WO2017064538A1 - Pharmaceutical compositions of nilotinib hydrochloride - Google Patents

Pharmaceutical compositions of nilotinib hydrochloride Download PDF

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Publication number
WO2017064538A1
WO2017064538A1 PCT/IB2015/057962 IB2015057962W WO2017064538A1 WO 2017064538 A1 WO2017064538 A1 WO 2017064538A1 IB 2015057962 W IB2015057962 W IB 2015057962W WO 2017064538 A1 WO2017064538 A1 WO 2017064538A1
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WO
WIPO (PCT)
Prior art keywords
crospovidone
nilotinib
composition according
pharmaceutical composition
amount
Prior art date
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Ceased
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PCT/IB2015/057962
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French (fr)
Inventor
Abdullah Uslu
Mustafa KOKTURK
Seyhan TURKKAN
Cumhur OKCELIK
Omer Hulki OCAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jsc <<nobel Almatinskaya Farmazevticheskaya Fabrica>>
NOBEL ILAC SANAYII VE TICARET AS
Original Assignee
Jsc <<nobel Almatinskaya Farmazevticheskaya Fabrica>>
NOBEL ILAC SANAYII VE TICARET AS
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Priority to EA201890944A priority Critical patent/EA036204B1/en
Priority to PCT/IB2015/057962 priority patent/WO2017064538A1/en
Publication of WO2017064538A1 publication Critical patent/WO2017064538A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K9/1629—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • Nilotinib with the structural formula I is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukaemia (CML) in patients with positive Philadelphia chromosome.
  • CML chronic myeloid leukaemia
  • Nilotinib as its monohydrate monohydrochloride salt is marketed under the brand name Tasignia in capsule form.
  • Nilotinib and its hydrochloride salt can be in different polymorphic forms. Different salts of nilotinib and their amorphous and crystalline forms have been described in prior art documents such as WO 2007/015870, WO 2007/015871 and WO 2010/054056.
  • T17 is disclosed in this document as an anhydrous form of nilotinib hydrochloride.
  • Form T17 of nilotinib hydrochloride does not convert to other forms when heated, it shows hygroscopic behaviour and tends to change to other forms in the presence of moisture and water.
  • WO 2013/074432 mentions difficulties in formulation and delivery of nilotinib due to low solubility characteristics of the compound. Polymers such as HPMC are used to improve solubility of nilotinib.
  • WO 2012/164578 mentions a similar problem, i.e. the solid-state form of nilotinib changes or it degrades chemically in the formulation due to exposure of the active ingredient to water during wet granulation. This problem has been solved by application of dry granulation instead of wet granulation. Formulations comprising microcrystalline cellulose, poloxamer, hydrophobic colloidal silica and magnesium stearate has also been disclosed in this prior art document.
  • WO 2013/105894 discloses hybrid amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component.
  • Form T17 is not compatible with most excipients used in pharmaceutical formulations.
  • common diluents and fillers such as lactose anhydrous, lactose monohydrate, cellulosic excipients such as microcrystalline cellulose, mannitol used in prior art formulations (WO 2008/037716, WO 2012/164578, WO 2014/060449, WO 2014/174496) comprising nilotinib have been observed to be incompatible with nilotinib anhydrous form T17.
  • the resulting formulation experiences high polymorphic conversion.
  • the aim of the present invention is to formulate nilotinib hydrochloride anhydrous form T17 with improved stability of the polymorphic form in the formulation.
  • the invention provides a composition comprising nilotinib hydrochloride anhydrous form T17, wherein crospovidone is used as filler in the formulation instead of prior art fillers like microcrystalline cellulose and lactose. It has been observed that whilst crospovidone is a good substitute for incompatible fillers such as microcrystalline cellulose, lactose and mannitol, it can also be used as stabilising agent in both inner and outer phase of the composition.
  • Nilotinib hydrochloride anhydrous Form T17 or "Form T17” as used herein within the scope of the invention has been disclosed and characterized in WO 2010/054056 by an x-ray powder diffraction pattern having peaks at about 5.7, 9.8, 15.0, 15.8 and 17.3 degrees two theta ⁇ 0.2 degrees two theta.
  • Nilotinib hydrochloride Form T17 is hygroscopic and tends to change into nilotinib hydrochloride dihydrate when exposed to moisture or water. It has also been observed that common fillers such as microcrystalline cellulose, mannitol, lactose anhydrous and lactose monohydrate are not compatible with the Form T17 and promote the polymorphic conversion of the compound.
  • the present invention provides a composition comprising nilotinib hydrochloride anhydrous form T17 and crospovidone as filler instead of microcrystalline cellulose, mannitol, lactose anhydrous and lactose monohydrate. Crospovidone can be used as filler in an amount of more than 20% of the weight of the total composition, preferably in an amount of 35-40%.
  • Crospovidone as used herein within the scope of the invention is cross-linked povidone.
  • Crospovidone is known to the skilled person in the field of pharmaceutical formulation technology as tablet disintegrant and dissolution enhancer at concentrations of 2-5%.
  • Examples and commercial grades of crospovidone can be used, e.g. Kollidon CL, Kollidon CL-M, Polyplasdone XL, Polyplasdone XL-10, Polyplasdone Ultra.
  • crospovidone used in the composition has a mean particle size of less than 150 pm.
  • the composition comprises an inner phase containing the active ingredient nilotinib hydrochloride Form T17 anhydrous and crospovidone, and an outer phase also containing crospovidone.
  • the inner phase of the composition is the "core" of the composition. It can be produced as granules, tablets, microtablets, pellets and like. Preferably the inner phase is produced by granulation of the active ingredient, crospovidone and optionally further excipients. Granulation can be made by the methods known to the skilled person in the art, e.g. agglomeration, wet granulation, dry granulation, compaction, milling etc.
  • the outer phase of the composition comprises crospovidone and optionally further excipients.
  • the inner phase can be mixed with the excipients of the "outer phase” to form the composition.
  • the outer phase may also be in form of a coating or a matrix formed by polymers.
  • the composition comprising inner and outer phase may be processed further into the final dosage forms.
  • crospovidone used in the inner and outer phase has a mean particle size of less than 90 pm, more preferably less than 50 pm.
  • the ratio of the amount of crospovidone in the inner phase to the amount of crospovidone in the outer phase is 3:7 - 7:3, preferably 4:6-6:4, more preferably 1 .
  • the inner phase is a granule prepared by dry granulation methods such as compaction of the active ingredient nilotinib HCI Form T17 anhydrous.
  • the granules can then be mixed with further excipients of the outer phase.
  • composition of the invention may be formulated into final dosage forms such as tablets, capsules etc.
  • Preferably composition is filled into capsules.
  • DSC Differential scanning calorimetry
  • Example 2 The following excipients have been blended and the resulting mixture is compacted.
  • Compacted granules are then mixed with crospovidone.
  • the composition is then filled into capsules and accelerated stability studies were conducted at 40°C/75% Relative Humidity and polymorphic stability was calculated in terms of percentage conversion of anhydrous Nilotinib to hydrate forms. Polymorphic conversions were calculated by data obtained from XRD (X-Ray Diffraction) analysis. All the following compositions are prepared in the same manner.
  • Example 3 The following compositions have been prepared and stability studies were performed according to the method of example 2. Table 1. Compositions Compl and Comp2
  • Comp2 shows improved polymorphic stability over Compl , when crospovidone is used both in the inner and outer phase of the composition.
  • compositions have been prepared and stability studies were performed both according to the method of example 2.
  • Comp4 and Comp5 show improved polymorphic stability over Comp3, when crospovidone is used in an amount of greater than 30% of the total composition.
  • Comp5 show significantly improved polymorphic stability over Comp3 and Comp 4, when the ratio of crospovidone used in the inner phase to the crospovidone used in the outer phase is closer to 1 .
  • Comp6 0 17-18 35-36 49-50 59-60 68-69 It has been observed that Comp6 show significantly improved polymorphic stability over Comp5, when the particle size of crospovidone is smaller.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a composition comprising nilotinib hydrochloride anhydrous form T17, wherein crospovidone is used as filler in the formulation instead of prior art fillers like microcrystalline cellulose and lactose.

Description

PHARMACEUTICAL COMPOSITIONS OF NILOTINIB HYDROCHLORIDE
State of the art
Nilotinib with the structural formula I is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukaemia (CML) in patients with positive Philadelphia chromosome.
Figure imgf000002_0001
Formula I Nilotinib as its monohydrate monohydrochloride salt is marketed under the brand name Tasignia in capsule form.
Formula I is first disclosed in WO 2004/005281 . Nilotinib and its hydrochloride salt can be in different polymorphic forms. Different salts of nilotinib and their amorphous and crystalline forms have been described in prior art documents such as WO 2007/015870, WO 2007/015871 and WO 2010/054056.
Prior art document WO 2010/054056 describes crystal forms T1 , 12, 13, 14, 15, 16, 17, 18, 19, T10, T1 1 , T12, T13, T14, T15, T16, T17, T18 and T19 of nilotinib hydrochloride. T17 is disclosed in this document as an anhydrous form of nilotinib hydrochloride. Although Form T17 of nilotinib hydrochloride does not convert to other forms when heated, it shows hygroscopic behaviour and tends to change to other forms in the presence of moisture and water. WO 2013/074432 mentions difficulties in formulation and delivery of nilotinib due to low solubility characteristics of the compound. Polymers such as HPMC are used to improve solubility of nilotinib.
WO 2012/164578 mentions a similar problem, i.e. the solid-state form of nilotinib changes or it degrades chemically in the formulation due to exposure of the active ingredient to water during wet granulation. This problem has been solved by application of dry granulation instead of wet granulation. Formulations comprising microcrystalline cellulose, poloxamer, hydrophobic colloidal silica and magnesium stearate has also been disclosed in this prior art document.
WO 2013/105894 discloses hybrid amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component. During formulation studies it has been found that Form T17 is not compatible with most excipients used in pharmaceutical formulations. Especially, common diluents and fillers such as lactose anhydrous, lactose monohydrate, cellulosic excipients such as microcrystalline cellulose, mannitol used in prior art formulations (WO 2008/037716, WO 2012/164578, WO 2014/060449, WO 2014/174496) comprising nilotinib have been observed to be incompatible with nilotinib anhydrous form T17. Hence the resulting formulation experiences high polymorphic conversion.
Compounds known to provide a stabilizing effect on nilotinib and/or crystalline forms of nilotinib hydrochloride, fail to provide sufficient stability for the hygroscopic T17 crystalline form of nilotinib hydrochloride anhydrous.
Thus there is a need to formulate a stable formulation of nilotinib anhydrous form T17.
Summary of the Invention
The aim of the present invention is to formulate nilotinib hydrochloride anhydrous form T17 with improved stability of the polymorphic form in the formulation. Thus the conversion of the crystalline anhydrous polymorphic form into nilotinib anhydrous or nilotinib monohydrate in the pharmaceutical composition is minimized with the present invention. The invention provides a composition comprising nilotinib hydrochloride anhydrous form T17, wherein crospovidone is used as filler in the formulation instead of prior art fillers like microcrystalline cellulose and lactose. It has been observed that whilst crospovidone is a good substitute for incompatible fillers such as microcrystalline cellulose, lactose and mannitol, it can also be used as stabilising agent in both inner and outer phase of the composition.
Description of the Invention
"Nilotinib hydrochloride anhydrous Form T17" or "Form T17" as used herein within the scope of the invention has been disclosed and characterized in WO 2010/054056 by an x-ray powder diffraction pattern having peaks at about 5.7, 9.8, 15.0, 15.8 and 17.3 degrees two theta ± 0.2 degrees two theta.
Nilotinib hydrochloride Form T17 is hygroscopic and tends to change into nilotinib hydrochloride dihydrate when exposed to moisture or water. It has also been observed that common fillers such as microcrystalline cellulose, mannitol, lactose anhydrous and lactose monohydrate are not compatible with the Form T17 and promote the polymorphic conversion of the compound. The present invention provides a composition comprising nilotinib hydrochloride anhydrous form T17 and crospovidone as filler instead of microcrystalline cellulose, mannitol, lactose anhydrous and lactose monohydrate. Crospovidone can be used as filler in an amount of more than 20% of the weight of the total composition, preferably in an amount of 35-40%.
"Crospovidone" as used herein within the scope of the invention is cross-linked povidone. Crospovidone is known to the skilled person in the field of pharmaceutical formulation technology as tablet disintegrant and dissolution enhancer at concentrations of 2-5%. Examples and commercial grades of crospovidone can be used, e.g. Kollidon CL, Kollidon CL-M, Polyplasdone XL, Polyplasdone XL-10, Polyplasdone Ultra. Preferably crospovidone used in the composition has a mean particle size of less than 150 pm.
In another embodiment of the invention, the composition comprises an inner phase containing the active ingredient nilotinib hydrochloride Form T17 anhydrous and crospovidone, and an outer phase also containing crospovidone. The inner phase of the composition is the "core" of the composition. It can be produced as granules, tablets, microtablets, pellets and like. Preferably the inner phase is produced by granulation of the active ingredient, crospovidone and optionally further excipients. Granulation can be made by the methods known to the skilled person in the art, e.g. agglomeration, wet granulation, dry granulation, compaction, milling etc. The outer phase of the composition comprises crospovidone and optionally further excipients. The inner phase can be mixed with the excipients of the "outer phase" to form the composition. The outer phase may also be in form of a coating or a matrix formed by polymers. The composition comprising inner and outer phase may be processed further into the final dosage forms. Preferably crospovidone used in the inner and outer phase has a mean particle size of less than 90 pm, more preferably less than 50 pm. The ratio of the amount of crospovidone in the inner phase to the amount of crospovidone in the outer phase is 3:7 - 7:3, preferably 4:6-6:4, more preferably 1 .
Preferably the inner phase is a granule prepared by dry granulation methods such as compaction of the active ingredient nilotinib HCI Form T17 anhydrous. The granules can then be mixed with further excipients of the outer phase.
The composition of the invention may be formulated into final dosage forms such as tablets, capsules etc. Preferably composition is filled into capsules. Preferably hard gelatine or HPMC capsule are used. More preferably hard gelatine capsule is used. Examples: Example 1
Excipient compatibility studies were conducted with nilotinib hydrochloride anhydrous Form T17. Differential scanning calorimetry (DSC) method has been used to analyse compatibility of the excipients and mannitol, lactose and microcrystalline cellulose are found to be incompatible and to promote the polymorphic conversion of the nilotinib form T17.
Example 2 The following excipients have been blended and the resulting mixture is compacted.
Colloidal silica anhydrous
Poloxamer
Crospovidone
Magnesium stearate
Nilotinib HCI anhydrous Form T17
Compacted granules are then mixed with crospovidone. The composition is then filled into capsules and accelerated stability studies were conducted at 40°C/75% Relative Humidity and polymorphic stability was calculated in terms of percentage conversion of anhydrous Nilotinib to hydrate forms. Polymorphic conversions were calculated by data obtained from XRD (X-Ray Diffraction) analysis. All the following compositions are prepared in the same manner.
Example 3 The following compositions have been prepared and stability studies were performed according to the method of example 2. Table 1. Compositions Compl and Comp2
Figure imgf000008_0001
It has been observed that Comp2 shows improved polymorphic stability over Compl , when crospovidone is used both in the inner and outer phase of the composition.
Example 4
The following compositions have been prepared and stability studies were performed both according to the method of example 2.
Table 2. Compositions Comp3, Comp4 and Comp5
Figure imgf000008_0002
Table 3. Polymorphic conversion percentage of compositions Comp3, Comp4 and
Comp5 stored in gelatine capsules
Figure imgf000009_0001
Table 4. Polymorphic conversion percentage of compositions Comp3 and Comp4 stored in HPMC capsules
Figure imgf000009_0002
It has been observed that Comp4 and Comp5 show improved polymorphic stability over Comp3, when crospovidone is used in an amount of greater than 30% of the total composition.
Comp5 show significantly improved polymorphic stability over Comp3 and Comp 4, when the ratio of crospovidone used in the inner phase to the crospovidone used in the outer phase is closer to 1 .
Example 5
The following compositions have been prepared and stability studi performed according to the method of example 2. Table 5. Compositions Comp5 and Comp6
Figure imgf000010_0001
Table 6. Polymorphic conversion percentage of compositions Comp5 and Comp6 stored in gelatine capsules:
40°C/75% 1 2 3 4 5 6 month months months months months months
Comp5 19-20 38-39 52-51 63-64 70-71 76-77
Comp6 0 17-18 35-36 49-50 59-60 68-69 It has been observed that Comp6 show significantly improved polymorphic stability over Comp5, when the particle size of crospovidone is smaller.
Stability studies were also conducted at 25°C/60% Relative Humidity and 30°C/65% Relative Humidity and the polymorphic conversion percentage of compositions stored in gelatine capsules are as follows:
Table 7. Polymorphic conversion percentage of compositions Comp5 and Comp6 stored in gelatine capsules and at 25°C/60% Relative Humidity
Figure imgf000011_0001
Table 8. Polymorphic conversion percentage of compositions Comp5 and Comp6 stored in gelatine capsules and 25°C/60% Relative Humidity
Figure imgf000011_0002

Claims

1. A pharmaceutical composition comprising nilotinib hydrochloride anhydrous Form T17 characterized by an x-ray powder diffraction pattern having peaks at about 5.7, 9.8, 15.0, 15.8 and 17.3 degrees two theta ± 0.2 degrees two theta, characterized in that the composition comprises an inner and an outer phase each comprising crospovidone.
2. A pharmaceutical composition according to claim 1 , wherein crospovidone is in an amount of more than 30% of the weight of the total composition.
3. A pharmaceutical composition according to claim 2, wherein crospovidone is in an amount of 35-40% by weight of the total composition.
4. A pharmaceutical composition according to any of the claims 1 -3, wherein crospovidone has a mean particle size of less than 90 pm.
5. A pharmaceutical composition according to claim 4, wherein crospovidone has a mean particle size of less than 50 pm.
6. A pharmaceutical composition according to any of the claims 1 -5, wherein the ratio of the amount of crospovidone in the inner phase to the amount of crospovidone in the outer phase is 3:7-7:3.
7. A pharmaceutical composition according to claim 6, wherein the ratio of the amount of crospovidone in the inner phase to the amount of crospovidone in the outer phase is about 1 .
8. A pharmaceutical composition according to any of the claims 1 -7, wherein the inner phase is in the form of a granule or a tablet.
9. A pharmaceutical formulation in form of a capsule comprising a composition according to any of the claims 1 -8.
10. A pharmaceutical formulation according to claim 9, wherein the capsule is a hard gelatine or HPMC capsule.
11. A pharmaceutical formulation according to claim 10, wherein the capsule is a hard gelatine capsule.
PCT/IB2015/057962 2015-10-16 2015-10-16 Pharmaceutical compositions of nilotinib hydrochloride Ceased WO2017064538A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3501505A1 (en) 2017-12-20 2019-06-26 Zentiva K.S. A drug form comprising crystalline nilotinib
WO2020101597A3 (en) * 2018-08-27 2020-07-02 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Capsule compositions comprising tyrosine-kinase inhibitors
US11389450B2 (en) 2020-01-31 2022-07-19 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
WO2022263510A1 (en) 2021-06-19 2022-12-22 Helm Ag Granulate composition comprising nilotinib
US11559485B2 (en) 2020-04-30 2023-01-24 Nanocopoeia, Llc Orally disintegrating tablet comprising amorphous solid dispersion of nilotinib
US12186316B2 (en) 2020-09-29 2025-01-07 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020123459A1 (en) * 2000-12-06 2002-09-05 Ault Joseph M. Pharmaceutical compositions for the oral delivery of pharmacologically active agents
WO2003053432A1 (en) * 2001-12-21 2003-07-03 Novartis Ag 5ht4 partial agonist pharmaceutical compositions
US20050042277A1 (en) * 2003-07-17 2005-02-24 Irukulla Srinivas Pharmaceutical compositions having a swellable coating
WO2010054056A2 (en) * 2008-11-05 2010-05-14 Teva Pharmaceutical Industries Ltd. Nilotinib hci crystalline forms

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020123459A1 (en) * 2000-12-06 2002-09-05 Ault Joseph M. Pharmaceutical compositions for the oral delivery of pharmacologically active agents
WO2003053432A1 (en) * 2001-12-21 2003-07-03 Novartis Ag 5ht4 partial agonist pharmaceutical compositions
US20050042277A1 (en) * 2003-07-17 2005-02-24 Irukulla Srinivas Pharmaceutical compositions having a swellable coating
WO2010054056A2 (en) * 2008-11-05 2010-05-14 Teva Pharmaceutical Industries Ltd. Nilotinib hci crystalline forms

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3501505A1 (en) 2017-12-20 2019-06-26 Zentiva K.S. A drug form comprising crystalline nilotinib
WO2020101597A3 (en) * 2018-08-27 2020-07-02 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Capsule compositions comprising tyrosine-kinase inhibitors
US11389450B2 (en) 2020-01-31 2022-07-19 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
US11998548B2 (en) 2020-01-31 2024-06-04 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
US12016861B2 (en) 2020-01-31 2024-06-25 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
US12029740B2 (en) 2020-01-31 2024-07-09 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
US12053471B2 (en) 2020-01-31 2024-08-06 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
US11559485B2 (en) 2020-04-30 2023-01-24 Nanocopoeia, Llc Orally disintegrating tablet comprising amorphous solid dispersion of nilotinib
US12186316B2 (en) 2020-09-29 2025-01-07 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions
US12527793B2 (en) 2020-09-29 2026-01-20 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions
WO2022263510A1 (en) 2021-06-19 2022-12-22 Helm Ag Granulate composition comprising nilotinib

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