WO2022090953A1 - Dispersion solide de chlorhydrate de ponatinib et son procédé de préparation - Google Patents

Dispersion solide de chlorhydrate de ponatinib et son procédé de préparation Download PDF

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Publication number
WO2022090953A1
WO2022090953A1 PCT/IB2021/059921 IB2021059921W WO2022090953A1 WO 2022090953 A1 WO2022090953 A1 WO 2022090953A1 IB 2021059921 W IB2021059921 W IB 2021059921W WO 2022090953 A1 WO2022090953 A1 WO 2022090953A1
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Prior art keywords
ponatinib hydrochloride
solid dispersion
ponatinib
solid
pharmaceutically acceptable
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PCT/IB2021/059921
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English (en)
Inventor
Mahesh KOTHADIYA
Chirag PANCHAL
Parimal TAMBOLI
Abhijit Kadam
Debasis Hazra
T.V.S.K. Vittal
Ashok Kumar Sahoo
Barada Prasanna SAHOO
Rahul Dabre
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Alembic Pharmaceuticals Limited
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Publication of WO2022090953A1 publication Critical patent/WO2022090953A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/20—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the present subject matter relates to a solid oral pharmaceutical composition comprising ponatinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient.
  • the present subject matter also relates to pharmaceutical compositions comprising a solid dispersion of ponatinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. Furthermore, it also relates to process of preparation of such compositions, and uses thereof.
  • Ponatinib hydrochloride has a chemical name 3-(imidazo[l,2-b]pyridazin- 3ylethynyl)-4-methyl-N- ⁇ 4-[(4-methylpiperazin-l-yl)methyl]-3-(trifluoromethyl) phenyl Jbenzamide hydrochloride.
  • Ponatinib hydrochloride is represented by the following chemical structure according to Formula (I).
  • Ponatinib hydrochloride is a kinase inhibitor which is indicated for the treatment of chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
  • CML chronic myeloid leukemia
  • Ph+ALL Philadelphia chromosome positive acute lymphoblastic leukemia
  • US 8,114,874 describe Ponatinib and its hydrochloride salt and a process for the preparation thereof.
  • US 10,221,184 describe Form alpha a propylene glycol solvate and Form beta a benzyl alcohol solvate of Ponatinib hydrochloride and a process of preparation thereof.
  • WO 2018232501 describes Form APO-I, Form APO-III, Form APO-IV and Form APO-V of Ponatinib hydrochloride and process of preparation thereof.
  • WO 2019246479 describes Form Z an acetic acid solvated hydrate of Ponatinib hydrochloride and a process of preparation thereof.
  • Solid dispersions of drugs are generally known to improve the stability and solubility of drug products. However, some of such amorphous solid dispersions are found to be unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material.
  • the present subject matter however provides stable amorphous solid dispersions of Ponatinib hydrochloride with improved solubility and stability and pharmaceutical composition comprising such solid dispersion containing Ponatinib hydrochloride and at least one pharmaceutical acceptable polymer and /or excipient.
  • An aspect of the present subject matter is to provide a solid dispersion of Ponatinib hydrochloride together with atleast one pharmaceutically acceptable excipient.
  • the solid dispersion of the present subject matter may be manufactured by processes such as adsorption, solvent evaporation, hot melt extrusion, freeze drying, spray drying, lyophilisation, complexation and use of anti-solvent precipitation and Supercritical fluid (SCF) technology.
  • processes such as adsorption, solvent evaporation, hot melt extrusion, freeze drying, spray drying, lyophilisation, complexation and use of anti-solvent precipitation and Supercritical fluid (SCF) technology.
  • Another aspect of the present subject matter is to provide process for preparation of solid dispersion comprising; a. providing a solution comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipients; b. removing solvent from the solution obtained in step (a); and c. isolating a solid dispersion comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipient.
  • Another aspect of the present subject matter is to provide process for preparing a solid dispersion containing an amorphous form of ponatinib hydrochloride and one or more pharmaceutically acceptable carriers, which comprises; a. providing a solution of Ponatinib or its salt and pharmaceutically acceptable carrier in suitable solvent(s), b. adding antisolvent to the above solution of step (a) c. isolating a solid dispersion containing an amorphous form of Ponatinib or its salt and one or more pharmaceutically acceptable carrier.
  • the present subject matter provides a pharmaceutical composition comprising solid dispersion of Ponatinib hydrochloride and atleast one pharmaceutical acceptable excipient.
  • the present subject matter relates to a pharmaceutical composition of Ponatinib. More particularly, this subject matter relates to pharmaceutical composition comprising amorphous Ponatinib, and to pharmaceutical compositions comprising a solid dispersion containing Ponatinib and at least one polymer / excipients. Furthermore present subject matter relates to methods for manufacturing such formulations and compositions and use thereof.
  • Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Betadex-HPB obtained from example 5.
  • Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Silicon dioxide obtained from example 18.
  • Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Hypromellose acetate succinate (1:3) obtained from example 12.
  • PXRD X-ray powder diffractogram
  • Fig 4 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with Carbopol 71 G obtained from example 15.
  • PXRD X-ray powder diffractogram
  • Fig 5 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Ponatinib hydrochloride with HPC (1:3) obtained from example 7.
  • the solid dispersion of the present subject matter may be manufactured by processes such as adsorption, solvent evaporation, hot melt extrusion, freeze drying, spray drying, lyophilisation, complexation and use of anti-solvent precipitation and Supercritical fluid (SCF) technology.
  • SCF supercritical fluid
  • the present subject matter is to provide a solid dispersion of Ponatinib hydrochloride together with atleast one pharmaceutically acceptable excipient, prepared by process comprising; a. providing a solution comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipients; b. removing solvent from the solution obtained in step (a); and c. isolating a solid dispersion comprising Ponatinib hydrochloride and one or more pharmaceutically acceptable excipient.
  • Another embodiment of the present subject matter is to provide process for preparing a solid dispersion containing an amorphous form of ponatinib hydrochloride and one or more pharmaceutically acceptable carriers, which comprises; a. providing a solution of ponatinib or its salt and pharmaceutically acceptable carrier in suitable solvent(s), b. adding antisolvent to the above solution of step (a) c. isolating a solid dispersion containing an amorphous form of ponatinib or its salt and one or more pharmaceutically acceptable carrier.
  • the present subject matter provides a pharmaceutical composition comprising solid dispersion of Ponatinib hydrochloride and atleast one pharmaceutical acceptable excipient.
  • the present application relates to a pharmaceutical composition of ponatinib. More particularly, this invention relates to pharmaceutical composition comprising amorphous Ponatinib, and to pharmaceutical compositions comprising a solid dispersion containing Ponatinib and at least one polymer / excipients. Furthermore present subject matter relates to methods for manufacturing such formulations and compositions and to their use. In yet another aspect, the solid dispersion comprising Ponatinib and the polymer and /or excipients is further mixed with one or more pharmaceutically acceptable excipients and / or additives to prepare pharmaceutical composition.
  • excipients and / or additives are not particularly limited, so long as they are pharmaceutically acceptable.
  • examples of the excipients and / or additives include filler, binder, disintegrant, lubricant, glidant and the like.
  • solid dispersion refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.
  • solid dispersion refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers.
  • solid dispersion as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers with or without adsorbent/absorbent.
  • amorphous drug substance it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
  • a solution in step (a) includes direct use of a reaction mixture containing Ponatinib hydrochloride that is obtained in the course of its synthesis or dissolving Ponatinib hydrochloride and pharmaceutically acceptable carrier in a suitable solvent or a mixture of solvents.
  • providing a solution at step (a) may be carried out by dissolving crystalline or amorphous Ponatinib hydrochloride and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.
  • a solution of Ponatinib hydrochloride and the excipient at step (a) may be prepared at any suitable temperatures of about 0°C to reflux temperature of the solvent used.
  • a solution of Ponatinib hydrochloride and the excipient may be filtered to make it clear and free of unwanted particles.
  • the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.
  • amorphous form of Ponatinib hydrochloride may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Ponatinib hydrochloride and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable polymer / excipients in step (a) include, but are not limited to copovidone, graft copolymer of polyethylene glycol, polyvinyl acetate phthalate, Hypromellose Cp-15, Hypromellose-CP-06 (HP-CP- 06): Polyvinyl pyrollidone-30 (PVP-30), Polyvinyl pyrrolidone-25 (PVP-25), Hypromellose-CP-06, Polyvinyl pyrollidine-90 (PVP-90), Plasdone S-630, Plasdone S-630 Ultra, Silicon dioxide, Silicon dioxide (Syloid 244FP), Silicon dioxide (Syloid AL-1FP/63FP), Silicon dioxide (Syloid XDP), Colloidal silicon dioxide (Aerosil 200 Pharma), Neusilin, Neusilin: Polyvinyl pyrollidine-90 (PVP- 90), Hydroxypropyl cellulose (HPC), Hydroxypropyl cellulose (HPC): Polyvinyl py
  • Solid dispersions of the present application also include the solid dispersions obtained by combining Ponatinib hydrochloride with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Hydroxypropyl betadex (HPB-Betadex).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with hydroxyl propyl methyl cellulose acetate succinate (HPMCAS).
  • HPMCAS hydroxyl propyl methyl cellulose acetate succinate
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Hydroxypropyl cellulose (HPC).
  • HPC Hydroxypropyl cellulose
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with croscarmellose sodium (CCS).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Carbopol 974 P.
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Carbopol 71 G.
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-90 (PVP-90).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-30 (PVP-90).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-25 (PVP-90).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-25 (PVP-25) and silicon dioxide (Syloid 244FP).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-30 (PVP-30) and silicon dioxide (Syloid 244FP). In an embodiment, the present application provides a solid dispersion of Ponatinib hydrochloride together with Polyvinylpyrrolidone-90 (PVP-90) and silicon dioxide (Syloid 244FP).
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Copovidone and silicon dioxide (Syloid 244FP).
  • the present application provides a solid dispersion of Ponatinib hydrochloride.
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with Hydroxypropyl methyl cellulose.
  • the present application provides a solid dispersion of Ponatinib hydrochloride together with silicon dioxide.
  • the suitable solvent that can be used include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, anisole, 2-methyl tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as heptane, cyclohexane, toluene, xylene
  • suitable techniques which can be used for the removal of solvent a solution in step (b) include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze drying, filtration or any other technique known in the art.
  • the solid dispersion can also prepared by technique like hot-melt extrusion. The hot-melt extrusion is preferably carried out in the absence of solvent.
  • the isolation of a solid dispersion of Ponatinib hydrochloride with excipient at step c) involves recovering the solid obtained in step b).
  • the solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
  • the solid dispersion of Ponatinib hydrochloride and excipient obtained from step b) may be optionally dried before or after isolating at step c).
  • Solid dispersion of Ponatinib hydrochloride obtained at step c) may be optionally combined with at least one additional pharmaceutically acceptable excipient.
  • solid dispersion of Ponatinib hydrochloride may be combined with additional excipient using a technique known in art or according to the previous aspects of the present application.
  • the stable Ponatinib hydrochloride solid dispersions are suitable for powder handling and downstream processes and highly stable under mechanical stress such as grinding and blending.
  • the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure.
  • the solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • compositions comprising a therapeutically effective amount of Ponatinib hydrochloride obtained according to present application, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
  • the X-ray powder diffraction (XRPD) spectrum according to the present subject matter was measured on a PANalytical X'Pert PRO X- Ray Diffractometer.
  • the parameters of the X-ray powder diffraction method of the present subject matter were as follows:
  • Scan range: from 2.5084 degree to 40.0 degree.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of isopropyl alcohol (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl alcohol and dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of acetonitrile (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with acetonitrile and dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of ethyl acetate (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with ethyl acetate and dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of Betadex-HPB (2 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum followed by addition of acetone (15 ml) and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with acetone and dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (5 g) was dissolved in methanol (300 ml) and followed by addition of Betadex-HPB (7.5 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained solution was dried in a spray dryer to obtain solid product.
  • Ponatinib hydrochloride (5 g) was dissolved in methanol (300 ml) and followed by addition of Betadex-HPB (6.25 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained solution was dried in a spray dryer to obtain solid product.
  • Ponatinib hydrochloride (4 g) was dissolved in methanol (300 ml) and followed by addition of HPC (12 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained solution was dried in a spray dryer to obtain solid product.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) and followed by addition of HPC (3 g). The obtained reaction mixture was stirred to obtain a clear solution and filtered through hyflo. The obtained filtrate was concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (3 g) followed by stirring and solvent concentrated under vacuum. Isopropyl ether (15 ml) added to the reaction mass and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl ether and dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (2.5 g) followed by stirring and solvent concentrated under vacuum. Isopropyl ether (15 ml) added to the reaction mass and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl ether and dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (2 g) followed by stirring and solvent concentrated under vacuum. Isopropyl ether (15 ml) added to the reaction mass and resulting slurry was stirred for 30 min. The obtained solid product was filtered and washed with isopropyl ether and dried under vacuum at 40-50°C for 10 hours.
  • Example 12 Preparation of Ponatinib hydrochloride solid dispersion with Hypromellose acetate succinate: Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added hypromellose acetate succinate (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added CCS (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added Carbopol 974 P (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added Carbopol 71 G (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added CP-6 (HP-6cps) (3 g) followed by stirring and solvent concentrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Ponatinib hydrochloride (1 g) was dissolved in methanol (60 ml) to obtain a clear solution and filtered through hyflo. To obtained filtrate added Silicon dioxide (3 g) followed by stirring and solvent con centrated under vacuum. The obtained solid product was dried under vacuum at 40-50°C for 10 hours.
  • Example 19 Ponatinib hydrochloride formulation prepared with adsorption
  • step 2 Syloid was added to step 1 and dispersion was stirred for 30 mins. 3. Solvent evaporation of step 2 dispersion was carried out in Rotavapor/ Spray Dryer/ Fluidised bed dryer. The solvent was removed under vacuum with desired process parameters.
  • the dried milled material was blended with extra granular material in blender and compressed in to tablets.
  • the compressed tablets were film coated in perforated coating pan.
  • Example 20 Ponatinib hydrochloride formulation prepared with solvent evaporation technology:
  • the milled intra granular material was blended with extra granular material and compressed in to tablets.
  • Example 21 Ponatinib hydrochloride formulation containing polymer prepared with solvent evaporation technology
  • the milled intra granular material was blended with extra granular material followed by compression.
  • step 2 Surfactant solution of step 2 was added to API and polymer mix under stirring.
  • the dried material was milled through desired screen in quadro co mill.
  • the milled intra granular material was blended with extra granular material and compressed in to tablet.
  • Examples 23A and 23B Ponatinib hydrochloride formulation prepared with hot melt extrusion
  • melt granulated material was milled using suitable screen in quadro comill.
  • the milled material was blended with extra granular material in blender and compressed in to tablets.
  • Examples 24A and 24B Ponatinib hydrochloride formulation prepared with lyophilization
  • step 2 Solution of step 2 was added to API and polymer Mix under stirring for Example 24B.
  • Example 24A and 24B The solution obtained for Example 24A and 24B was subjected for solvent evaporation in lyophilizer with desired process parameters.
  • the dried material was sifted through desired screen.
  • the milled intra granular material was blended with extra granular material and compressed in to tablets.
  • Examples 25A, 25B and 25C Ponatinib hydrochloride formulation prepared with complexation
  • the dried material was milled through desired screen in quadro co mill.
  • the milled intra granular material was blended with extra granular material and compressed in to tablets.
  • the blended intra granular material was mixed with extra granular material and compressed in to tablets.
  • Anti-solvent water, isopropyl alcohol
  • the dispersion formed was subjected to solvent evaporation in Rotavapor/ Spray Dryer/ Fluidised spray dryer with desired process parameters.
  • the dried material was milled through desired screen in quadro co mill.
  • the milled intra granular material was blended with extra granular material and compressed in to tablets.
  • the milled intra granular material was blended with extra granular material and compressed in to tablets.

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Abstract

La présente invention concerne une composition pharmaceutique orale solide comprenant du ponatinib ou un sel pharmaceutiquement acceptable de celui-ci et au moins un excipient pharmaceutiquement acceptable. La présente invention concerne également des compositions pharmaceutiques comprenant une dispersion solide de ponatinib ou un sel pharmaceutiquement acceptable de celui-ci et au moins un excipient pharmaceutiquement acceptable. De plus, l'invention concerne également un procédé de préparation de telles compositions, et leurs utilisations.
PCT/IB2021/059921 2020-10-29 2021-10-27 Dispersion solide de chlorhydrate de ponatinib et son procédé de préparation WO2022090953A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
WO2015001098A1 (fr) * 2013-07-04 2015-01-08 Sandoz Ag Formes cristallines du chlorhydrate de ponatinib
CN104650086A (zh) * 2013-11-22 2015-05-27 天津市汉康医药生物技术有限公司 盐酸帕纳替尼化合物
WO2015085973A1 (fr) * 2013-12-09 2015-06-18 Zentiva, K.S. Modifications de sel de chlorhydrate de 3-(2-imidazo[1,2-b]pyridazine-3-yléthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl] benzamide
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