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WO2014115082A1 - Formulations pharmaceutiques d'imatinib - Google Patents

Formulations pharmaceutiques d'imatinib Download PDF

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Publication number
WO2014115082A1
WO2014115082A1 PCT/IB2014/058456 IB2014058456W WO2014115082A1 WO 2014115082 A1 WO2014115082 A1 WO 2014115082A1 IB 2014058456 W IB2014058456 W IB 2014058456W WO 2014115082 A1 WO2014115082 A1 WO 2014115082A1
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WO
WIPO (PCT)
Prior art keywords
tablet formulation
stable pharmaceutical
diluent
imatinib
imatinib mesylate
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2014/058456
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English (en)
Inventor
Vinod Kumar Reddy Bondu
Irfan BABLA
Saravanan Kannusamy
Raja Kumar Seshadri
Prasad Vure
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.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories Ltd
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 Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of WO2014115082A1 publication Critical patent/WO2014115082A1/fr
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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • aspects of the present invention relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects relate to processes for preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient.
  • the drug having the adopted name "imatinib mesylate” has a chemical name 4-[(4-Methyl1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate, and its structural formula is shown below.
  • Imatinib mesylate has the empirical formula C 29 H 3 i and its molecular weight is 589.7. Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. It is soluble in aqueous buffers at pH ⁇ 5.5, but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.
  • Imatinib is a small molecule kinase inhibitor, used for the treatment of chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia, myelodysplasia/ myeloproliferative diseases (MDS/MPD), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), dermatofibrosarcoma protuberans (DFSP), and gastrointestinal stromal tumors (GIST).
  • CML chronic myeloid leukemia
  • MDS/MPD myelodysplasia/ myeloproliferative diseases
  • ASM aggressive systemic mastocytosis
  • HES hypereosinophilic syndrome
  • CEL chronic eosinophilic leukemia
  • DFSP dermatofibrosarcoma protuberans
  • GIST gastrointestinal stromal tumors
  • Imatinib mesylate is the active ingredient in products sold as GLEEVECTM for oral administration, in film-coated tablets containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base, in US.
  • imatinib mesylate is sold as GLIVECTM for oral administration, which is available as tablet dosage forms containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base.
  • Imatinib is also available as GLIVECTM hard gelatin capsules in some European countries, each capsule containing 50 mg or 100 mg imatinib mesylate.
  • doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.
  • U.S. Patent No. 5,521 ,184 discloses imatinib and the use thereof, especially as an anti-tumor agent.
  • U.S. Patent No. 6,894,051 discloses various polymorphic forms of imatinib or its salts.
  • International application Publication No's WO 2007/136510, WO 2011/023146 and WO 201 1/157450 disclose polymorphic forms of imatinib or its salts, amorphous form and processes for their preparation.
  • Form a and form ⁇ Two different crystalline forms of anhydrous imatinib mesylate, form a and form ⁇ , are known in the art.
  • Form a has a lower melting enthalpy than form ⁇ , which indicates an enantiotropic relationship between both forms.
  • Form ⁇ is the more stable polymorph at 25°C and 50°C, but at high temperatures Form ⁇ is converted to Form a. Both polymorphs show similar aqueous solubility characteristics.
  • the ⁇ form is thermodynamically stable and shows a suitable morphology with respect to flow properties.
  • imatinib mesylate Apart from Polymorph a and ⁇ , other polymorphic forms of imatinib mesylate are also known in the art, such as, a2, F, G, H, I , K, Delta, Epsilon, and H 1. Two amorphous forms of imatinib mesylate are also known in the art.
  • imatinib mesylate salt is highly soluble as per BCS classification system.
  • 201 1/161689 discloses pharmaceutical tablet, comprising Imatinib in an amount of 50-75%w/w of the total tablet weight and comprising at least one pharmaceutically acceptable excipient without a binding agent.
  • International Application Publication No. 2011/160798 discloses pharmaceutical tablet comprising at least one pharmaceutically acceptable excipient without a binding agent.
  • U.S. Patent No. 7,943, 172 discloses dry granulation processes of preparation of film-coated tablets comprising 25% by weight to 80% by weight imatinib mesylate in alpha crystalline form based on the total weight of the tablet cores or granule cores.
  • US'172 patent explicitly teaches that imatinib mesylate should be first compacted along with filler-binder to prepare pellets, which are broken up into granular bodies and processed subsequently to tablets or granules and such process provides tablets and granules with the required properties in respect of hardness, disintegration, dissolution rate and storage stability, especially when using imatinib mesylate in the alpha crystalline form.
  • U.S. Patent Application No's 2008/0226731 and 2010/0240672 disclose sustained release pharmaceutical compositions of Imatinib Mesylate, melt granulated with a release retardant using an extruder.
  • aspects of the present invention relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects relate to processes for preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient.
  • the invention provides pharmaceutical formulations, wherein such formulations comprise from about 30% to about 86% of imatinib or pharmaceutically acceptable salt thereof per dosage unit.
  • the invention provides pharmaceutical formulations, wherein such formulations comprise from about 30% to about 86% of imatinib mesylate per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations retain polymorphic form of imatinib mesylate and ensure desired drug release characteristics during storage for commercially relevant times.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise at least one pharmaceutically acceptable excipient.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations do not comprise any binder.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise diluent, disintegrant, glidant, lubricant, colouring agent, coating materials and the like.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise combination of soluble and insoluble diluent.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise diluent from about 30% to about 65% per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise soluble diluent from about 25% to about 60% per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise insoluble diluent from about 5% to about 40% per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise disintegrant selected form the group consisting of croscarmellose, crospovidone, starch, low-substituted hydroxypropylcellulose and the like and suitable combinations thereof.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise disintegrant from about 1 % to about 8% per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations are prepared by dry granulation technique, such as roller compaction, slugging, or direct compression technique.
  • the invention provides pharmaceutical formulations comprising imatinib mesylate, wherein such formulations ensure good bioavailability by exhibiting desirable dissolution profile.
  • the invention provides pharmaceutical formulations comprising imatinib mesylate, wherein such formulations ensure good bioavailability by exhibiting desirable dissolution profile by releasing at least 85 % of drug within 15 minutes of duration in a pH 1.2 to 7.5.
  • aspects of the present invention relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects relate to processes for preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient.
  • salts that are known to be non-toxic and are commonly used in pharmaceutical practice.
  • Acid salts include, for example, mineral acid salts, such as a hydrochloride, hydrobromide, sulfate, etc.
  • Salts with organic acids include, for example, a succinate, maleate, fumarate, malate, tartrate, etc.
  • Sulfonate salts include, for example, a methanesulfonate (mesylate), benzenesulfonate, toluenesulfonate, etc.
  • Basic salts include alkali metal salts, for example a sodium salt, potassium salt, and alkaline earth metal salt, for example calcium salt, etc.
  • the invention provides pharmaceutical formulations, wherein such formulations comprise from about 30% to about 86% of imatinib or pharmaceutically acceptable salt thereof, per dosage unit. In preferred embodiments such formulations comprise from about 35% to about 55% of imatinib or pharmaceutically acceptable salt thereof per dosage unit. In embodiments, the invention provides pharmaceutical formulations, wherein such formulations comprise from about 30% to about 86% of imatinib mesylate per dosage unit. In preferred embodiments such formulations comprise from about 35% to about 55% of imatinib mesylate per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise imatinib mesylate from about 5 to 1000 mg per dosage unit. In one preferred embodiment, formulations comprise imatinib mesylate from about 20 to 900 mg per dosage unit. In another preferred embodiment, formulations comprise imatinib mesylate from about 50 to 800 mg per dosage unit.
  • imatinib mesylate can be used in any crystalline form, amorphous form, or combinations thereof.
  • imatinib mesylate can be anhydrous or in the form of hydrates, solvates, etc.
  • the invention provides pharmaceutical formulation comprising imatinib mesylate, wherein imatinib mesylate is in alpha crystalline form.
  • imatinib mesylate is in un-micronized alpha crystalline form.
  • imatinib mesylate is in micronized alpha crystalline form.
  • pharmaceutically acceptable excipient means a component of a pharmaceutical product that is not an active ingredient, such as diluent, disintegrant, glidant, lubricant, colouring agent, coating materials and the like.
  • formulation refers to dosage forms for administration to a patient, comprising imatinib mesylate and at least on pharmaceutically acceptable excipient, wherein dosage forms may be solid oral dosage forms such as tablets, capsules, pills, granules, sachets, etc.
  • dosage form is tablet. In another embodiment, dosage form is capsule.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations do not comprise any binder.
  • the invention provides pharmaceutical formulations of imatinib mesylate, comprising at least one pharmaceutically acceptable excipient such as diluent, disintegrant, glidant, lubricant, colouring agent, coating material and the like.
  • pharmaceutically acceptable excipient may include Co- processed excipients.
  • Diluents for the purpose of this invention may be soluble or insoluble diluent.
  • Soluble diluents include, but are not limited to, sugar alcohols such as mannitol, lactose, sorbitol, xylitol and the like.
  • Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tabletting), lactose anhydrous, FlowlacTM (available from Meggle Products), PharmatoseTM (available from DMV), and others.
  • Insoluble diluents include, but are not limited to, different grades of starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starches (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starches (commercially available as National 78- 1551 from Essex Grain Products) and others.
  • Different celluloses that can be used include crystalline celluloses and powdered celluloses.
  • crystalline cellulose products include, but are not limited to, CEOLUSTM KG801 , AvicelTM PH101 , PH102, PH301 , PH302 and PH-F20, microcrystalline cellulose (“MCC”) 1 14, and microcrystalline cellulose 112.
  • MCC microcrystalline cellulose
  • Other useful insoluble diluents include, but are not limited to, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, directly compressible grades of dibasic calcium phosphate (EmcompressTM), tribasic calcium phosphate, and any combinations thereof.
  • Silicified MCC PROSOLVE VTM from JRS Pharma, Germany
  • Silicified MCC is a multifunctional ingredient containing 98% microcrystalline cellulose and 2% colloidal silica, where silica is distributed over the surface of particles. This ingredient is useful for improving flowability and compaction.
  • diluent is soluble or insoluble diluent.
  • soluble diluent is lactose and insoluble diluent is MCC.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise diluent from about 30% to about 65% per dosage unit, or from about 35% to about 60% per dosage unit, or from about 40% to about 55% per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise soluble diluent from about 25% to about 60% per dosage unit, or from about 28% to about 45% per dosage unit, or from about 30% to about 40% per dosage unit.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise insoluble diluent from about 5% to about 40% per dosage unit, or from about 6% to about 30% per dosage unit, or from about 8% to about 15% per dosage unit.
  • Disintegrants may be incorporated into intragranular or extragranular blends, or both.
  • Various useful disintegrants include, but are not limited to, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium (e.g., Ac-di-solTM from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KOLLIDONTM CL from BASF (Germany), POLYPLASDONETM XL, XL10, and INF-10 from ISP Inc. (USA), and low-substituted hydroxypropylcelluloses ("L- HPC").
  • carmellose calcium carboxymethyl starch sodium
  • croscarmellose sodium e.g., Ac-di-solTM from FMC-Asahi Chemical Industry Co., Ltd.
  • crospovidones examples of commercially available crospovidone products including but not limited to cross
  • low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH 11 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.).
  • Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, starches, and any combinations thereof.
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise disintegrant from about 1 % to about 8% per dosage unit.
  • Glidants or anti-sticking agents can be used, including but not limited to talc, silica derivatives, colloidal silicon dioxide, and the like, and any mixtures thereof, and lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, glyceryl monostearates, calcium stearate, zinc stearate, polyoxyethylene monostearates, fumed silicas (e.g., Aerosil® products), sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats castor oils, waxes, and any combinations thereof.
  • stearic acid and stearic acid derivatives such as magnesium stearate, glyceryl monostearates, calcium stearate, zinc stearate, polyoxyethylene monostearates, fumed silicas (e.g., Aerosil
  • the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise glidants from about 0.1 % to about 5% per dosage unit. In embodiments, the invention provides pharmaceutical formulations of imatinib mesylate, wherein such formulations comprise lubricants from about 0.1 % to about 5% per dosage unit.
  • Various useful acidifiers include, but are not limited to, organic acids such as citric acid, acetic acid, lactic acid, malic acid, fumaric acid, or succinic acid and combinations of organic acids such as malic acid, fumaric acid, and pyruvic acid.
  • organic acids such as citric acid, acetic acid, lactic acid, malic acid, fumaric acid, or succinic acid and combinations of organic acids such as malic acid, fumaric acid, and pyruvic acid.
  • Inorganic acids such as phosphoric acid, may also be used.
  • PharmaburstTM available as three different grades like Pharmaburst B1 , Pharmaburst B2, and Pharmaburst C1 , is described as "delivery system” products used by pharmaceutical industry in the production of "quick dissolve” tablets.
  • Pharmaburst B1 is composed of 85 percent mannitol (a sweetenter), 7.5 percent starch (a tabletting aid), 4.5 percent polyplasdone, 3 percent sodium croscarmellose (disintegrants), and less than one percent each of colloidal silica and syloid (anti-adherents).
  • Pharmaburst B2 consists of 85 percent mannitol, 10 percent polyplasdone, 5 percent sorbitol (a sweetener), and less than one percent syloid.
  • Pharmaburst C1 is made of 84 percent mannitol, 16 percent polyplasdone, and less than one percent syloid.
  • F-MELT® is a co-spray dried excipient system containing 5 pharmaceutical excipients such as carbohydrates, disintegrants and inorganic ingredients.
  • Various useful colourants include, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, iron oxides, and any combinations thereof.
  • an outer continuous phase in the form of a film coating may be used, optionally containing additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, the like, including any combinations thereof.
  • Film-forming agents include, but are not limited to: soluble alkyl- or hydroalkyl- cellulose derivatives, for example and not limited to methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, and hydroxypropyl celluloses.
  • plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycol, triacetin, triethyl citrate and mixtures thereof.
  • a plasticizer is frequently present in an amount ranging from 5% to 30%, based on the total weight of the film coating.
  • An opacifier like titanium dioxide may also be present, in amounts ranging from about 10% to about 20%, based on the total weight of the coating.
  • Anti- adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying.
  • An example of an anti-adhesive for this purpose is talc.
  • the anti-adhesive typically is present in the film coating in an amount of about 5% to 15%, based upon the total weight of the coating.
  • pre-formulated coating products such as those sold as OPADRYTM (supplied by Colorcon) will be used, for example Opadry Blue 13B50579 or Opadry White OY 59800 or Opadry AMB or Opadry Orange or Opadry Brown.
  • OPADRYTM supplied by Colorcon
  • the products sold in a solid form require only mixing with a liquid before use.
  • film-forming agents may be applied as powders, using suitable powder coating equipment known in the art.
  • aspects of the present invention also relate to pharmaceutical formulations of imatinib mesylate, wherein such formulations are prepared by dry granulation technique, such as roller compaction, slugging, or direct compression technique.
  • the invention provides dry granulation processes of preparation of pharmaceutical formulations of imatinib mesylate, wherein such process comprise following steps:
  • step 1) Granulating step 1) materials using by dry granulation such as roller compaction or slugging and milling the prepared granules.
  • granules prepared by dry granulation techniques may be filled into capsules or sachets.
  • the invention provides direct compression processes of preparation of pharmaceutical formulations of imatinib mesylate, wherein such process comprise following steps: 1) Sifting drug substance and other excipients such as diluent, disintegrant, glidant, lubricant etc., through a sieve, and mixing.
  • lubricated blend prepared by direct compression technique may be filled into capsules or sachets.
  • Equipment suitable for processing pharmaceutical formulations of the present application include any one or a combination of mechanical sifters, blenders, roller compactors, compression machines, rotating bowls or coating pans, etc.
  • content uniformity refers to an assessment of how uniformly a micronized or submicron active ingredient is dispersed in a formulation. Content uniformity can be measured according to USP test method 905 "Uniformity of Dosage Units.”
  • disintegration refers to the breakdown of unit dosage forms into smaller granules or particles. Disintegration can be evaluated according to USP test method 701 "Disintegration".
  • the application provides pharmaceutical dosage forms of imatinib having content uniformities (CU) from about 90% to about 110% by weight, with relative standard deviations (RSD) of not more than about 5%.
  • the invention relates to pharmaceutical formulations having a disintegration time of less than about 15 minutes.
  • the invention relates to pharmaceutical formulations having friability not more than about 1 % w/w.
  • compositions prepared as above can be subjected to in vitro drug dissolution evaluations according to USP test 711 "Dissolution" to determine the rate at which the active substance is released from the dosage forms, and the content of active ingredient can conveniently be determined in solutions using techniques such as high performance liquid chromatography.
  • the term "stability” for purposes of the present application relates to physical stability, chemical stability, and thermodynamic stability.
  • the term “physical stability” refers to maintenance of the polymorphic form of the drug, such as crystalline or amorphous
  • the term “chemical stability” relates to formation of drug-related impurities.
  • stability is required for commercially relevant times after manufacturing, such as for about 6, 12, 18, or 24 months, during which a product is kept in its original packaging under normal ambient conditions. Stability testing frequently is conducted using storage conditions such as room temperature, e.g., 25°C and 60% relative humidity (“RH"), intermediate conditions (e.g., 30°C and 65% RH), and accelerated conditions (e.g., 40°C and 75% RH).
  • room temperature e.g., 25°C and 60% relative humidity (“RH")
  • intermediate conditions e.g., 30°C and 65% RH
  • accelerated conditions e.g., 40°C and 75% RH.
  • the content of maximum unknown impurity is not greater than about 0.20%. In embodiments, the content of total impurity is not greater than about 2.0%. All of these impurity contents are expressed as weight percentages of the labeled drug content. Solid compositions of imatinib mesylate can be analyzed by common techniques, such as high performance liquid chromatography, to determine their drug content and the concentrations of impurities.
  • EXAMPLE 1-5 Imatinib mesylate tablets prepared using dry granulation.
  • **Opadry Orange is a formulated coating product of Colorcon, containing hypromellose 6 cP, triacetin/glycerol triacetate, titanium dioxide, and pharmaceutically acceptable pigment.
  • Imatinib Mesylate and crospovidone or mannitol or croscarmellose sodium or sodium starch glycolate or L-HPC are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.
  • Sieved imatinib mesylate and crospovidone or mannitol or croscarmellose sodium or sodium starch glycolate or L-HPC are made in to slugs with 25 mm round punches with desirable hardness.
  • step 3 The granules from step 3 are made in to slugs second time with 25 mm round punches with desirable hardness and the slugs are milled though a QuadroTM ComilTM to obtain desirable granule size.
  • Sodium stearyl fumarate previously passed through a #60 mesh sieve, is mixed with the blend from step 4, and then the mixture is compressed using desired oval shaved punches on rotary tablet press.
  • Opadry Orange is dispersed in IPA and DCM.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, and then dried.
  • Tablets prepared of Examples 1 and 2 are packaged in closed HDPE containers, together with desiccant canister, and stored at three different conditions: 25°C and 60% relative humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and 75% RH (Condition 3) for one month. Dissolution testing results of initial and stored samples are shown in Table 1 and Table 2 respectively. The dissolution study is conducted in 1000 mL of 0.1 N HCI medium, using USP type 2 apparatus, while stirred at 50 rpm for 30 minutes.
  • **Opadry AMB is a formulated coating product of Colorcon, containing polyvinyl alcohol, lecithin, soy, xanthan gum, polyethylene glycol (PEG 3350), titanium dioxide, talc, and pharmaceutically acceptable pigment.
  • Non-coating ingredients except for colloidal silicon dioxide and sodium stearyl fumarate, are sifted through a #30 mesh sieve and blended.
  • Colloidal silicon dioxide and sodium stearyl fumarate previously passed through a #60 mesh sieve, is mixed with the blend from step 1 , and then the mixture is compressed into tablets.
  • Opadry AMB is dispersed in IPA and DCM.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, then dried.
  • lubricated granules prepared in Examples 1-5 or a lubricated blends prepared in Example 6-9 are filled into capsules of suitable size.
  • Imatinib mesylate is sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.
  • step 2 The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.
  • the granules are blended with extra granular material (Sifted sodium stearyl fumarate) for 3 minutes.
  • Imatinib mesylate and crospovidone are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.
  • step 2 The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.
  • the lubricated blend is compressed with the suitable size punches.
  • step 2 The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.
  • the lubricated blend is compressed with the suitable size punches.
  • Dissolution testing results of tablets of Examples 1 1 , 13 and 15 are shown in Table 4.
  • the dissolution study is conducted in 900 mL of 6.8 pH phosphate buffer medium, using USP type 2 apparatus, while stirred at 50 rpm for 30 minutes.
  • the lubricated blend is compressed with the suitable size punches.
  • **Opadry Brown is a formulated coating product of Colorcon, containing Hypromellose, Macrogol, Titanium dioxide, iron oxide (s).
  • Imatinib Mesylate and crospovidone and colloidal silicon dioxide are sifted through a quadro sifter using 49R screen 2.
  • Sodium stearyl fumarate is sifted through #40 mesh.
  • step 3 Sifted material from step 1 is blended in a double cone blender for 10 minutes, and subsequently sodium stearyl fumarate added into the blender and again blended for 5 minutes.
  • Blend of step 3 is compacted in a roller compactor.
  • step 4 Granules of step 4 are blended with pre-sifted anhydrous lactose, microcrystalline cellulose, crospovidone and colloidal silicon dioxide followed by lubrication for 5 minutes with magnesium stearate (previously sifted through #40 mesh).
  • the lubricated blend is compressed with the suitable size punches.
  • Opadry Brown is dispersed in I PA and purified water.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 45-50°C, and then dried.
  • Example 29 Tablets of Example 29, stored in at two different conditions, 25°C and 60% relative humidity (Condition 1) or 40°C and 75% RH (Condition 3) for three months, are analyzed for dissolution or impurity content. Results are shown in Table 8.

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Abstract

La présente invention concerne selon certains aspects des formulations pharmaceutiques comprenant de l'imatinib ou ses sels, isomères, racémates, énantiomères, hydrates, solvates, métabolites, et polymorphes, et leurs mélanges. Des aspect supplémentaires concernent des procédés de préparation de formulations pharmaceutiques comprenant de l'imatinib ou ses sels, conjointement avec au moins un excipient pharmaceutiquement acceptable.
PCT/IB2014/058456 2013-01-22 2014-01-22 Formulations pharmaceutiques d'imatinib Ceased WO2014115082A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same
US10777331B2 (en) 2016-11-11 2020-09-15 Curium Us Llc Processes for generating germanium-68 with reduced volatiles
US20220175774A1 (en) * 2020-12-07 2022-06-09 Alembic Pharmaceuticals Limited Bioavailable Oral Dosage Form Of Tyrosine-Kinase Inhibitor

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Publication number Priority date Publication date Assignee Title
CN102349874A (zh) * 2011-08-26 2012-02-15 石药集团中奇制药技术（石家庄）有限公司 一种甲磺酸伊马替尼组合物及其制备方法
CN102552268A (zh) * 2010-12-23 2012-07-11 天津泰普药品科技发展有限公司 一种含有α晶型甲磺酸伊马替尼的药物制剂

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN102552268A (zh) * 2010-12-23 2012-07-11 天津泰普药品科技发展有限公司 一种含有α晶型甲磺酸伊马替尼的药物制剂
CN102349874A (zh) * 2011-08-26 2012-02-15 石药集团中奇制药技术（石家庄）有限公司 一种甲磺酸伊马替尼组合物及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same
US10777331B2 (en) 2016-11-11 2020-09-15 Curium Us Llc Processes for generating germanium-68 with reduced volatiles
US20220175774A1 (en) * 2020-12-07 2022-06-09 Alembic Pharmaceuticals Limited Bioavailable Oral Dosage Form Of Tyrosine-Kinase Inhibitor

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