 2-propanol and dried in a vacuum tray dryer for 20 hours at 25°C, p ⁇ 50 mbar, 18.9 g of Ribociclib hydrochloride dihydrate was obtained.
  • Ribociclib base (3.3 g) and 15 mb 50 % 2-propanol in water was charged into 100 mL overhead glass reactor with pitchblade stirrer. The reaction mass was heated to 55°C. Into the reaction mass 0.6 mL of 37% hydrochloric acid (1.05 eq.) was added dropwise. The obtain suspension was cooled to 40°C and 15 mL 2-propanol was added dropwise and further cooled to 0°C in 6h, stirred for 15 hours and fdtered using vacuum fdtration. Wet cake was washed with 6 mL of precooled 2-propanol and dried in a vacuum tray dryer for 18 hours at 50°C, p ⁇ 50 mbar, 2.8 g of Ribociclib hydrochloride dihydrate was obtained.
  • Ribociclib base (5 g) and 150 mL 2-propanol was charged into 250 mL overhead glass reactor with pitchblade stirrer. The reaction mass was heated to 80°C and mixed until the clear solution was formed. Into the reaction mass 2.32 mL of hydrochloric acid in 2-propanol solution (1.05 eq) was added dropwise. The obtained suspension was cooled to 25°C in 4h and stirred for 5 hours, further cooled to 0°C in 2h, stirred for 15 hours and fdtered using vacuum fdtration. Wet cake was washed with 10 mL of precooled 2-propanol and dried in a vacuum tray dryer for 18 hours at 50°C, p ⁇ 50 mbar, 4.1 g of Ribociclib hydrochloride anhydrate was obtained.
  • Example 4 - pharmaceutical dosage forms (dry granulation): [0134] Film-coated pharmaceutical dosage forms (compressed tablets) in table of Example 4 below are prepared by dry granulation process. The manufacturing process includes five main steps: blending of intra-granular components, roller compaction, milling and blending with extra-granular excipients, compression, and film coating.
  • Example 5 pharmaceutical dosage forms (wet granulation):
  • Film-coated pharmaceutical dosage forms (compressed tablets) in table of Example 5 below are prepared by wet granulation process.
  • the manufacturing process includes five main steps: granulation solution preparation, wet granulation and drying of granulate, milling and blending with extra-granular excipients, compression, and film coating.
  • Film-coated pharmaceutical dosage forms (compressed tablets) in table of Example 6 below are prepared by dry granulation process.
  • the manufacturing process includes five main steps: blending of intra- granular components, roller compaction, milling and blending with extra-granular excipients, compression, and film coating.
  • Ribociclib succinate anhydrous is prepared in accordance with WO2012/064805 (and EP 3 283 058).
  • Example 8 pharmaceutical formulation stability:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des sels d'addition acide physiologiquement acceptables de ribociclib et des compositions pharmaceutiques les contenant. En particulier, l'invention concerne des formulations de comprimés contenant du monohydrate de malate de ribociclib, du dihydrate de chlorhydrate de ribociclib ou de l'anhydrate de chlorhydrate de ribociclib.
PCT/EP2023/083781 2022-12-01 2023-11-30 Sels de ribociclib et formulations de ceux-ci WO2024115680A1 (fr)

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