WO2015071432A1 - Pharmaceutical compositions of ibrutinib - Google Patents

Pharmaceutical compositions of ibrutinib Download PDF

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Publication number
WO2015071432A1
WO2015071432A1 PCT/EP2014/074662 EP2014074662W WO2015071432A1 WO 2015071432 A1 WO2015071432 A1 WO 2015071432A1 EP 2014074662 W EP2014074662 W EP 2014074662W WO 2015071432 A1 WO2015071432 A1 WO 2015071432A1
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WO
WIPO (PCT)
Prior art keywords
starch
pharmaceutical composition
cellulose
ibrutinib
derivatives
Prior art date
Application number
PCT/EP2014/074662
Other languages
French (fr)
Inventor
Johannes Raneburger
Franz Xaver Schwarz
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2015071432A1 publication Critical patent/WO2015071432A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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
    • A61K9/14—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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/20—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to pharmaceutical formulations of Ibrutinib, processes for their preparation and their medical use.
  • Ibrutinib is novel BTK inhibitor currently tested in clinical phase III against different kinds of cancer, in particular mantle-cell lymphoma and chronic lymphocytic leukemia.
  • WO 2008/039218 A2 discloses the chemical synthesis of Ibrutinib and its analogues. It also discloses in general terms pharmaceutical compositions containing it and capsules containing 750 mg of starch and 100 mg of a compound of the invention. For this formulation a large amount of starch and consequently the biggest size (00) of capsules are needed.
  • Ibrutinib consists of three capsules, each containing 140 mg of active ingredient, taken three times a day for a total of 1260 mg per day, this translates into a tremendous pill burden for the patient, who has to take three difficult to swallow capsules three times a day.
  • Ibrutinib is a weak base, is poorly soluble in water and shows an electrostatic behavior and a strong tendency to agglomerate. This results in a low bulk density and in difficulties to get a homogeneous distribution of the active ingredient within solid oral dosage forms, like immediate release capsules and tablets. Moreover formulations of Ibrutinib with sugars or sugar alcohols show less disintegration when filled in capsules or compressed into tablets when stored at higher temperature and/or humidity, which has a negative influence on dissolution and bioavailability.
  • An object of the present invention is thus the provision of pharmaceutical compositions of Ibrutinib having a homogeneous distribution of the active ingredient.
  • a further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having a high drug load.
  • a further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having fast disintegration after dispersion in water.
  • a further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having fast dissolution and high bioavailability.
  • a further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having less scattering of blood levels and optimal absorption into the blood.
  • a further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib for use in the treatment of cancer having reduced pill burden and improved patient compliance.
  • a further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib for use in the treatment of cancer having lower dosages of the active ingredient.
  • compositions comprising ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient.
  • ibrutinib is mixed with a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof and with at least one hydrophilic polymeric pharmaceutically acceptable excipient, the before mentioned problems can be solved and an homogeneous distribution of the active ingredient in capsules or tablets can be achieved. In addition no negative effect of temperature and/or humidity is observed on disintegration and dissolution of the pharmaceutical compositions.
  • Suitable sugars include lactose, saccharose, fructose, glucose, mannose, maltose, galactose, rhamnose, dextrin, maltodextrin and trehalose.
  • Preferred sugars include lactose, saccharose and glucose. The most preferred sugar is lactose.
  • Suitable sugar alcohols include mannitol, sorbitol, xylitol, isomalt, lactitol, maltitol, erythritol and arabitol.
  • Preferred sugar alcohols include mannitol and sorbitol.
  • the most preferred sugar alcohol is mannitol.
  • the hydrophilic polymeric pharmaceutically acceptable excipients are preferably selected from the group consisting of cellulose and cellulose derivatives, starch and starch derivatives, polyvinylpyrrolidones and their derivatives and mixtures thereof.
  • Cellulose and cellulose derivatives include macrocrystalline cellulose, microfine cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and croscaramellose sodium.
  • Preferred cellulose and cellulose derivatives include microcrystalline cellulose and sodium carboxymethylcellulose.
  • Starch and starch derivatives include maize starch, rice starch, potato starch, wheat starch, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), hydroxyethyl starch.
  • the preferred starch derivative is sodium carboxymethyl starch.
  • Polyvinylpyrrolidones and their derivatives include polyvinylpyrrolidone K17, K25, K30 or K90, polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64).
  • Preferred polyvinylpyrrolidones are polyvinylpyrrolidone K25 and K30,
  • the water soluble carrier is preferably used in an amount between 15 and 60% of the total weight of the pharmaceutical composition, preferably in an amount between 20 and 50%.
  • the hydrophilic polymeric pharmaceutically acceptable excipient is preferably used in an amount between 1 and 40%, preferably in an amount between 2 and 30%.
  • Preferred pharmaceutical compositions are tablets, capsules, granules, preferably tablets.
  • compositions of the invention can be manufactured by mixing the ingredients and filling them into capsules or by directly compressing them into tablets. Alternatively they may be made by wet or dry granulation.
  • the pharmaceutical composition of the invention can be advantageously used in the treatment of cancer, in particular mantle-cell lymphoma and chronic lymphocytic leukemia.
  • compositions of the invention show a homogeneous distribution of Ibrutinib and the excipients, which allows filling into capsules or compression into tablets with high drug load. This results in small capsule and tablet size and consequently a reduced pill burden and improved patient compliance.
  • compositions show improved stability, fast disintegration after dispersion in water, fast dissolution of Ibrutinib and consequently high bioavailability, less scattering of blood levels, optimal absorption into the blood and lower dosages of the active ingredient.
  • Capsules Ibrutinib 140 mg, lactose spray dried 53 mg, microcrystalline cellulose phl02 49 mg, crosspovidone 5 mg, fumed silica (Aerosil) 1.25 mg, magnesium stearate 1.5 mg - total 250 mg, filled in a hard gelatine capsule size 1.
  • Manufacturing procedure is two step mixing (blender, high shear mixer) - first mixing Ibrutinib with all excipients except magnesium stearate - second mixing with magnesium stearate and afterwards filling the mixture into capsules.
  • Example 2 Capsules: Ibrutinib 140 mg, mannitol DC 102 mg, microcrystalline cellulose phl02 47 mg, croscaramellose sodium (Acdisol) 8 mg, fumed silica (Aerosil) 1 mg, magnesium stearate 1.5 mg - total 300 mg filled in hard gelatine capsule size 0.
  • mannitol DC 102 mg mannitol DC 102 mg
  • microcrystalline cellulose phl02 47 mg croscaramellose sodium (Acdisol) 8 mg
  • fumed silica (Aerosil) 1 mg fumed silica (Aerosil) 1 mg
  • For the manufacturing procedure see example 1.
  • Capsules Ibrutinib 140 mg, lactose monohydrate 96 mg, sodium starch glycolate 8 mg, fumed silica (Aerosil) 3 mg, magnesium stearate 1.5 mg, sodium lauryl sulfate 1.2 mg - in total 250 mg; manufacturing procedure is wet granulation of all components except magnesium stearate, mixing granules with magnesium stearate and filling them into capsule size 1.
  • Capsules ibrutinib 140 mg, mannitol 90 mg, povidone 10 mg, croscaramellose sodium (Acdisol) 7 mg, magnesium stearate 2 mg, sodium lauryl sulfate 1 mg - in total 250 mg, manufacturing process similar to example 3.
  • Capsules ibrutinib 280 mg, lactose 270 mg, povidone 25 mg, croscaramellose sodium 15 mg, sodium lauryl sulfate 5 mg, magnesium stearate 5 mg - in total 500 mg filled into capsule size 0 - elongated; manufacturing procedure similar to example 3.
  • Tablets ibrutinib 140 mg, microcrystalline cellulose phlOl internal 81 mg, lactose monohydrate 116 mg, povidone K30 10 mg, sodium starch glycolate internal 7.5 mg, microcrystalline cellulose phi 02 external 37.5 mg, crosspovidone XL external 5 mg, fumed silica (Aerosil) 1.2 mg, magnesium stearate 1.5 mg - in total 400 mg tablet; manufacturing is wet granulation with inner phase, mixing the resulting granules with the external phase, compression.

Abstract

Ibrutinib is novel BTK inhibitor currently tested in clinical phase III against different kinds of cancer. Pharmaceutical compositions comprising Ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient show homogeneous distribution of the active ingredient, improved stability, fast disintegration and dissolution and high bioavailability.

Description

PHARMACEUTICAL COMPOSITIONS OF IBRUTINIB FIELD OF INDUSTRIAL APPLICABILITY
The present invention relates to pharmaceutical formulations of Ibrutinib, processes for their preparation and their medical use.
BACKGROUND OF THE DISCLOSURE
Ibrutinib is novel BTK inhibitor currently tested in clinical phase III against different kinds of cancer, in particular mantle-cell lymphoma and chronic lymphocytic leukemia. WO 2008/039218 A2 discloses the chemical synthesis of Ibrutinib and its analogues. It also discloses in general terms pharmaceutical compositions containing it and capsules containing 750 mg of starch and 100 mg of a compound of the invention. For this formulation a large amount of starch and consequently the biggest size (00) of capsules are needed. Considering that the typical dosage of Ibrutinib consists of three capsules, each containing 140 mg of active ingredient, taken three times a day for a total of 1260 mg per day, this translates into a tremendous pill burden for the patient, who has to take three difficult to swallow capsules three times a day.
Ibrutinib is a weak base, is poorly soluble in water and shows an electrostatic behavior and a strong tendency to agglomerate. This results in a low bulk density and in difficulties to get a homogeneous distribution of the active ingredient within solid oral dosage forms, like immediate release capsules and tablets. Moreover formulations of Ibrutinib with sugars or sugar alcohols show less disintegration when filled in capsules or compressed into tablets when stored at higher temperature and/or humidity, which has a negative influence on dissolution and bioavailability.
An object of the present invention is thus the provision of pharmaceutical compositions of Ibrutinib having a homogeneous distribution of the active ingredient. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having a high drug load.
A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having fast disintegration after dispersion in water.
A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having fast dissolution and high bioavailability. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having less scattering of blood levels and optimal absorption into the blood.
A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib for use in the treatment of cancer having reduced pill burden and improved patient compliance.
A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib for use in the treatment of cancer having lower dosages of the active ingredient. SUMMARY OF THE DISCLOSURE
The present disclosure provides pharmaceutical compositions comprising ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE DISCLOSURE
Surprisingly it was found that if ibrutinib is mixed with a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof and with at least one hydrophilic polymeric pharmaceutically acceptable excipient, the before mentioned problems can be solved and an homogeneous distribution of the active ingredient in capsules or tablets can be achieved. In addition no negative effect of temperature and/or humidity is observed on disintegration and dissolution of the pharmaceutical compositions. Suitable sugars include lactose, saccharose, fructose, glucose, mannose, maltose, galactose, rhamnose, dextrin, maltodextrin and trehalose. Preferred sugars include lactose, saccharose and glucose. The most preferred sugar is lactose.
Suitable sugar alcohols include mannitol, sorbitol, xylitol, isomalt, lactitol, maltitol, erythritol and arabitol. Preferred sugar alcohols include mannitol and sorbitol. The most preferred sugar alcohol is mannitol. The hydrophilic polymeric pharmaceutically acceptable excipients are preferably selected from the group consisting of cellulose and cellulose derivatives, starch and starch derivatives, polyvinylpyrrolidones and their derivatives and mixtures thereof.
Cellulose and cellulose derivatives include macrocrystalline cellulose, microfine cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and croscaramellose sodium. Preferred cellulose and cellulose derivatives include microcrystalline cellulose and sodium carboxymethylcellulose.
Starch and starch derivatives include maize starch, rice starch, potato starch, wheat starch, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), hydroxyethyl starch. The preferred starch derivative is sodium carboxymethyl starch.
Polyvinylpyrrolidones and their derivatives include polyvinylpyrrolidone K17, K25, K30 or K90, polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64).
Preferred polyvinylpyrrolidones are polyvinylpyrrolidone K25 and K30,
polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64).
The water soluble carrier is preferably used in an amount between 15 and 60% of the total weight of the pharmaceutical composition, preferably in an amount between 20 and 50%. The hydrophilic polymeric pharmaceutically acceptable excipient is preferably used in an amount between 1 and 40%, preferably in an amount between 2 and 30%.
Preferred pharmaceutical compositions are tablets, capsules, granules, preferably tablets.
The compositions of the invention can be manufactured by mixing the ingredients and filling them into capsules or by directly compressing them into tablets. Alternatively they may be made by wet or dry granulation. The pharmaceutical composition of the invention can be advantageously used in the treatment of cancer, in particular mantle-cell lymphoma and chronic lymphocytic leukemia.
The compositions of the invention show a homogeneous distribution of Ibrutinib and the excipients, which allows filling into capsules or compression into tablets with high drug load. This results in small capsule and tablet size and consequently a reduced pill burden and improved patient compliance. In addition such compositions show improved stability, fast disintegration after dispersion in water, fast dissolution of Ibrutinib and consequently high bioavailability, less scattering of blood levels, optimal absorption into the blood and lower dosages of the active ingredient.
EXAMPLES
Example 1:
Capsules: Ibrutinib 140 mg, lactose spray dried 53 mg, microcrystalline cellulose phl02 49 mg, crosspovidone 5 mg, fumed silica (Aerosil) 1.25 mg, magnesium stearate 1.5 mg - total 250 mg, filled in a hard gelatine capsule size 1. Manufacturing procedure is two step mixing (blender, high shear mixer) - first mixing Ibrutinib with all excipients except magnesium stearate - second mixing with magnesium stearate and afterwards filling the mixture into capsules.
Example 2 Capsules: Ibrutinib 140 mg, mannitol DC 102 mg, microcrystalline cellulose phl02 47 mg, croscaramellose sodium (Acdisol) 8 mg, fumed silica (Aerosil) 1 mg, magnesium stearate 1.5 mg - total 300 mg filled in hard gelatine capsule size 0. For the manufacturing procedure see example 1.
Example 3
Capsules: Ibrutinib 140 mg, lactose monohydrate 96 mg, sodium starch glycolate 8 mg, fumed silica (Aerosil) 3 mg, magnesium stearate 1.5 mg, sodium lauryl sulfate 1.2 mg - in total 250 mg; manufacturing procedure is wet granulation of all components except magnesium stearate, mixing granules with magnesium stearate and filling them into capsule size 1.
Example 4
Capsules: ibrutinib 140 mg, mannitol 90 mg, povidone 10 mg, croscaramellose sodium (Acdisol) 7 mg, magnesium stearate 2 mg, sodium lauryl sulfate 1 mg - in total 250 mg, manufacturing process similar to example 3.
Example 5
Capsules: ibrutinib 280 mg, lactose 270 mg, povidone 25 mg, croscaramellose sodium 15 mg, sodium lauryl sulfate 5 mg, magnesium stearate 5 mg - in total 500 mg filled into capsule size 0 - elongated; manufacturing procedure similar to example 3.
Example 6
Tablets: ibrutinib 140 mg, microcrystalline cellulose phlOl internal 81 mg, lactose monohydrate 116 mg, povidone K30 10 mg, sodium starch glycolate internal 7.5 mg, microcrystalline cellulose phi 02 external 37.5 mg, crosspovidone XL external 5 mg, fumed silica (Aerosil) 1.2 mg, magnesium stearate 1.5 mg - in total 400 mg tablet; manufacturing is wet granulation with inner phase, mixing the resulting granules with the external phase, compression.
Example 7 Tablets: Ibnitinib 140 mg, mannitol 62 mg, microcrystalline cellulose phlOl internal 38mg, hydroxypropyl methylcellulose 3 cp 6.4 mg, sodium lauryl sulfate 1 mg, croscaramellose sodium (Acdisol) internal 6.2 mg, microcrystalline cellulose phl02 external 32 mg, croscaramellose sodium (Acdisol) external 8 mg, fumed silica (Aerosil) 3 mg, magnesium stearate 4 mg - in total 300 mg tablet, manufacturing procedure similar to example 6.

Claims

CLAIMS What is claimed is:
1. A pharmaceutical composition comprising Ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient.
2. The pharmaceutical composition of claim 1, wherein the sugar is selected from
lactose, saccharose, fructose, glucose, mannose, maltose, galactose, rhamnose, dextrin, maltodextrin and trehalose, preferably from lactose, saccharose and glucose, most preferably the sugar is lactose.
3. The pharmaceutical composition of claim 1-2, wherein the sugar alcohol is selected from mannitol, sorbitol, xylitol, isomalt, lactitol, maltitol, erythritol and arabitol, preferably from mannitol and sorbitol, most preferably the sugar alcohol is mannitol.
4. The pharmaceutical composition of claim 1-3, wherein the hydrophilic polymeric pharmaceutically acceptable excipient is selected from the group consisting of cellulose and cellulose derivatives, starch and starch derivatives,
polyvinylpyrrolidones and their derivatives and mixtures thereof.
5. The pharmaceutical composition of claim 4, wherein the cellulose and cellulose
derivatives are selected from microcrystalline cellulose, microfine cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose and croscaramellose sodium, preferably from
microcrystalline cellulose and sodium carboxymethylcellulose.
6. The pharmaceutical composition of claim 4, wherein the starch and starch derivatives are selected from maize starch, rice starch, potato starch, wheat starch, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), hydroxyethyl starch, preferably the starch derivative is sodium carboxymethyl starch.
7. The pharmaceutical composition of claim 4, wherein polyvinylpyrrolidones and their derivatives are selected from polyvinylpyrrolidone K17, K25, K30 or K90, polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64).
8. The pharmaceutical composition of claims 1-7, wherein the water soluble carrier is used in an amount between 15 and 60% of the total weight of the pharmaceutical composition, preferably in an amount between 20 and 50%.
9. The pharmaceutical composition of claims 1-8, wherein the hydrophilic polymeric pharmaceutically acceptable excipient is used in an amount between 1 and 40%, preferably in an amount between 2 and 30%.
10. The pharmaceutical composition of claims 1-9, which is selected from tablets, capsules, granules.
11. The pharmaceutical composition of claims 1-10, which is a tablet.
12. A process for the preparation of the pharmaceutical composition of claims 1-11 comprising the steps of mixing the ingredients and filling them into capsules or compressing them into tablets.
13. The process according to claim 12 comprising the additional step of granulating the ingredients prior to filling them into capsules or compressing them into tablets.
14. The pharmaceutical composition of claims 1-11 for use in the treatment of cancer.
15. The pharmaceutical composition of claim 15, wherein the cancer is mantle-cell lymphoma and chronic lymphocytic leukemia.
PCT/EP2014/074662 2013-11-14 2014-11-14 Pharmaceutical compositions of ibrutinib WO2015071432A1 (en)

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US10294232B2 (en) 2012-06-04 2019-05-21 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10106548B2 (en) 2012-06-04 2018-10-23 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10125140B1 (en) 2012-06-04 2018-11-13 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
US10294231B2 (en) 2012-06-04 2019-05-21 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10752634B2 (en) 2012-06-04 2020-08-25 Pharmacyclics Llc Crystalline forms of a brutons tyrosine kinase inhibitor
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