WO2012080703A1 - Composition pharmaceutique comprenant de l'imatinib - Google Patents

Composition pharmaceutique comprenant de l'imatinib Download PDF

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Publication number
WO2012080703A1
WO2012080703A1 PCT/GB2011/001726 GB2011001726W WO2012080703A1 WO 2012080703 A1 WO2012080703 A1 WO 2012080703A1 GB 2011001726 W GB2011001726 W GB 2011001726W WO 2012080703 A1 WO2012080703 A1 WO 2012080703A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
solid oral
imatinib
oral pharmaceutical
composition according
Prior art date
Application number
PCT/GB2011/001726
Other languages
English (en)
Inventor
Geena Malhotra
Shrinivas Madhukar Purandare
Original Assignee
Cipla Limited
Turner, Craig Robert
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
Application filed by Cipla Limited, Turner, Craig Robert filed Critical Cipla Limited
Publication of WO2012080703A1 publication Critical patent/WO2012080703A1/fr

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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
    • A61K9/14—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a solid oral pharmaceutical composition comprising imatinib, a process for preparing such pharmaceutical composition, therapeutic uses thereof and methods of treatment employing the same.
  • Imatinib is used to treat certain types of cancer.
  • the mesylate salt, imatinib mesylate is chemically named as 4-[(4-Methyl-l-piperazinyl) methyl]-N-[4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl] amino] -phenyl] benzamide methanesulfonate, and has the following chemical structure.
  • Bcr-Abl tyrosine kinase the constitutive abnormal tyrosine kinase created by Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines, as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.
  • Imatinib its salts and various compositions have been described extensively in patent and non patent literature.
  • U.S.5, 521,184 discloses imatinib, its structural analogs and their salts. It also specifically discloses capsules of imat iib arid its salts and their use in the treatment of tumors. However, the amount of active ingredient (imatinib) present in these capsules is 1 Omg.
  • WO2009/100176 discloses the solid dispersion product of tyrosine kinase inhibitors including imatinib, for the treatment of proliferative disorders. The dispersion shows resistance against recrystallization or decomposition of the active ingredient(s). However, the active ingredient is present in an amount of 0.5-40% by weight (0.1 mg to 100 mg) of the said tyrosine kinase inhibitor.
  • EP1888040 discloses oral sustained release pharmaceutical composition
  • a sustained release pharmaceutical composition comprising melt granules of imatinib and a release retardant polymer, wherein the amount of the drug in the composition is at least 50% by weight of the composition.
  • US2011206827 discloses film-coated tablets or granules comprising imatinib mono- methanesulfonate in the crystalline alpha form, wherein the tablet cores and the granules are prepared by pressing the starting materials i.e. by pressing of the active ingredient (imatinib) together with the additives in the mixture, and, prior to pressing of the starting materials, at least one of them is dry-granulated, preferably compressed or compacted.
  • Imatinib is currently marketed in the form of imatinib mesylate by Novartis under the trade name Gleevec.
  • the recommended dosage of Gleevac is 400 mg/day for patients in chronic phase chronic myelogenous leukemia (CML) and 600 mg day for patients in accelerated phase or blast crisis.
  • CML chronic myelogenous leukemia
  • Dose increase from 400 mg to 600 mg in patients with chronic phase disease, or from 600 mg to 800 mg (administered as 400 mg twice daily) in patients with accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in circumstances such as disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of treatment and loss of a previously achieved hematologic response.
  • EMEA European Medicines Agency
  • the object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of imatinib, or any of its salts, solvates, enantiomers, derivatives, esters, hydrates, complexes, polymorphs or prodrugs with one or more pharmaceutically acceptable excipients.
  • Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of imatinib mesylate.
  • Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of alpha form of imatinib mesylate.
  • Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising a therapeutically effective amount of beta form of imatinib mesylate.
  • a further object of the present invention is to provide solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to up to 1000 mg of imatinib free base.
  • Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to 800 mg of imatinib free base.
  • Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to 600 mg of imatinib free base.
  • Another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to 400 mg of imatinib free base.
  • Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules comprising imatinib mesylate equivalent to not less than 100 mg of imatinib free base.
  • Another object of the present invention is to provide a process for preparing the solid oral pharmaceutical compositions comprising imatinib mesylate.
  • Yet another object of the present invention is to provide a solid oral pharmaceutical composition preferably in the form of capsules for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
  • CML chronic myeloid leukemia
  • a solid oral pharmaceutical composition comprising greater than 100 mg of imatinib, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in the form of a capsule.
  • a solid oral pharmaceutical composition preferably in the form of a capsule comprising greater than 100 mg of imatinib, and from 40% or less by weight of the composition of pharmaceutically acceptable excipients, wherein the weight of the composition is the weight of the pharmaceutical composition not including the capsule if present.
  • Imatinib is present in an amount of greater than lOOmg, 200 mg or more, 400 mg or more, 600 or more, or 800 mg or more.
  • imatinib is present in an amount of 1000 mg or less.
  • imatinib is present in an amount of from 100 mg to 400 mg, 400 mg to 600 mg, or from 600 mg to 800 mg or from 800 mg to 1000 mg.
  • these defined weights of imatinib correspond to weights of imatinib free base.
  • the pharmaceutically acceptable excipients are present in an amount of from 40% or less or from 35% or less by weight of the pharmaceutical composition.
  • the pharmaceutically acceptable excipients may be present in lower amounts, such as 30% or less, 25% or less, 20% or less, 15% or less, or 10% or less by weight of the composition.
  • weight of the pharmaceutical composition refers to the weight of the pharmaceutical composition not including the weight of the capsule if present.
  • Imatinib is preferably in the form of a pharmaceutically acceptable salt, most preferably in the form of the salt imatinib mesylate.
  • mesylate refers to the methanesulphonate salt of imatinib.
  • the mesylate anion has structural formula CH3SO3 " .
  • the amount of imatinib mesylate present in the pharmaceutical composition is equivalent to from 100 mg to 400 mg, 400 mg to 1000 mg, from 400 mg to 600 mg, or from 600 mg to 800 mg. or from 800 mg to 1000 mg of imatinib free base.
  • the amount of imatinib mesylate present in the compositions can be an amount equivalent to 100 mg, 400mg, 600mg, 800 mg or 1000 mg of imatinib free base.
  • free base is used to refer to molecular imatinib as an uncharged molecule, as opposed to imatinib as a salt where it may exist as a cation, with a corresponding anion such as mesylate, tartrate, citrate etc. These terms are understood clearly by persons having skill in the art.
  • a pharmaceutical composition according to the present invention for use in medicine.
  • this use is in the treatment of chronic myeloid leukemia.
  • the myeloid leukemia is in blast phase, accelerated phase, or chronic phase after failure of interferon-alpha therapy.
  • the use comprises administration of one or two capsules per day to a patient.
  • a process for preparing a solid oral pharmaceutical composition according to the invention comprising preparing a pharmaceutical composition by granulating imatimib with one or more pharmaceutically acceptable excipients, and preferably filling a capsule with said pharmaceutical composition to form a capsule of the invention.
  • a solid oral pharmaceutical composition according to the invention for use in medicine.
  • the use is for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
  • CML chronic myeloid leukemia
  • the pharmaceutical composition is in the form of a capsule.
  • a solid oral pharmaceutical composition according to the invention for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
  • CML chronic myeloid leukemia
  • a method of treating chronic myeloid leukemia in a human or other mammal comprises administering to a patient in need thereof a solid oral pharmaceutical composition according to the present invention.
  • the method is for the treatment of chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
  • a solid oral pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of chronic myeloid leukaemia, preferably chronic myeloid leukemia in blast phase, accelerated phase, or chronic phase after failure of interferon-alpha therapy.
  • Imatinib is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It is used for the treatment of various types of cancers .
  • the recommended dose of imatinib is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. Also higher initial dosage (600 mg and 800 mg) can induce better results than a standard dosage (400 mg).
  • Imatinib capsules are only commercially available in lOOmg strength. As per the recommended dosage regimen of imatinib, a patient may have to ingest 4, 6 or even 8 capsules at a time to achieve the therapeutically effective dose. This can lead to patient inconvenience especially for geriatric patients and children. Elderly patients may even forget to keep a count of the number of capsules that have been consumed by them during the day in the course of the treatment.
  • the inventors of the present invention have developed a solid oral pharmaceutical composition preferably in the form of a capsule that can deliver higher dosage of imatinib.
  • the pharmaceutical composition of the present invention preferably delivers up to 800 mg of imatinib.
  • the inventors of the present invention have found that higher dose strength of imatinib, such as greater than 100 mg, i. e 400mg, 600 mg, 800 mg or 1000 mg can be administered, preferably in the form of a capsule dosage form. .
  • the solid oral pharmaceutical composition according to the present invention can be formulated in such a way that the capsule size is not too large, so as to be convenient for patient administration and yet can deliver higher dose of imatinib
  • the solid oral pharmaceutical composition according to the present invention may be particularly useful in patients who are unable or unwilling to consume multiple doses of imatinib mesylate regularly or in the large amounts necessary for the treatment of patients with chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • Imatinib' is used in a broad sense to include not only "Imatinib” per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable hydrates, pharmaceutically acceptable complexes, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
  • “Pharmaceutically acceptable salts of imatinib free base” include, but are not limited to, pharmaceutically acceptable acid addition salts.
  • Such acid addition salts include, but are not limited to, inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di- carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroar
  • acid addition salts include, but are not limited to, tartrate salt, such as a (£ ) )(-) tartrate salt or a (L)(+) tartrate salt, a hydrochloride salt, a citrate salt, a malate salt, particularly a £>-malate salt, a fumarate salt, a succinate salt, a benzoate salt, a benzenesulfonate salt, a pamoate salt, a formate salt, a malonate salt, a 1,5- naphthalenedisulfonate salt, a salicylate salt, a cyclohexanesulfamate salt, a lactate salt, particularly a (5)-lactate salt, a mandelate salt, particularly an (i?)(-) mandelate salt, a glutarate salt, an adipate salt, a squarate salt, a vanillate salt, an oxaloacetate salt, an ascorbate salt, particularly an (
  • free base is used to refer to molecular imatinib as an uncharged molecule, as opposed to imatinib as a salt where it may exist as a cation, with a corresponding anion such as mesylate, tartrate, citrate etc. These terms are understood clearly by persons having a skill in the art.
  • the imatinib salt in the capsule of the present invention is imatinib mesylate.
  • mesylate refers to the methanesulphonate salt of imatinib.
  • the mesylate anion has structural formula CH 3 S0 3 " .
  • the amount of imatinib mesylate in the pharmaceutical composition of the present invention is equivalent to greater than 100 mg, but up to 400 mg, 400 mg to 1000 mg, from 400 mg to 600 mg, or from 600 mg to 800 mg of imatinib free base.
  • the amount of imatinib mesylate present in the pharmaceutical compositions can be m an amount equivalent to greater than 100 mg, or in an amount equivalent to 400 mg, 600 mg, or 800 mg of imatinib free base.
  • the solid oral pharmaceutical composition of the present invention when in the form of a capsule is administered as one or two capsules per day to a patient in need thereof.
  • Imatinib may be in different polymorphic form such as alpha (a, a2 etc), beta ( ⁇ ), gamma ( ⁇ ), epsilon ( ⁇ ), HI, I, II, F, G, H, I, K and the like.
  • imatinib is present in the a form.
  • imatinib is substantially free of genotoxic impurity.
  • imatinib mesylate is present in the a form and is also free of genotoxic impurity.
  • Imatinib is preferably present in an amount of greater than 100 mg; or 200 mg or more, 400 mg or more, 600 mg or more.
  • imatinib is present in an amount of 1000 mg or less.
  • imatinib is present in an amount of greater than 100 mg and up to 400 mg, or 400 mg to 600 mg, from 600 mg to 800 mg, or from 800 mg to 1000 mg.
  • these defined weights of imatinib correspond to weight of imatinib free base.
  • the solid oral pharmaceutical composition of the present invention further comprises pharmaceutically acceptable excipients.
  • compositions of the present invention comprise disintegrating agents, binders, fillers, lubricants, glidants, diluents, stabilizers and any other suitable excipients that are employed in the formulation of a conventional capsule dosage form.
  • the pharmaceutical compositions of the present invention are also preferably free of a release retardant.
  • the pharmaceutically acceptable excipients are present in an amount, of 40% or less or from 35% or less, by weight of the pharmaceutical composition comprising imatinib.
  • the pharmaceutically acceptable excipients can also be present in an amount of 30% or less, 25% or less, 20% or less, 15% or less, or 10% or less, 5% or less by weight of the pharmaceutical composition present in the capsule.
  • the definition "by weight of the composition” refers to by weight of the pharmaceutical composition in the absence of the capsule shell, i. e. the total weight of the pharmaceutical composition that is to be placed in the capsule.
  • the excipients may be present in an amount of 40% or less by weight of the total capsule weight.
  • the excipients are present in an amount of 30% or less by weight of the total capsule weight.
  • the excipients may also be present in an amount of 20% or less by weight of the total weight of the filled capsule.
  • Suitable stabilizers include, but are not limited to, amino acids and carboxylic acid.
  • the stabilizer (s) is added in the capsule formulation to prevent cross linking of gelatin shell. Stabilizer acts as scavenger and stabilizes pH and prevents the reaction that occurs between the composition in the capsule and capsule shell thereby preventing cross linking.
  • amino acids are selected form the group comprising glycine, tryptophan, lysine, leucine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, cysteine, phenylalanine, tyrosine, histidine, acetylcysteine, valine, alanine, isoleucine, ornithine, p-aminobenzoic acid, nicotinic acid or mixtures thereof.
  • the amino acid stabilizer preferably is in a quantity ranging from 1 to 5 % if present.
  • the amino acid is glycine.
  • carboxylic acids are selected form the group comprising benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid, and gluconic acid, or a salt and mixtures thereof.
  • the carboxylic acid stabilizer is preferably in a quantity ranging from 0.1 to 1 %, if present.
  • the carboxylic acid is citric acid.
  • Suitable diluents include, but are not limited to, one or more of calcium phosphate- dibasic, calcium sulfate, cellulose-microcrystalline, calcium carbonate, calcium phosphate-tribasic, copovidone, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, equivalents and mixtures thereof .
  • the diluents may be preferably present in a quantity ranging from 10 to 40 %.
  • Suitable binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, other cellulose derivatives, equivalents and mixtures thereof.
  • the binders may be preferably present in a quantity ranging from 1 tol5%
  • Suitable disintegrating agents include, but are not limited to, hydroxypropyl cellulose, carboxymethylcellulose, calciumcarboxymethylcellulose, sodiumcarboxymethylcellulose, croscarmellose sodium, starch, crystalline cellulose, sodium starch glycollate, hydroxypropyl starch, partly pregelatinized starch, crospovidone, equivalents and mixtures thereof.
  • the disintegrating agents may be preferably present in a quantity ranging from 1 to 10%
  • Suitable lubricants and glidants include, but are not limited to, stearic acid, fumaric acid, adipic acid, hydrogenated castor oil, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose and mixtures thereof.
  • the lubricants may be preferably present in a quantity ranging from 0.5 to 5%.
  • the solid oral pharmaceutical composition may be encapsulated in capsules of suitable size so as to ensure that the size is not too large yet can incorporate higher dose of imatinib.
  • capsules of size 000, OOel, 00, Oel, 0, 1, 2el, 2, 3, 4, 5 can be used. These capsule sizes are standard sizes known to the person having skill in the art of medicament formulation.
  • the size of the empty capsule shell is 00, OOel Oel or 0.
  • the capsules may be made of different material such as, but not limited to gelatin, polyethylene glycol (PEG), hydroxypropyl methyl cellulose (HPMC) and may be filled with the fill material such as, but not limited to powder, beads or granules.
  • PEG polyethylene glycol
  • HPMC hydroxypropyl methyl cellulose
  • the solid oral pharmaceutical composition may be manufactured by conventional techniques such as, but not limited to, dry granulation, wet granulation or direct compression.
  • the solid oral pharmaceutical composition of the present may be manufactured by hydro alcoholic granulation.
  • the drug (Imatinib mesylate) is sifted with one or more pharmaceutically acceptable excipients and then sieved to form a premix. This premix is then loaded in fluidized bed processor and a granulating solvent (s) is sprayed to form granules that are subsequently dried. These dried granules are then blended with other pharmaceutically acceptable excipients such as lubricants and then filled into empty capsule shells.
  • the drug is sifted with one or more pharmaceutically acceptable and then sieved to form a premix.
  • the premix is then roll compacted and sifted to obtain granules.
  • the granules are then lubricated with pharmaceutically acceptable excipients such as lubricant and then filled into empty capsule shells.
  • the solid oral pharmaceutical composition, preferably in the form of capsules, of the present invention may also be manufactured by a slugging method where the drug (Imatinib mesylate) is sifted with one or more pharmaceutically acceptable and then sieved to form a premix.
  • the premix is than slugged and broken into granules .
  • the granules are lubricated with pharmaceutically acceptable excipients such lubricant and then filled into empty capsule shells.
  • the present invention also provides the use of a solid oral pharmaceutical composition according to the invention for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon- alpha therapy.
  • CML chronic myeloid leukemia
  • the present invention further provides a method for the treatment in a mammal, such as a human, of chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy, which method comprises administering to a patient in need thereof a solid oral pharmaceutical composition according to the present invention .
  • a solid oral pharmaceutical composition according to the present invention .
  • the solid oral pharmaceutical composition is administered as one or two capsules per day to a patient in need thereof.
  • Imatinib mesylate and crospovidone were co-sifted through a sieve to form a premix.
  • step (2) The premix obtained in step (1) was loaded in a fluid bed processor.
  • step (3) The granules obtained in step (3) were dried and sifted through sieves.
  • step (4) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells.
  • Imatinib mesylate and crospovidone were co-sifted through a sieve to form premix.
  • step (2) The premix obtained in step (1) was loaded in a fluid bed processor.
  • step (3) The granules obtained in step (3) were dried and sifted through sieves.
  • step (4) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells.
  • Imatinib mesylate and crospovidone were co-sifted through a sieve to form premix.
  • step (1) The premix obtained in step (1) was loaded in a fluid bed processor.
  • step (2) A mixture of isopropyl alcohol and purified water was sprayed on to the powder bed in fluid bed processor to form granules to produce granules.
  • step (3) The granules obtained in step (3) were dried and sifted through sieves.
  • step (4) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells.
  • step (4) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells.
  • Imatinib mesylate and crospovidone were co-sifted through a sieve to form premix.
  • step (2) The premix obtained in step (1) was loaded in a fluid bed processor.
  • step (3) The granules obtained in step (3) were dried and sifted through sieves.
  • step (4) The dried granules obtained in step (4) was mixed with crospovidone and magnesium stearate was added to form a blend which was filled in empty capsule shells.

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Abstract

L'invention porte sur une composition pharmaceutique orale solide comprenant plus de 100 mg d'imatinib et un ou plusieurs excipients pharmaceutiquement acceptables. L'invention porte également sur un procédé pour la préparation d'une composition pharmaceutique comprenant plus de 100 mg d'imatinib et un ou plusieurs excipients pharmaceutiquement acceptables, comprenant la fabrication d'une composition pharmaceutique orale solide par granulation d'imatinib avec un ou plusieurs excipients pharmaceutiquement acceptables. L'invention porte également sur une composition pharmaceutique orale solide destinée à être utilisée en médecine comprenant plus de 100 mg d'imatinib et un ou plusieurs excipients pharmaceutiquement acceptables.
PCT/GB2011/001726 2010-12-15 2011-12-15 Composition pharmaceutique comprenant de l'imatinib WO2012080703A1 (fr)

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IN3423MU2010 2010-12-15

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2497464A3 (fr) * 2011-03-09 2012-09-19 Adamed SP. Z O.O. Composition pharmaceutique de l'imatinibe methanesulphonate et son procédé de fabrication
EP2803352A1 (fr) 2013-05-14 2014-11-19 Hetero Research Foundation Compositions d'imatinib
EP3019159A4 (fr) * 2013-07-09 2017-01-18 Shilpa Medicare Limited Compositions pharmaceutiques orales comprenant du mésylate d'imatinib
EP3257499A1 (fr) 2016-06-17 2017-12-20 Vipharm S.A. Procédé pour la préparation de capsules de méthanesulfonate d'imatinib

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EP1762230A1 (fr) * 2005-08-15 2007-03-14 Siegfried Generics International AG Tablette enrobé ou granulate comprenante un pyridylpyrimidine
EP2000139A1 (fr) * 2007-06-07 2008-12-10 Novartis AG Formes amorphes stabilisées du mésylate de l'imatinib
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