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US20200390771A1 - Ribociclib Tablet - Google Patents

Ribociclib Tablet Download PDF

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Publication number
US20200390771A1
US20200390771A1 US17/003,771 US202017003771A US2020390771A1 US 20200390771 A1 US20200390771 A1 US 20200390771A1 US 202017003771 A US202017003771 A US 202017003771A US 2020390771 A1 US2020390771 A1 US 2020390771A1
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Prior art keywords
ribociclib
tablet
coating
core
tablets
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Abandoned
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US17/003,771
Inventor
Rui Costa
Arnaud Grandeury
Bindhumadhavan GURURAJAN
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Novartis AG
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Novartis AG
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Application filed by Novartis AG filed Critical Novartis AG
Priority to US17/003,771 priority Critical patent/US20200390771A1/en
Publication of US20200390771A1 publication Critical patent/US20200390771A1/en
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COSTA, RUI, GRANDEURY, ARNAUD, GURURAJAN, Bindhumadhavan
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA AG
Priority to US17/805,956 priority patent/US12064434B2/en
Priority to US18/588,259 priority patent/US20250090531A1/en
Priority to US18/977,228 priority patent/US12419894B2/en
Priority to US18/977,210 priority patent/US20250134893A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to tablet formulation of ribociclib and/or its pharmaceutically acceptable salts, as well as methods of treatment using the same.
  • ribociclib is known as ribociclib. Its chemical name is 7-cyclopentyl-N,N-dimethyl-2- ⁇ [5-(piperazin-1-yl)pyridin-2-yl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and its synthesis is specifically described in WO 2010/020675 A1, Example 74.
  • Ribociclib and its pharmaceutically acceptable salt(s) have valuable pharmacological properties and can be used, for example, (1) as inhibitors of cyclin dependent kinases, (in particular, cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9); and (2) as modulators and/or inhibitors of glycogen synthase kinase-3 (GSK-3).
  • cyclin dependent kinases in particular, cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9
  • GSK-3 glycogen synthase kinase-3
  • Ribociclib is also known under the code name LEE011.
  • the present disclosure is directed to oral formulations of ribociclib including its salt(s) and/or solvate(s).
  • One embodiment of the present disclosure is directed to tablet formulations of ribociclib with high drug load with an immediate release profile.
  • One embodiment of the present disclosure is directed to coated tablet formulations of ribociclib.
  • Another embodiment of the present disclosure is directed to coated tablet formulations of ribociclib where the coating is an advanced moisture barrier coating (e.g., Opadry® amb II coating where the coating is PVA based).
  • FIGS. 1A and 1B depict a process flow diagram for making ribociclib tablets. Uncoated tablets are made according to Steps 1 - 8 . Coated tablets are made according to Steps 1 - 9 .
  • FIG. 2 shows the images of the tablets manufactured with Opadry® (standard HPMC based) and with Opadry® amb II (advance moisture barrier (AMB) coating material with PVA based).
  • Opadry® standard HPMC based
  • Opadry® amb II advanced moisture barrier (AMB) coating material with PVA based
  • FIG. 3 shows the Dynamic Vapor Sorption (DVS) data of the ribociclib tablets coated with standard Opadry® and Opadry® amb II.
  • FIG. 4 shows the dissolution profile of ribociclib (LEE011) tablets coated with Opadry® amb II obtained with the rotating basket at 100 rpm with dissolution media having different pH values, at 37° C.
  • the present disclosure relates to a solid oral tablet dosage form of ribociclib or its pharmaceutically acceptable salt.
  • Such formulation has very good process performance and high stability.
  • the tablet of the present disclosure has an immediate release profile. These tablets release at least 75% (Q) (where Q refers to the acceptance criteria defined by USP chapter ⁇ 711>) of the active after 45 minutes under standard dissolution test. In embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of HCl pH 1 as dissolution medium at 37° C. In another embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of HCl pH 2 as dissolution medium at 37° C.
  • the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of acetate buffer pH 4.5 as dissolution medium at 37° C. In another embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of phosphate buffer pH 6.8 as dissolution medium at 37° C.
  • the tablets of the present disclosure can be coated or uncoated.
  • the tablets of the present disclosure have high drug load of at least 40%, 45%, 50%, 55% or 60%, when measured in w/w percentage of the ribociclib succinate of the core tablet.
  • the tablets of the present disclosure have high drug load of at least 32%, 40%, 44%, 47% or 52%, when measured in w/w percentage of the ribociclib free base of the core tablet.
  • the % of ribociclib succinate (w/w) is at least 40% of the core tablet. In one embodiment, the % of ribociclib succinate (w/w) is at least 50% of the core tablet. In another embodiment, the % of ribociclib succinate (w/w) is at least 55% of the core tablet. In another embodiment, the % of ribociclib succinate (w/w) is at about 55% to 65% of the core tablet. In another embodiment, the % of ribociclib succinate (w/w) is at about 60% of the core tablet.
  • the % of ribociclib (w/w) is at least 32% of the core tablet. In one embodiment, the % of ribociclib (w/w) is at least 40% of the core tablet. In another embodiment, the % of ribociclib (w/w) is at least 44% of the core tablet. In another embodiment, the % of ribociclib (w/w) is at about 44% to 52% of the core tablet. In another embodiment, the % of ribociclib (w/w) is at about 47% of the core tablet.
  • Core tablet is also referred to as “tablet core”.
  • the tablet core is the whole tablet.
  • the tablet core is the portion of the tablet excluding the coating.
  • the tablet formulation according to the disclosure may contain pharmaceutically acceptable excipients commonly used in pharmaceutical formulations, particularly those for oral administration for example, as fillers, binders, disintegrants and lubricants.
  • Fillers for example, can be cellulose, mannitol, di-calcium phosphate, lactose, microcrytalline cellulose, alone or in combination thereof
  • Binders for example, can be hydroxypropyl cellulose, polyvinyl-pyrrolidone, alone or in combination thereof.
  • Disintegrants for example, can be crosslinked polyvinyl-pyrrolidone, crosslinked sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, sodium starch glycolate, alone or in combination thereof.
  • Lubricants for example, can be magnesium stearate, stearic acid, talc, silicon dioxide, sodium stearyl fumarate, alone or in combination thereof.
  • FIGS. 1A and 1B show the process flow diagram of making ribociclib tablets. Uncoated tablets are made according to Steps 1 - 8 . Coated tablets are made according to Steps 1 - 9 .
  • the core ribociclib tablets have an inner phase comprising ribociclib or salt(s) thereof, and an outer phase.
  • the ribociclib tablets of the present disclosure are immediate release tablets and can be coated with any immediate release coating materials.
  • the coating material can be Opadry®, Opadry® 200, Opadry® amb II, Opadry® fxTM, Opadry® II, Opalux®, or mixtures thereof.
  • Opadry®, Opadry® 200, Opadry® amb II, Opadry® fxTM, Opadry® II, and Opalux® are all commercially available through Colorcon, Inc.
  • the coating material is Opadry®.
  • Opadry® is a HPMC (hydroxypropyl methylcellulose) coating material and has the following composition: HPMC (Pharmacoat 603) 71.4%, polyethylene glycol 7.15%, talc 7.15%, and iron oxide 14.3%.
  • the coating material is Opadry® amb II.
  • Opadry® amb II is a PVA (polyvinyl alcohol) based coating material and has the following composition: polyvinyl alcohol 45.52%, iron oxide 32%, talc 20%, lecithin (soya) 2%, and xanthan gum 0.48%.
  • the ribociclib tablets When the ribociclib tablets are coated with Opadry® amb II, the tablets show improved appearances and are essentially free of cracking defects.
  • Table 1 below details the composition of uncoated 50 mg and 200mg ribociclib tablets. These tablets are made according to Steps 1 - 8 of the process flow diagram ( FIGS. 1A-1B ).
  • composition per dosage form unit Composition per unit [mg/unit] 50 mg of 200 mg of Ingredient Ribociclib Ribociclib Inner phase Ribociclib (LEE011) succinate 1 63.600 254.40 Microcrystalline cellulose/ Cellulose, microcrystalline 16.860 67.44 Hydroxypropyl cellulose 12.030 48.12 Crospovidone 7.300 29.20 Colloidal silicon dioxide/ 0.530 2.12 Silica, colloidal anhydrous Magnesium stearate 2 1.590 6.36 Outer phase Crospovidone 3.210 12.84 Colloidal silicon dioxide/ 0.265 1.06 Silica, colloidal anhydrous Magnesium stearate 2 2.115 8.46 Tablet weight 107.500 430.00 1
  • the salt factor is 1.272.
  • the drug substance quantity is increased if the content is ⁇ 99.5% with a corresponding reduction in the microcrystalline cellulose content. 2 Vegetable origin
  • Table 2 below details the composition of uncoated 100 mg, 150 mg, and 300mg ribociclib tablets. These tablets are made according to Steps 1 - 8 of the process flow diagram ( FIGS. 1A-1B ).
  • composition per dosage form unit Composition per unit [mg/unit] 100 mg of 150 mg of 300 mg of Ingredient Ribociclib Ribociclib Ribociclib Inner phase Ribociclib (LEE011) succinate 1 127.2 190.8 381.6 Microcrystalline cellulose/ Cellulose, microcrystalline 33.72 50.58 101.16 Hydroxypropylcellulose 24.06 36.09 72.18 Crospovidone 14.60 21.9 43.8 Colloidal silicon dioxide/ 1.06 1.59 3.18 Silica, colloidal anhydrous Magnesium stearate 2 3.18 4.77 9.54 Outer phase Crospovidone 6.420 9.63 19.26 Colloidal silicon dioxide/ 0.53 0.795 1.59 Silica, colloidal anhydrous Magnesium stearate 2 4.23 6.345 12.69 Tablet weight 215.00 322.5 645.00 1 The salt factor is 1.272. The drug substance quantity is increased if the content is ⁇ 99.5% with a corresponding reduction in the microcrystalline cellulose content. 2 Vegetable origin
  • Table 3 below details the composition of film-coated 50 mg and 200mg ribociclib tablets. These tablets were made according to Steps 1 - 9 of the process flow diagram ( FIGS. 1A-1B ).
  • the coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • the drug substance quantity is increased if the content is ⁇ 99.5% with a corresponding reduction in the microcrystalline cellulose content.
  • 2 Vegetable origin 3 Excess coating is prepared to compensate for losses during the coating process 4
  • the coating premix is a commercially available product 5 Removed during processing
  • Table 4 below details the composition of film-coated 100 mg, 150 mg and 300mg ribociclib tablets. These tablets are made according to Steps 1 - 9 of the process flow diagram ( FIGS. 1A-1B ).
  • the coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • composition per dosage form unit Composition per unit [mg/unit] 100 mg of 150 mg of 300 mg of Ingredient Ribociclib Ribociclib Ribociclib Inner phase Ribociclib (LEE011) succinate 1 127.2 190.8 381.6 Microcrystalline cellulose/ Cellulose, microcrystalline 33.72 50.58 101.16 Hydroxypropylcellulose 24.06 36.09 72.18 Crospovidone 14.60 21.9 43.8 Colloidal silicon dioxide/ Silica, colloidal anhydrous 1.06 1.59 3.18 Magnesium stearate 2 3.18 4.77 9.54 Outer phase Crospovidone 6.420 9.63 19.26 Colloidal silicon dioxide/ 0.53 0.795 1.59 Silica, colloidal anhydrous Magnesium stearate 2 4.23 6.345 12.69 Core tablet weight 215.00 322.5 645.00 Coating 3 Coating premix, white 4 1.548 2.322 4.644 Coating premix, yellow 4 5.074 7.611 15.222 Coating premix, red 4 1.548 2.322 4.644 Coating premix, black 4 0.43
  • the drug substance quantity is increased if the content is ⁇ 99.5% with a corresponding reduction in the microcrystalline cellulose content.
  • 2 Vegetable origin 3 Excess coating is prepared to compensate for losses during the coating process 4
  • the coating premix is a commercially available product 5 Removed during processing
  • Ribociclib tablets coated with different coatings were compared. Coating was carried out in Bohle coater 1 Kg scale with spray rate of 3 g/min. With standard Opadry® coating, tablet logo bridging issue and tablet cracking defects were observed. In contrast, no cracking was observed with the PVA based Opadry® amb II coated tablets.
  • FIG. 2 shows the images of the tablets manufactured with Opadry® (standard HPMC based) and with Opadry® amb II (advance moisture barrier (AMB) coating material with PVA based).
  • Opadry® standard HPMC based
  • Opadry® amb II advanced moisture barrier (AMB) coating material with PVA based
  • FIG. 4 shows the dissolution profile of the Opadry® amb II film-coated ribociclib tablet in different pH media.
  • EXAMPLE 8 COATED (WITH OPADRY® AMB II COATING) 50 mg AND 200mg RIBOCICLIB TABLETS WITH DIFFERENT COATING PREMIX COMBINATION
  • Table 5 below details the composition of film-coated 50 mg and 200mg ribociclib tablets with different coating premix combination compared to Example 3. These tablets were made according to Steps 1 - 9 of the process flow diagram ( FIGS. 1A-1B ).
  • the coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • composition per dosage form unit Composition per unit [mg/unit] 50 mg of 200 mg of Ingredient Ribociclib Ribociclib Inner phase Ribociclib (LEE011) succinate 1 63.600 254.40 Microcrystalline cellulose/ Cellulose, microcrystalline 16.860 67.44 Hydroxypropylcellulose 12.030 48.12 Crospovidone 7.300 29.20 Colloidal silicon dioxide/ 0.530 2.12 Silica, colloidal anhydrous Magnesium stearate 2 1.590 6.36 Outer phase Crospovidone 3.210 12.84 Colloidal silicon dioxide/ 0.265 1.06 Silica, colloidal anhydrous Magnesium stearate 2 2.115 8.46 Core tablet weight 107.500 430.00 Coating 3 Coating premix, white 4 4.201 16.804 Coating premix, red 4 0.037 0.146 Coating premix, black 4 0.062 0.25 Purified water 5 Qs Qs Film coated tablet weight 111.800 447.20 1 The salt factor is 1.272.
  • the drug substance quantity is increased if the content is ⁇ 99.5% with a corresponding reduction in the microcrystalline cellulose content.
  • 2 Vegetable origin 3 Excess coating is prepared to compensate for losses during the coating process 4
  • the coating premix is a commercially available product 5 Removed during processing
  • EXAMPLE 9 COATED (WITH OPADRY® AMB II COATING) 100 mg, 150mg AND 300mg RIBOCICLIB TABLETS WITH DIFFERENT COATING PREMIX COMBINATION
  • Table 6 below details the composition of film-coated 100 mg, 150 mg and 300mg ribociclib tablets with different coating premix combination compared to Example 4. These tablets are made according to Steps 1 - 9 of the process flow diagram ( FIGS. 1A-1B ).
  • the coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • composition per dosage form unit 100 mg of 150 mg of 300 mg of Ingredient Ribociclib Ribociclib Ribociclib Inner phase Ribociclib (LEE011) succinate 1 127.2 190.8 381.6 Microcrystalline cellulose/ Cellulose, microcrystalline 33.72 50.58 101.16 Hydroxypropyl cellulose 24.06 36.09 72.18 Crospovidone 14.60 21.9 43.8 Colloidal silicon dioxide/ 1.06 1.59 3.18 Silica, colloidal anhydrous Magnesium stearate 2 3.18 4.77 9.54 Outer phase Crospovidone 6.420 9.63 19.26 Colloidal silicon dioxide/ 0.53 0.795 1.59 Silica, colloidal anhydrous Magnesium stearate 2 4.23 6.345 12.69 Core tablet weight 215.00 322.5 645.00 Coating 3 Coating premix, white 4 8.402 12.603 25.206 Coating premix, red 4 0.074 0.111 0.222 Coating premix, black 4 0.124 0.186 0.372 Purified water 5 Qs qs
  • the drug substance quantity is increased if the content is ⁇ 99.5% with a corresponding reduction in the microcrystalline cellulose content.
  • 2 Vegetable origin 3 Excess coating is prepared to compensate for losses during the coating process 4
  • the coating premix is a commercially available product 5 Removed during processing

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Abstract

The present disclosure is directed to oral tablet of ribociclib including its salt(s). One embodiment of the present disclosure is directed to tablet of ribociclib with high drug load with an immediate release profile. One embodiment of the present disclosure is directed to coated tablet of ribociclib. Another embodiment of the present disclosure is directed to coated tablet of ribociclib where the coating is an advanced moisture barrier coating (e.g., Opadry® amb II coating where the coating is PVA based).

Description

    FIELD OF THE INVENTION
  • The present disclosure relates to tablet formulation of ribociclib and/or its pharmaceutically acceptable salts, as well as methods of treatment using the same.
    • BACKGROUND ART
  • The compound of Formula (I)
  • Figure US20200390771A1-20201217-C00001
  • is known as ribociclib. Its chemical name is 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and its synthesis is specifically described in WO 2010/020675 A1, Example 74.
  • The succinate salt of ribociclib is described by Formula (II):
  • Figure US20200390771A1-20201217-C00002
  • and is described in WO2012/064805.
  • Ribociclib and its pharmaceutically acceptable salt(s) have valuable pharmacological properties and can be used, for example, (1) as inhibitors of cyclin dependent kinases, (in particular, cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9); and (2) as modulators and/or inhibitors of glycogen synthase kinase-3 (GSK-3).
  • Ribociclib is also known under the code name LEE011.
    • SUMMARY OF THE INVENTION
  • The present disclosure is directed to oral formulations of ribociclib including its salt(s) and/or solvate(s). One embodiment of the present disclosure is directed to tablet formulations of ribociclib with high drug load with an immediate release profile. One embodiment of the present disclosure is directed to coated tablet formulations of ribociclib. Another embodiment of the present disclosure is directed to coated tablet formulations of ribociclib where the coating is an advanced moisture barrier coating (e.g., Opadry® amb II coating where the coating is PVA based).
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • The invention is illustrated by reference to the accompanying drawing described below.
  • FIGS. 1A and 1B depict a process flow diagram for making ribociclib tablets. Uncoated tablets are made according to Steps 1-8. Coated tablets are made according to Steps 1-9.
  • FIG. 2 shows the images of the tablets manufactured with Opadry® (standard HPMC based) and with Opadry® amb II (advance moisture barrier (AMB) coating material with PVA based).
  • FIG. 3. shows the Dynamic Vapor Sorption (DVS) data of the ribociclib tablets coated with standard Opadry® and Opadry® amb II.
  • FIG. 4 shows the dissolution profile of ribociclib (LEE011) tablets coated with Opadry® amb II obtained with the rotating basket at 100 rpm with dissolution media having different pH values, at 37° C.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The present disclosure relates to a solid oral tablet dosage form of ribociclib or its pharmaceutically acceptable salt. Such formulation has very good process performance and high stability.
  • The tablet of the present disclosure has an immediate release profile. These tablets release at least 75% (Q) (where Q refers to the acceptance criteria defined by USP chapter <711>) of the active after 45 minutes under standard dissolution test. In embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of HCl pH 1 as dissolution medium at 37° C. In another embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of HCl pH 2 as dissolution medium at 37° C. In another embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of acetate buffer pH 4.5 as dissolution medium at 37° C. In another embodiment, the tablets release at least 75% of the active after 45 minutes when using the rotating basket at 100 rpm, with 900 ml of phosphate buffer pH 6.8 as dissolution medium at 37° C.
  • The tablets of the present disclosure can be coated or uncoated.
  • The tablets of the present disclosure have high drug load of at least 40%, 45%, 50%, 55% or 60%, when measured in w/w percentage of the ribociclib succinate of the core tablet.
  • The tablets of the present disclosure have high drug load of at least 32%, 40%, 44%, 47% or 52%, when measured in w/w percentage of the ribociclib free base of the core tablet.
  • The % of ribociclib succinate (w/w) is at least 40% of the core tablet. In one embodiment, the % of ribociclib succinate (w/w) is at least 50% of the core tablet. In another embodiment, the % of ribociclib succinate (w/w) is at least 55% of the core tablet. In another embodiment, the % of ribociclib succinate (w/w) is at about 55% to 65% of the core tablet. In another embodiment, the % of ribociclib succinate (w/w) is at about 60% of the core tablet.
  • When measured in terms of ribociclib free base, the % of ribociclib (w/w) is at least 32% of the core tablet. In one embodiment, the % of ribociclib (w/w) is at least 40% of the core tablet. In another embodiment, the % of ribociclib (w/w) is at least 44% of the core tablet. In another embodiment, the % of ribociclib (w/w) is at about 44% to 52% of the core tablet. In another embodiment, the % of ribociclib (w/w) is at about 47% of the core tablet.
  • Core tablet is also referred to as “tablet core”.
  • In an uncoated tablet, the tablet core is the whole tablet. In a coated tablet, the tablet core is the portion of the tablet excluding the coating.
  • The tablet formulation according to the disclosure may contain pharmaceutically acceptable excipients commonly used in pharmaceutical formulations, particularly those for oral administration for example, as fillers, binders, disintegrants and lubricants.
  • Fillers, for example, can be cellulose, mannitol, di-calcium phosphate, lactose, microcrytalline cellulose, alone or in combination thereof
  • Binders, for example, can be hydroxypropyl cellulose, polyvinyl-pyrrolidone, alone or in combination thereof.
  • Disintegrants, for example, can be crosslinked polyvinyl-pyrrolidone, crosslinked sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, sodium starch glycolate, alone or in combination thereof.
  • Lubricants, for example, can be magnesium stearate, stearic acid, talc, silicon dioxide, sodium stearyl fumarate, alone or in combination thereof.
  • As an example, FIGS. 1A and 1B show the process flow diagram of making ribociclib tablets. Uncoated tablets are made according to Steps 1-8. Coated tablets are made according to Steps 1-9.
  • In one embodiment, the core ribociclib tablets have an inner phase comprising ribociclib or salt(s) thereof, and an outer phase.
  • Coating material:
  • The ribociclib tablets of the present disclosure are immediate release tablets and can be coated with any immediate release coating materials. For example, the coating material can be Opadry®, Opadry® 200, Opadry® amb II, Opadry® fx™, Opadry® II, Opalux®, or mixtures thereof. Opadry®, Opadry® 200, Opadry® amb II, Opadry® fx™, Opadry® II, and Opalux® are all commercially available through Colorcon, Inc.
  • In one embodiment, the coating material is Opadry®. Opadry® is a HPMC (hydroxypropyl methylcellulose) coating material and has the following composition: HPMC (Pharmacoat 603) 71.4%, polyethylene glycol 7.15%, talc 7.15%, and iron oxide 14.3%.
  • In another embodiment, the coating material is Opadry® amb II. Opadry® amb II is a PVA (polyvinyl alcohol) based coating material and has the following composition: polyvinyl alcohol 45.52%, iron oxide 32%, talc 20%, lecithin (soya) 2%, and xanthan gum 0.48%.
  • When the ribociclib tablets are coated with Opadry® amb II, the tablets show improved appearances and are essentially free of cracking defects.
  • The present invention(s) is further described in the following example. The following non-limiting examples illustrate the invention(s) and are not to be construed as limiting the scope of the appended claims.
    • EXAMPLE 1 UNCOATED 50 mg AND 200mg RIBOCICLIB TABLETS
  • Table 1 below details the composition of uncoated 50 mg and 200mg ribociclib tablets. These tablets are made according to Steps 1-8 of the process flow diagram (FIGS. 1A-1B).
  • TABLE 1
    Composition per dosage form unit
    Composition per unit [mg/unit]
    50 mg of 200 mg of
    Ingredient Ribociclib Ribociclib
    Inner phase
    Ribociclib (LEE011) succinate1 63.600 254.40
    Microcrystalline cellulose/
    Cellulose, microcrystalline 16.860 67.44
    Hydroxypropyl cellulose 12.030 48.12
    Crospovidone 7.300 29.20
    Colloidal silicon dioxide/ 0.530 2.12
    Silica, colloidal anhydrous
    Magnesium stearate2 1.590 6.36
    Outer phase
    Crospovidone 3.210 12.84
    Colloidal silicon dioxide/ 0.265 1.06
    Silica, colloidal anhydrous
    Magnesium stearate2 2.115 8.46
    Tablet weight 107.500 430.00
    1The salt factor is 1.272. The drug substance quantity is increased if the content is ≤99.5% with a corresponding reduction in the microcrystalline cellulose content.
    2Vegetable origin
    • EXAMPLE 2 UNCOATED 100 mg, 150 mg AND 300 mg RIBOCICLIB TABLETS
  • Table 2 below details the composition of uncoated 100 mg, 150 mg, and 300mg ribociclib tablets. These tablets are made according to Steps 1-8 of the process flow diagram (FIGS. 1A-1B).
  • TABLE 2
    Composition per dosage form unit
    Composition per unit [mg/unit]
    100 mg of 150 mg of 300 mg of
    Ingredient Ribociclib Ribociclib Ribociclib
    Inner phase
    Ribociclib (LEE011) succinate1 127.2 190.8 381.6
    Microcrystalline cellulose/
    Cellulose, microcrystalline 33.72 50.58 101.16
    Hydroxypropylcellulose 24.06 36.09 72.18
    Crospovidone 14.60 21.9 43.8
    Colloidal silicon dioxide/ 1.06 1.59 3.18
    Silica, colloidal anhydrous
    Magnesium stearate2 3.18 4.77 9.54
    Outer phase
    Crospovidone 6.420 9.63 19.26
    Colloidal silicon dioxide/ 0.53 0.795 1.59
    Silica, colloidal anhydrous
    Magnesium stearate2 4.23 6.345 12.69
    Tablet weight 215.00 322.5 645.00
    1The salt factor is 1.272. The drug substance quantity is increased if the content is ≤99.5% with a corresponding reduction in the microcrystalline cellulose content.
    2Vegetable origin
    • EXAMPLE 3 COATED (WITH OPADRY® AMB II COATING) 50 mg AND 200mg RIBOCICLIB TABLETS
  • Table 3 below details the composition of film-coated 50 mg and 200mg ribociclib tablets. These tablets were made according to Steps 1-9 of the process flow diagram (FIGS. 1A-1B). The coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • TABLE 3
    Composition per dosage form unit
    Composition per unit [mg/unit]
    50 mg of 200 mg of
    Ingredient Ribociclib Ribociclib
    Inner phase
    Ribociclib (LEE011) succinate1 63.600 254.40
    Microcrystalline cellulose/
    Cellulose, microcrystalline 16.860 67.44
    Hydroxypropylcellulose 12.030 48.12
    Crospovidone 7.300 29.20
    Colloidal silicon dioxide/ 0.530 2.12
    Silica, colloidal anhydrous
    Magnesium stearate2 1.590 6.36
    Outer phase
    Crospovidone 3.210 12.84
    Colloidal silicon dioxide/ 0.265 1.06
    Silica, colloidal anhydrous
    Magnesium stearate2 2.115 8.46
    Core tablet weight 107.500 430.00
    Coating3
    Coating premix, white4 0.774 3.096
    Coating premix, yellow4 2.537 10.148
    Coating premix, red4 0.774 3.096
    Coating premix, black4 0.215 0.860
    Purified water5 Qs Qs
    Film coated tablet weight 111.800 447.20
    1The salt factor is 1.272. The drug substance quantity is increased if the content is ≤99.5% with a corresponding reduction in the microcrystalline cellulose content.
    2Vegetable origin
    3Excess coating is prepared to compensate for losses during the coating process
    4The coating premix is a commercially available product
    5Removed during processing
    • EXAMPLE 4 COATED (WITH OPADRY® AMB II COATING) 100 mg, 150mg AND 300mg RIBOCICLIB TABLETS
  • Table 4 below details the composition of film-coated 100 mg, 150 mg and 300mg ribociclib tablets. These tablets are made according to Steps 1-9 of the process flow diagram (FIGS. 1A-1B). The coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • TABLE 4
    Composition per dosage form unit
    Composition per unit [mg/unit]
    100 mg of 150 mg of 300 mg of
    Ingredient Ribociclib Ribociclib Ribociclib
    Inner phase
    Ribociclib (LEE011) succinate1 127.2 190.8 381.6
    Microcrystalline cellulose/
    Cellulose, microcrystalline 33.72 50.58 101.16
    Hydroxypropylcellulose 24.06 36.09 72.18
    Crospovidone 14.60 21.9 43.8
    Colloidal silicon dioxide/
    Silica, colloidal anhydrous 1.06 1.59 3.18
    Magnesium stearate2 3.18 4.77 9.54
    Outer phase
    Crospovidone 6.420 9.63 19.26
    Colloidal silicon dioxide/ 0.53 0.795 1.59
    Silica, colloidal anhydrous
    Magnesium stearate2 4.23 6.345 12.69
    Core tablet weight 215.00 322.5 645.00
    Coating3
    Coating premix, white4 1.548 2.322 4.644
    Coating premix, yellow4 5.074 7.611 15.222
    Coating premix, red4 1.548 2.322 4.644
    Coating premix, black4 0.43 0.645 1.29
    Purified water5 Qs qs qs
    Film coated tablet weight 223.6 335.4 670.8
    1The salt factor is 1.272. The drug substance quantity is increased if the content is ≤99.5% with a corresponding reduction in the microcrystalline cellulose content.
    2Vegetable origin
    3Excess coating is prepared to compensate for losses during the coating process
    4The coating premix is a commercially available product
    5Removed during processing
    • EXAMPLE 5
  • Ribociclib tablets coated with different coatings (Opadry® (standard HPMC based) vs. Opadry® amb II (advance moisture barrier (AMB) coating material, PVA based)) were compared. Coating was carried out in Bohle coater 1 Kg scale with spray rate of 3 g/min. With standard Opadry® coating, tablet logo bridging issue and tablet cracking defects were observed. In contrast, no cracking was observed with the PVA based Opadry® amb II coated tablets.
  • FIG. 2 shows the images of the tablets manufactured with Opadry® (standard HPMC based) and with Opadry® amb II (advance moisture barrier (AMB) coating material with PVA based).
    • EXAMPLE 6
  • Dynamic vapor sorption (DVS) data on the ribociclib tablets coated with standard Opadry® and Opadry® amb II are presented in FIG. 3. At both 50 mg and 200 mg dosage unit, the tablets coated with the AMB coating (Opadry® amb II) show better performance than the standard Opadry® tablets.
    • EXAMPLE 7
  • The dissolution profiles of the Opadry® amb II coated ribociclib tablets are evaluated in different pH media. Apparatus: basket, Rotation: 100 rpm, Volume: 900 mL, Media: HCl pH 1, HCl pH 2, acetate buffer pH 4.5, phosphate buffer pH 6.8. FIG. 4 shows the dissolution profile of the Opadry® amb II film-coated ribociclib tablet in different pH media.
    • EXAMPLE 8 COATED (WITH OPADRY® AMB II COATING) 50 mg AND 200mg RIBOCICLIB TABLETS WITH DIFFERENT COATING PREMIX COMBINATION
  • Table 5 below details the composition of film-coated 50 mg and 200mg ribociclib tablets with different coating premix combination compared to Example 3. These tablets were made according to Steps 1-9 of the process flow diagram (FIGS. 1A-1B). The coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • TABLE 5
    Composition per dosage form unit
    Composition per unit [mg/unit]
    50 mg of 200 mg of
    Ingredient Ribociclib Ribociclib
    Inner phase
    Ribociclib (LEE011) succinate1 63.600 254.40
    Microcrystalline cellulose/
    Cellulose, microcrystalline 16.860 67.44
    Hydroxypropylcellulose 12.030 48.12
    Crospovidone 7.300 29.20
    Colloidal silicon dioxide/ 0.530 2.12
    Silica, colloidal anhydrous
    Magnesium stearate2 1.590 6.36
    Outer phase
    Crospovidone 3.210 12.84
    Colloidal silicon dioxide/ 0.265 1.06
    Silica, colloidal anhydrous
    Magnesium stearate2 2.115 8.46
    Core tablet weight 107.500 430.00
    Coating3
    Coating premix, white4 4.201 16.804
    Coating premix, red4 0.037 0.146
    Coating premix, black4 0.062 0.25
    Purified water5 Qs Qs
    Film coated tablet weight 111.800 447.20
    1The salt factor is 1.272. The drug substance quantity is increased if the content is ≤99.5% with a corresponding reduction in the microcrystalline cellulose content.
    2Vegetable origin
    3Excess coating is prepared to compensate for losses during the coating process
    4The coating premix is a commercially available product
    5Removed during processing
    • EXAMPLE 9 COATED (WITH OPADRY® AMB II COATING) 100 mg, 150mg AND 300mg RIBOCICLIB TABLETS WITH DIFFERENT COATING PREMIX COMBINATION
  • Table 6 below details the composition of film-coated 100 mg, 150 mg and 300mg ribociclib tablets with different coating premix combination compared to Example 4. These tablets are made according to Steps 1-9 of the process flow diagram (FIGS. 1A-1B). The coating material is Opadry® amb II, which is commercially available and is an advanced moisture barrier (AMB) coating, PVA based.
  • TABLE 6
    Composition per dosage form unit
    Composition per unit [mg/unit]
    100 mg of 150 mg of 300 mg of
    Ingredient Ribociclib Ribociclib Ribociclib
    Inner phase
    Ribociclib (LEE011) succinate1 127.2 190.8 381.6
    Microcrystalline cellulose/
    Cellulose, microcrystalline 33.72 50.58 101.16
    Hydroxypropyl cellulose 24.06 36.09 72.18
    Crospovidone 14.60 21.9 43.8
    Colloidal silicon dioxide/ 1.06 1.59 3.18
    Silica, colloidal anhydrous
    Magnesium stearate2 3.18 4.77 9.54
    Outer phase
    Crospovidone 6.420 9.63 19.26
    Colloidal silicon dioxide/ 0.53 0.795 1.59
    Silica, colloidal anhydrous
    Magnesium stearate2 4.23 6.345 12.69
    Core tablet weight 215.00 322.5 645.00
    Coating3
    Coating premix, white4 8.402 12.603 25.206
    Coating premix, red4 0.074 0.111 0.222
    Coating premix, black4 0.124 0.186 0.372
    Purified water5 Qs qs qs
    Film coated tablet weight 223.6 335.4 670.8
    1The salt factor is 1.272. The drug substance quantity is increased if the content is ≤99.5% with a corresponding reduction in the microcrystalline cellulose content.
    2Vegetable origin
    3Excess coating is prepared to compensate for losses during the coating process
    4The coating premix is a commercially available product
    5Removed during processing

Claims (26)

We claim:
1. A pharmaceutical oral tablet comprising ribociclib or its pharmaceutically acceptable salt.
2. The tablet of claim 1 comprising ribociclib succinate.
3. The tablet of claim 1 comprising ribociclib or its salt wherein the tablet releases at least 75% of the ribociclib or its salt after 45 minutes when tested with the rotating basket at 100 rpm with 900 ml of dissolution media pH 2 or pH4.5, at 37° C., according to USP <711>.
4. The tablet of claim 1 comprising ribociclib or its salt in a tablet core wherein the tablet core comprises at least 32% (w/w) of ribociclib measured in terms of ribociclib free base.
5. The tablet of claim 4 wherein the % of ribociclib (w/w) is at least 40% of the tablet core.
6. The tablet of claim 5 wherein the % of ribociclib (w/w) is at least 44% of the tablet core.
7. The tablet of claim 6, wherein the % of ribociclib (w/w) is at about 44% to 52% of the tablet core.
8. The tablet of claim 4 wherein the % of ribociclib (w/w) is at about 47% of the tablet core.
9. A pharmaceutical oral tablet comprising ribociclib succinate, wherein the % of ribociclib succinate (w/w) is at least 40% of the tablet core.
10. The tablet of claim 9 wherein the % of ribociclib succinate (w/w) is at least 50% of the tablet core.
11. The tablet of claim 10 wherein the % of ribociclib succinate (w/w) is at least 55% of the tablet core.
12. The tablet of claim 11, wherein the % of ribociclib succinate (w/w) is at about 55% to 65% of the tablet core.
13. The tablet of claim 9 wherein the % of ribociclib (w/w) is at about 60% of the tablet core.
14. A coated pharmaceutical oral tablet comprising ribociclib or its pharmaceutically acceptable salt wherein the coating comprises polyvinyl alcohol (PVA).
15. A coated pharmaceutical oral tablet comprising ribociclib succinate wherein the coating comprises PVA.
16. A coated pharmaceutical oral tablet comprising ribociclib or its salt wherein the tablet releases at least 75% of the ribociclib or its salt after 45 minutes when tested with the rotating basket at 100 rpm with 900 ml of dissolution media pH 2 or pH4.5, at 37° C., according to USP <711> and wherein the coating comprises PVA.
17. A coated pharmaceutical oral tablet comprising ribociclib or its salt wherein, measured in terms of ribociclib free base, the % of ribociclib (w/w) is at least 32% of the tablet core, and wherein the coating comprises PVA.
18. The tablet of claim 17 wherein the % of ribociclib (w/w) is at least 40% of the tablet core.
19. The tablet of claim 18 wherein the % of ribociclib (w/w) is at least 44% of the tablet core.
20. The tablet of claim 19, wherein the % of ribociclib (w/w) is at about 44% to 52% of the tablet core.
21. The tablet of claim 17 wherein the % of ribociclib (w/w) is at about 47% of the tablet core.
22. A coated pharmaceutical oral tablet comprising ribociclib succinate, wherein the % of ribociclib succinate (w/w) is at least 40% of the tablet core.
23. The tablet of claim 22 wherein the % of ribociclib succinate (w/w) is at least 50% of the tablet core.
24. The tablet of claim 23 wherein the % of ribociclib succinate (w/w) is at least 55% of the tablet core.
25. The tablet of claim 24, wherein the % of ribociclib succinate (w/w) is at about 55% to 65% of the tablet core.
26. The tablet of claim 22 wherein the % of ribociclib (w/w) is at about 60% of the tablet core.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12064434B2 (en) 2015-04-16 2024-08-20 Novartis Ag Ribociclib tablet

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3048036A1 (en) 2018-07-02 2020-01-02 Apotex Inc Novel crystalline form of ribociclib succinate
MX2022002415A (en) 2019-08-26 2022-03-22 Arvinas Operations Inc Methods of treating breast cancer with tetrahydronaphthalene derivatives as estrogen receptor degraders.
MX2022007488A (en) 2019-12-16 2022-08-02 Lunella Biotech Inc Selective cdk4/6 inhibitor cancer therapeutics.
MX2022007487A (en) 2019-12-16 2022-08-04 Lunella Biotech Inc Selective cdk4/6 inhibitor cancer therapeutics.
US20230310327A1 (en) * 2020-08-03 2023-10-05 Natco Pharma Limited Pharmaceutical compositions comprising ribociclib
EP4180036A4 (en) * 2020-09-29 2024-01-31 Laboratorios Silanes, S.A. de C.V. Pharmaceutical combinations of statins and fibrates for the treatment and prevention of hyperlipidaemia and cardiovascular diseases
WO2022162122A1 (en) 2021-01-29 2022-08-04 Biotx.Ai Gmbh Genetically verified netosis inhibitor for use in the treatment of a sars-cov2 infection
CA3217661A1 (en) 2021-07-16 2023-01-19 Alyssa VERANO Small molecule cyclin dependent kinase 4/6 (cdk4/6) and ikzf2 (helios) degraders and methods of use thereof
TWI848533B (en) 2022-01-25 2024-07-11 瑞士商諾華公司 Ribociclib pharmaceutical compositions
TW202539669A (en) 2022-08-31 2025-10-16 美商亞文納營運公司 Dosage regimens of estrogen receptor degraders
EP4626890A1 (en) 2022-12-01 2025-10-08 KRKA, d.d., Novo mesto Ribociclib salts and formulations thereof
AU2024244511A1 (en) 2023-03-27 2025-09-25 Novartis Ag Method of treating early breast cancer with ribociclib in combination with an aromatase inhibitor
US20250319032A1 (en) 2024-04-15 2025-10-16 Novartis Ag Pharmaceutical compositions of ribociclib

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5428812A (en) * 1977-08-09 1979-03-03 Yoshitomi Pharmaceut Ind Ltd Preparation of coated tablet
CN1097619C (en) * 1994-07-12 2003-01-01 伯温德药品服务公司 Moisture barrier film coating composition, method, and coated products
GB9414045D0 (en) 1994-07-12 1994-08-31 Berwind Pharma Service Moisture barrier film coating composition, method, and coated form
US6448323B1 (en) * 1999-07-09 2002-09-10 Bpsi Holdings, Inc. Film coatings and film coating compositions based on polyvinyl alcohol
PL2331547T3 (en) 2008-08-22 2015-01-30 Novartis Ag Pyrrolopyrimidine compounds as cdk inhibitors
US8871263B2 (en) * 2009-09-24 2014-10-28 Mcneil-Ppc, Inc. Manufacture of tablet in a die utilizing radiofrequency energy and meltable binder
US20120115878A1 (en) 2010-11-10 2012-05-10 John Vincent Calienni Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof
HRP20161291T1 (en) * 2011-02-11 2016-11-18 Wista Laboratories Ltd. Phenothiazine diaminium salts and their use
KR102122941B1 (en) * 2012-07-13 2020-06-15 지티엑스, 인코포레이티드 A method of treating androgen receptor(ar)-positive breast cancers with selective androgen receptor modulator(sarms)
EP3251673A1 (en) * 2012-12-13 2017-12-06 IP Gesellschaft für Management mbH Combination therapy comprising a cdk4/6 inhibitor and a pi3k inhibitor for use in the treatment of cancer
EP2934515B1 (en) * 2012-12-20 2018-04-04 Novartis AG A pharmaceutical combination comprising binimetinib
WO2014147573A2 (en) * 2013-03-21 2014-09-25 Novartis Ag Combination therapy
EP2810644A1 (en) * 2013-06-06 2014-12-10 Ferrer Internacional, S.A. Oral formulation for the treatment of cardiovascular diseases
MX2017013350A (en) * 2015-04-16 2018-01-25 Novartis Ag Ribociclib tablet.
CN109953966A (en) * 2017-12-26 2019-07-02 天津耀辰实业发展有限公司 A kind of pharmaceutical composition and preparation method thereof containing Rui Boxini
JP7347388B2 (en) 2020-09-25 2023-09-20 信越化学工業株式会社 Ultraviolet curable organically modified silicone composition and cured product

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12064434B2 (en) 2015-04-16 2024-08-20 Novartis Ag Ribociclib tablet
US12419894B2 (en) 2015-04-16 2025-09-23 Novartis Ag Ribociclib tablet

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