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US20160101105A1 - High drug load tablet - Google Patents

High drug load tablet Download PDF

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Publication number
US20160101105A1
US20160101105A1 US14/974,658 US201514974658A US2016101105A1 US 20160101105 A1 US20160101105 A1 US 20160101105A1 US 201514974658 A US201514974658 A US 201514974658A US 2016101105 A1 US2016101105 A1 US 2016101105A1
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US
United States
Prior art keywords
tablet
small
compound
methylpiperazin
ylamino
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.)
Abandoned
Application number
US14/974,658
Inventor
Christian-Peter Luftensteiner
Jean-Claude Bianchi
Joerg Ogorka
Oskar Kalb
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.)
Individual
Original Assignee
Individual
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Filing date
Publication date
Family has litigation
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Application filed by Individual filed Critical Individual
Priority to US14/974,658 priority Critical patent/US20160101105A1/en
Publication of US20160101105A1 publication Critical patent/US20160101105A1/en
Abandoned 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C43/00—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor
    • B29C43/003—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor characterised by the choice of material

Definitions

  • the present invention relates to pharmaceutical tablets comprising 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide or pharmaceutically acceptable salts thereof and is hereinafter referred as Compound I.
  • Compound I has the formula (1)
  • the present invention provides a tablet with high drug loading comprising a pharmacologically effective amount of Compound I or a pharmaceutically acceptable salt thereof present in an amount of from about 30% to 80%, e.g. at least about 35, 40, 45, 50 or 55% to about e.g. 60, 65, 70, 75 or 80%, preferably more than 55%.
  • the amount of Compound I may vary from 45 to 80%, e.g. 50 to 70% in weight based on the total weight of the tablet.
  • Compound I may be in the free base form or pharmaceutically acceptable salts thereof, e.g. monomesylate form.
  • the active moiety corresponds to Compound I in the free base form.
  • 119.5 mg of Compound I mesylate salt correspond to 100 mg of Compound I free base active moiety.
  • the present invention also provides a tablet comprising
  • At least one pharmaceutically acceptable excipient suitable for the preparation of tablets wherein the amount of Compound I or pharmaceutically acceptable salt thereof, calculated as the percentage of the content in weight of the active moiety based on the total the tablet, is from about 30% to 80%, e.g. at least about 35, 40, 45, 50 or 55% to about e.g. 60, 65, 70, 75 or 80%, preferably more than 55%.
  • the amount of Compound I may vary from 45 to 80%, e.g. 50 to 70% in weight of the active moiety based on the total weight of the tablet.
  • the present invention provides a tablet wherein the Compound I is in crystalline form.
  • the monomesylate salt of Compound I is in crystalline form, e.g. alpha of beta crystal form, most preferably, the monomesylate salt of Compound I is in the beta crystal form.
  • One or more pharmaceutically acceptable excipients may be present in the tablets, e.g. those conventionally used, e.g. (1.1) at least one binder, e.g. microcrystalline cellulose, hydroxypropylmethyl cellulose, (1.2) at least one disintegrant, e.g. cross-linked polyvinylpyrrolidinone, e.g. Crospovidone®, (1.3) at least one glidant, e.g. colloidal silicon dioxide, (1.4) at least one lubricant, e.g. magnesium stearate and/or (1.5) basic coating.
  • microcrystalline cellulose is used as a binder.
  • Suitable disintegrates (1.2) include but are not restricted to maize starch; CMC-Ca; CMC-Na; microcrystalline cellulose; cross-linked PVP, e.g. as known and commercially available under the trade names Crospovidone®, Polyplasdone®, available commercially from the ISP company, or Kollidon® XL; alginic acid; sodium alginate; and guar gum.
  • cross-linked PVP e.g. Crospovidone® is used.
  • glidants one or more of the following may be used: silica; colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200, magnesium trisilicat, powdered cellulose, starch and talc.
  • colloidal silica anhydrous or/and colloidal silicon dioxide are used.
  • One or more of these excipients can be selected and used having regard to the particular desired properties of the tablet by routine experimentation.
  • the amount of binder (1.1) may vary within a range of from about 1 to 40%, preferably 1 to 30%, in particular 1 to 25% in weight bases on the total weight of the tablet.
  • the amount of glidant (1.3) may vary within ranges of from 0.1 to 10%, in particular 0.1 to 5%, e.g. 0.5 to 3% in weight based on the total weight of the tablet or 2 to 4% in weight based on the total weight of the tablet.
  • the amount of lubricant (1.4) may vary within a range of from 0.1 to 5%, e.g. 0.5 to 2% in weight based on the total weight of the tablet.
  • the amount of basic coating (1.5) may vary from 1 to 10% preferably from 1.5 to 5% in weight based on the total weight of the tablet.
  • any given excipient may serve more than one function e.g. as disintegrant, binder, glidant, and/or lubricant.
  • each excipient and the amounts relative to other excipients is similarly dependent on the desired properties of the tablet and may also be chosen by routine experimentation.
  • the tablet may be chosen to exhibit accelerated and/or delayed release of Compound I with or without quantitative control of the release of active agent.
  • the tablet is chosen to exhibit immediate release of the Compound I, e.g. the Compound I monomesylate salt beta crystal form.
  • compositions comprising Compound I are obtainable.
  • pharmaceutically acceptable oral solid dosage forms in the form of tablets may be obtained by preparation of tablets by compression methods. More specifically, the tablets of the invention may be prepared by granulation, preferably wet-granulation, followed by compression methods.
  • Compound I especially the mesylate salt, exhibits high particle size, e.g. 60% of the Compound I starting material having a particle size greater or equal to 100 ⁇ m, e.g. 90% of the particles are smaller or equal to 420 ⁇ m.
  • Wet-granulation process is usually performed with a starting material of particle size lower than 100 ⁇ m.
  • the tablet according to the invention contains a high content of Compound I given the relatively small amount of excipients. This enables the production of physically small tablets.
  • the total amount of excipients in a given unit dosage may be about 70% or less by weight based on the total weight of the tablet, more particularly about 50% or less.
  • the excipient content is in the range of about 30 to 55%, more particularly 35 to 50% in weight based on the total weight of the tablet.
  • Tablets according to the invention surprisingly provide for the administration of Compound I in a smaller size than was hitherto possible for a given unit dose of Compound I.
  • the tablets of the invention are, despite the high drug loading, small, and, therefore, convenient to administer. This leads to a better patient compliance.
  • this invention provides a tablet comprising from 50 mg to 600 mg Compound I, e.g. of from 100 mg to about 400 mg. Most preferably, tablets according to the invention are tablets containing 100 mg and/or tablets containing 400 mg of Compound I.
  • the present invention provides for tablets containing an amount of Compound I mesylate, e.g. Compound I mesylate alpha crystal form and/or Compound I mesylate beta crystal form, equal to 100 mg and/or 400 mg of Compound I free base.
  • the Compound I mesylate form used for the tablet according to the invention is the beta crystal form.
  • the process for the preparation of the tablets consists in forming an inner phase, mixing it together with an outer phase, compressing the obtained mixture and optionally coating the tablet.
  • the inner phase comprises Compound I.
  • the inner phase comprises Compound I and one or more excipients, more preferably one or more binders and most preferably the amount of one or more binders in the inner phase is ranging from about 1 to 30%, preferably 1 to 20% and more preferably 1 to 15%.
  • the binders of the inner phase according to the invention are preferably microcrystalline cellulose and hydroxypropylmethyl cellulose.
  • the amount of microcrystalline cellulose in the inner phase may vary from about 10 to 29%, in particular 12 to 14% in weight based on the total weight of the tablet.
  • the amount of hydroxypropylmethyl cellulose in the inner phase may vary from 1 to 5%, preferably 1 to 2% in weight based on the total weight of the tablet.
  • the Compound I and the pharmaceutically acceptable excipients of the inner phase are mixed together with water and the mixture is processed for granulation, e.g. using a wet high-shear granulator to form the wet-granulates.
  • the wet-granulates may be then, dried, e.g. using a fluid bed dryer.
  • the present invention pertains to a process for the preparation of tablets comprising an outer phase.
  • the outer phase consists in a mixture of the inner phase with one or more excipients.
  • the inner phase and one or more excipients of the outer phase are mixed together using, e.g. a diffusion mixer.
  • one or more binders are added.
  • Most preferably cellulose microcrystalline is added.
  • macrocrystalline cellulose is added in the range of 1 to 10% in weight based on the total weight of the tablet.
  • the amount of microcrystalline cellulose is around 5% in weight based on the total weight of the tablet.
  • the outer phase according to the invention may also contain one or snore disintegrant, most preferably Crospovidone®.
  • the amount of disintegrant in the outer phase is ranging from about 10 to 30%, preferably 12 to 25%, most preferably about 15%.
  • one or more glidants are incorporated into the outer phase.
  • one of more lubricants are incorporated into the outer phase.
  • tablets are performed by compression of the mixture of the inner and the outer phases using, e.g. a tablet press.
  • the tablets may be coated, preferably as described herein after.
  • the present invention provides a process comprising:
  • excipients e.g. sieved excipients, such as one or more disintegrants, e.g. Crospovidone®, one or more binders, e.g. microcrystalline cellulose, one or more glidant, e.g. colloidal silicon dioxide, and mixing, e.g. in a diffusion mixer;
  • pharmaceutically acceptable excipients e.g. sieved excipients, such as one or more disintegrants, e.g. Crospovidone®, one or more binders, e.g. microcrystalline cellulose, one or more glidant, e.g. colloidal silicon dioxide, and mixing, e.g. in a diffusion mixer;
  • step (v) tabletting the mixture obtained in step (iv) by compression, e.g. in a conventional tablet press, e.g. in an EK-0 Korsch eccentric tabletting machine or a rotary tabletting machine, preferably a rotary machine and
  • core is meant the granulate phase (steps (i) and (ii)) including the active drug Compound I and the outer phase consisting of the excipients.
  • total weight of the tablet is meant the weight of a tablet being the inner and the outer phases and the coating (if any).
  • the coating process may be performed at low temperature, e.g. between 30 and 40° C., preferably between 32 and 39° C., most preferably at a temperature ranging from around 35 to around 38° C.
  • the coating process may be performed with a spray rate preferably in the range of 30 to 105 g of coating dispersion per kg of cores per hour, preferably of 35 to 105 g. It has surprisingly been found that swelling of the disintegrants, e.g. Crospovidone®, nor sticking of the cores occurred during spraying of the coating mixture, as it would be expected by the person skilled in the art by processing at low temperatures.
  • the tablets exhibit improved abrasion resistance.
  • the physical and chemical stability may be tested in conventional manner, e.g. the tablets may be tested as such by measurement of dissolution, friability, disintegration time, assay for Compound I degradation products, appearance and/or microscopy, e.g. after storage at room temperature, i.e. 25° C., and/or storage at 40° C.
  • the tablet cores may vary in shape and be, for example, round, oval, oblong, cylindrical or any other suitable shape.
  • a characteristic of tablets according to the invention is their small size having regard to the amount of Compound I or Compound I salt contained therein.
  • tablets obtained by the compression method described above are round or oval.
  • the edges of the tablets may be beveled or rounded.
  • the tablets are ovaloid and/or round.
  • the tablets according to the invention may be scored.
  • the ovaloid tablet may be small in dimension e.g. 10 to 20 mm in length, preferably 15 to 20 mm, most preferably 17 to 19 mm; 5 to 10 mm in width, preferably 6.5 to 8 mm.
  • the thickness of the tablet is from 4 to 8 mm, preferably 6 to 8 mm.
  • Compression forces of between 10 to 20 kN are used to prepare the compressed tablet, preferably, 12 to 18 kN.
  • the ovaloid tablet contains 400 mg of Compound I.
  • the round tablet may be of the following dimensions, e.g. 5 to 15 mm in diameter, preferably 7 to 10 mm, most preferably about 9 mm.
  • the thickness of the tablet may be from 2 to 5 mm, preferably 2.5 to 4 mm. Compression forces of between 6 to 18 kN are used to prepare the compressed tablet, preferably, 8 to 14 kN.
  • the round tablet contains 100 mg of Compound I.
  • the 100 mg tablet is a scored tablet, most preferably the tablet has a break score on one side.
  • the tablets of the invention comprising about 100 mg of Compound I may furthermore have a hardness of from about 30 to 140 N, e.g. 40 to 140 N, 30 to 100 N, 40 to 100 N, preferably 50 to 80 N.
  • the tablets of the invention comprising about 400 mg of Compound I may have a hardness of 100 to 270 N, e.g. 100 to 250 N, 160 to 270 N, 160 to 250 N, preferably 195 to 235 N.
  • the disintegration time of the tablet may be of about 20 min or less.
  • the disintegration time is ranging from about 2 to 10 min, preferably 4 to 10 min, e.g. 4 to 8 min.
  • the disintegration time is, preferably ranging from about 7 to 15 min, preferably 8 to 15 min, e.g. 8 to 14 min.
  • the friability of the tablets is measured according to the US Pharmacopeia.
  • the friability of the tablets according to the invention monitored following the recommendation of the US Phramacopeia is 0%.
  • the tablets of the invention may furthermore be colored and/or the tablets or coating marked so as to impart an individual appearance and to make them instantly recognizable.
  • the use of dyes can serve to enhance the appearance as well as to identify the tablets.
  • Dyes suitable for use in pharmacy typically include carotinoids, iron oxides of chlorophyll.
  • the tablets of the invention may be marked using an imprint code.
  • Procedures which may be used may be conventional or known in the art or based on such procedures e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutician Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutician für für Science, 4th Ed. (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions.
  • the tablets of the invention are useful for human indication of Compound I, e.g. anti-tumor treatment, as indicated by standard tests.
  • the activity and characteristics of the tablets of the invention may be indicated in standard clinical trials and/or animal trials.
  • the tablets of the invention are particularly useful for, e.g. treatment of non-malignant and malignant proliferative disorders, e.g. leukemia, gliomas, sarcomas, prostate-, breast-, gastro-intestinal lung-, ovary tumors.
  • non-malignant and malignant proliferative disorders e.g. leukemia, gliomas, sarcomas, prostate-, breast-, gastro-intestinal lung-, ovary tumors.
  • the tablets of the invention comprising a pharmacologically effective amount of Compound I or Compound I salt may be administered as the sole active drug or with another active drug may be envisaged, e.g. together with simultaneous or separate administration of other drugs.
  • the tablets of the invention obtained are stable both to the production process and during storage, e.g. for 2 years or even 3 years in conventional packaging, e.g. sealed aluminium blister packs. Less than about 5%, e.g. 2 or 3% or less of Compound I or Compound I salt may degrade daring this time as determined in conventional tests.
  • the tablets of the invention e.g. the 100 and 400 mg tablets, are bioequivalent with the marketed hard gelatine capsules (100 mg) of Compound I.
  • the administration of 400 mg of Compound I in hard gelatine capsules (4 ⁇ 100 mg) in the form of a single film coated tablet is well tolerated.
  • effective doses for example daily dosing of tablets of the invention comprising, e.g. 100-1000 mg, e.g. 100 to 800 mg, preferably 100 to 600 mg, especially 400 mg of Compound I, are administered to patients of about 70 kg bodyweight.
  • the invention relates also to a method for administering to a human subject in need of such a treatment, Compound I or a pharmaceutically acceptable salt thereof in the form of a tablet, once daily for a period, exceeding 3 months.
  • the invention plates especially to such method wherein a daily dose of 100 to 1000 mg, preferably 100 to 800 mg, especially 200 to 600 mg, preferably 400 mg, of Compound I is administered to an adult. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the age, the body weight, general health, drug combination with one or more active drugs, type and severity of the disease.
  • the present invention provides a method of treating a subject which comprises administering a tablet according to the invention comprising a pharmacologically effective amount of Compound I salt to a subject in need of such a treatment, optionally with the simultaneous, sequential or separate administration of another drug e.g. a cyclosporin, a rapamycin, an ascomycin, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid and/or mycophenolate mofetil.
  • another drug e.g. a cyclosporin, a rapamycin, an ascomycin, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid and/or mycophenolate mofetil.
  • the dosages of the Compound I mesylate may be reduced e.g. to one-half to one-third their dosages when used alone.
  • the medicament package comprises tablets according to the invention and printed instructions directing that one or more tablets of Compound I be administered orally.
  • Tablets of 100 mg of Compound I free base according to the invention and of the above tablet were prepared by wet granulation of a mixture of Compound I salt with (1.1), mixing with 3 (1.1), (1-2), (1.3) and (1.4), compressing and coating the resultant tablets with an aqueous dispersion of the coating mixture (1.5).
  • the coating process may be performed at low temperature, e.g. ranging from around 35 to around 38° C.
  • the coating process may be performed with a spray rate preferably in the range of 30 to 105 g of coating dispersion per kg of cores (“core” corresponds to the compressed inner and outer phase) per hour, e.g. 35 to 105 g per kg of cores per h.
  • Tablets of 400 mg of Compound I according to the invention and of the following tablet were prepared by wet granulation of a mixture of Compound I salt with (1.1), mixing with 3 (1.1), (1.2), (1.3) and (1.4), compressing and coating the resultant tablets with an aqueous dispersion of the coating mixture (1.5).
  • the coating process may be performed at low temperature, e.g. ranging from around 35 to around 38° C.
  • the coating process may be performed with a spray rate preferably in the range of 30 to 105 g of coating dispersion per kg of cores (“core” corresponds to the compressed inner and outer phase) per hour, e.g. 35 to 105 g per kg of cores per h.
  • Compound I free base/tablet Shape and Dimensions 100 mg Round, 9.1-9.3 mm diameter, curved, bevelled edges, thickness: 2.8-3.4 mm break score on one side 400 mg Ovaloid, 18.1-18.3 ⁇ 7.2-7.4 mm, curved, bevelled edges, thickness: 6.6-7.2 mm
  • Compound I free base/tablet Shape and Dimensions 100 mg Round, 9.1-9.4 mm diameter, curved, bevelled edges, thickness: 2.8-3.4 mm break score on one side 400 mg Ovaloid, 18.1-18.4 ⁇ 7.2-7.5 mm, curved, bevelled edges, thickness: 6.6-7.2 mm

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Abstract

The present invention pertains to a high drug load tablet comprising as active ingredient Compound I of formula
Figure US20160101105A1-20160414-C00001
or a pharmaceutically acceptable salt thereof in an amount from about 30% to 80% in weight of the active moiety based on the total weight of the tablet.

Description

  • The present invention relates to pharmaceutical tablets comprising 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide or pharmaceutically acceptable salts thereof and is hereinafter referred as Compound I.
  • Compound I has the formula (1)
  • Figure US20160101105A1-20160414-C00002
  • Compound I free base and its acceptable salts thereof are disclosed in the European Patent application 0564409. Compound I mesylate and Compound I mesylate alpha and beta crystal forms are disclosed in International Patent application WO 99/03854.
  • Typically, prescribed daily dosages of Compound I mesylate for the treatment of leukemia are high, e.g. 400-800 mg in adults. Thus, there is a need for an oral dosage form which is convenient to administer and provides a daily dosage amount of Compound I.
  • Accordingly, the present invention provides a tablet with high drug loading comprising a pharmacologically effective amount of Compound I or a pharmaceutically acceptable salt thereof present in an amount of from about 30% to 80%, e.g. at least about 35, 40, 45, 50 or 55% to about e.g. 60, 65, 70, 75 or 80%, preferably more than 55%. In particular, the amount of Compound I may vary from 45 to 80%, e.g. 50 to 70% in weight based on the total weight of the tablet.
  • Compound I may be in the free base form or pharmaceutically acceptable salts thereof, e.g. monomesylate form. The active moiety corresponds to Compound I in the free base form. For example, 119.5 mg of Compound I mesylate salt correspond to 100 mg of Compound I free base active moiety.
  • The present invention also provides a tablet comprising
  • (a) a pharmacologically effective amount of Compound I, and
  • (b) at least one pharmaceutically acceptable excipient suitable for the preparation of tablets wherein the amount of Compound I or pharmaceutically acceptable salt thereof, calculated as the percentage of the content in weight of the active moiety based on the total the tablet, is from about 30% to 80%, e.g. at least about 35, 40, 45, 50 or 55% to about e.g. 60, 65, 70, 75 or 80%, preferably more than 55%. In particular the amount of Compound I may vary from 45 to 80%, e.g. 50 to 70% in weight of the active moiety based on the total weight of the tablet.
  • In another aspect, the present invention provides a tablet wherein the Compound I is in crystalline form.
  • In a further aspect of the invention, the monomesylate salt of Compound I is used.
  • In a preferred embodiment of the invention, the monomesylate salt of Compound I is in crystalline form, e.g. alpha of beta crystal form, most preferably, the monomesylate salt of Compound I is in the beta crystal form.
  • One or more pharmaceutically acceptable excipients may be present in the tablets, e.g. those conventionally used, e.g. (1.1) at least one binder, e.g. microcrystalline cellulose, hydroxypropylmethyl cellulose, (1.2) at least one disintegrant, e.g. cross-linked polyvinylpyrrolidinone, e.g. Crospovidone®, (1.3) at least one glidant, e.g. colloidal silicon dioxide, (1.4) at least one lubricant, e.g. magnesium stearate and/or (1.5) basic coating. In the tablet according to the present invention, microcrystalline cellulose is used as a binder.
  • Reference is made to the extensive literature on the subject for these and other excipients and procedures mentioned herein, see in particular Handbook of Pharmaceutical Excipients, Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions which are incorporated herein by reference.
  • Binders (1.1) include but are not restricted to starches, e.g. potato, wheat or corn starch; microcrystalline cellulose, e.g. products such as Avicel®, Filtrak®, Heweten® or Pharmacel®; hydroxypropyl cellulose; hydroxyethyl cellulose; hydroxypropylmethyl cellulose, e.g. hydroxypropylmethyl cellulose-Type 2910 USP, hypromellose, and polyvinylpyrrolidone, e.g. Povidone® K30 from BASF. Preferably, hydroxypropylmethyl cellulose-Type 2910 USP is used.
  • Suitable disintegrates (1.2) according to the invention include but are not restricted to maize starch; CMC-Ca; CMC-Na; microcrystalline cellulose; cross-linked PVP, e.g. as known and commercially available under the trade names Crospovidone®, Polyplasdone®, available commercially from the ISP company, or Kollidon® XL; alginic acid; sodium alginate; and guar gum. Preferably, cross-linked PVP, e.g. Crospovidone® is used.
  • As glidants (1.3), one or more of the following may be used: silica; colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200, magnesium trisilicat, powdered cellulose, starch and talc. Preferably colloidal silica anhydrous or/and colloidal silicon dioxide are used.
  • As lubricants (1.4) one or more of the following may be used Mg-, Al- or Ca-stearate, PEG 4000-8000 and/or talc. Preferably magnesium stearate is used.
  • One or more of these excipients can be selected and used having regard to the particular desired properties of the tablet by routine experimentation.
  • According to the present invention, the amount of binder (1.1) may vary within a range of from about 1 to 40%, preferably 1 to 30%, in particular 1 to 25% in weight bases on the total weight of the tablet.
  • The amount of disintegrant (1.2) may vary within a range of front to 5 to 40%, e.g. 10 to 35% in weight based on the total weight of the tablet.
  • The amount of glidant (1.3) may vary within ranges of from 0.1 to 10%, in particular 0.1 to 5%, e.g. 0.5 to 3% in weight based on the total weight of the tablet or 2 to 4% in weight based on the total weight of the tablet.
  • The amount of lubricant (1.4) may vary within a range of from 0.1 to 5%, e.g. 0.5 to 2% in weight based on the total weight of the tablet.
  • The amount of basic coating (1.5) may vary from 1 to 10% preferably from 1.5 to 5% in weight based on the total weight of the tablet.
  • It will be appreciated that any given excipient may serve more than one function e.g. as disintegrant, binder, glidant, and/or lubricant.
  • In a preferred aspect of the invention, the tablet comprises the following excipients, one or more binders in a total amount of about 1% to 25% in weight based on the total weight of the tablet, one or more disintegrants in a total amount of about 10% to 35% in weight based on the total weight of the tablet, one or more glidants in a total amount of about 0.5% to 3% in weight based on the total weight of the tablet, and/or one or more lubricants in a total amount of about 0.5% to 2% in weight based on the total weight of the tablet.
  • The absolute amounts of each excipient and the amounts relative to other excipients is similarly dependent on the desired properties of the tablet and may also be chosen by routine experimentation. For example, the tablet may be chosen to exhibit accelerated and/or delayed release of Compound I with or without quantitative control of the release of active agent. Preferably the tablet is chosen to exhibit immediate release of the Compound I, e.g. the Compound I monomesylate salt beta crystal form.
  • The present inventors have encountered difficulties in the production of Compound I tablets due to high inability values and poor abrasion resistance. Further, the flexibility in the quantity of excipients, e.g. disintegrants, is limited due to the high drug load of the product. Thus, there still exists a need for commercially acceptable Compound I dosage forms for oral administration with good patient convenience and acceptance.
  • In accordance with the present invention, it has now unexpectedly been found that stable and convenient galenic tablets comprising Compound I are obtainable. The present Applicants have found that pharmaceutically acceptable oral solid dosage forms in the form of tablets, being particularly convenient to administer and stable, may be obtained by preparation of tablets by compression methods. More specifically, the tablets of the invention may be prepared by granulation, preferably wet-granulation, followed by compression methods. Compound I, especially the mesylate salt, exhibits high particle size, e.g. 60% of the Compound I starting material having a particle size greater or equal to 100 μm, e.g. 90% of the particles are smaller or equal to 420 μm. Wet-granulation process is usually performed with a starting material of particle size lower than 100 μm.
  • It is a characteristic of the tablet according to the invention that it contains a high content of Compound I given the relatively small amount of excipients. This enables the production of physically small tablets. The total amount of excipients in a given unit dosage may be about 70% or less by weight based on the total weight of the tablet, more particularly about 50% or less. Preferably the excipient content is in the range of about 30 to 55%, more particularly 35 to 50% in weight based on the total weight of the tablet.
  • Tablets according to the invention surprisingly provide for the administration of Compound I in a smaller size than was hitherto possible for a given unit dose of Compound I. The tablets of the invention are, despite the high drug loading, small, and, therefore, convenient to administer. This leads to a better patient compliance.
  • In another embodiment this invention provides a tablet comprising from 50 mg to 600 mg Compound I, e.g. of from 100 mg to about 400 mg. Most preferably, tablets according to the invention are tablets containing 100 mg and/or tablets containing 400 mg of Compound I.
  • Accordingly, the present invention provides for tablets containing an amount of Compound I mesylate, e.g. Compound I mesylate alpha crystal form and/or Compound I mesylate beta crystal form, equal to 100 mg and/or 400 mg of Compound I free base. Most preferably, the Compound I mesylate form used for the tablet according to the invention is the beta crystal form.
  • According to the invention, the process for the preparation of the tablets consists in forming an inner phase, mixing it together with an outer phase, compressing the obtained mixture and optionally coating the tablet.
  • The inner phase comprises Compound I. Preferably, the inner phase comprises Compound I and one or more excipients, more preferably one or more binders and most preferably the amount of one or more binders in the inner phase is ranging from about 1 to 30%, preferably 1 to 20% and more preferably 1 to 15%. The binders of the inner phase according to the invention are preferably microcrystalline cellulose and hydroxypropylmethyl cellulose. The amount of microcrystalline cellulose in the inner phase may vary from about 10 to 29%, in particular 12 to 14% in weight based on the total weight of the tablet. The amount of hydroxypropylmethyl cellulose in the inner phase may vary from 1 to 5%, preferably 1 to 2% in weight based on the total weight of the tablet. The Compound I and the pharmaceutically acceptable excipients of the inner phase are mixed together with water and the mixture is processed for granulation, e.g. using a wet high-shear granulator to form the wet-granulates. The wet-granulates may be then, dried, e.g. using a fluid bed dryer.
  • The present invention pertains to a process for the preparation of tablets comprising an outer phase. The outer phase consists in a mixture of the inner phase with one or more excipients. The inner phase and one or more excipients of the outer phase are mixed together using, e.g. a diffusion mixer. Preferably, one or more binders are added. Most preferably cellulose microcrystalline is added. Even more preferably, macrocrystalline cellulose is added in the range of 1 to 10% in weight based on the total weight of the tablet. In a preferred embodiment of the invention, in the outer phase, the amount of microcrystalline cellulose is around 5% in weight based on the total weight of the tablet. The outer phase according to the invention may also contain one or snore disintegrant, most preferably Crospovidone®. In a preferred embodiment, the amount of disintegrant in the outer phase is ranging from about 10 to 30%, preferably 12 to 25%, most preferably about 15%.
  • In a particular aspect of the invention, one or more glidants are incorporated into the outer phase.
  • According to the invention, one of more lubricants are incorporated into the outer phase.
  • In a former aspect of the invention, tablets are performed by compression of the mixture of the inner and the outer phases using, e.g. a tablet press.
  • Optionally, the tablets may be coated, preferably as described herein after.
  • In one embodiment of the invention, the process for the preparation of a tablet which comprises
      • (a) forming an inner phase comprising
        • (i) mixing the Compound I together with pharmaceutically acceptable excipients
        • (ii) wet-granulating
      • (b) forming an outer phase comprising
        • (iii) adding further pharmaceutically acceptable excipients to the inner phase and mixing;
      • (c) forming the tablet by
        • (iv) compressing the mixture obtained in step (iii) and, optionally
      • (d) coating.
  • More specifically, in one aspect the present invention provides a process comprising:
  • (i) mixing the Compound I and pharmaceutically acceptable excipients, e.g. one or more binders, e.g. macrocrystalline cellulose, in a high shear mixer;
  • (ii) adding water, subjecting the mixture to wetting/kneading, e.g. in a high shear mixer, screening using a screening mill with a rotating impeller, and drying, e.g. in a fluidized bed dryer;
  • (iii) adding pharmaceutically acceptable excipients, e.g. sieved excipients, such as one or more disintegrants, e.g. Crospovidone®, one or more binders, e.g. microcrystalline cellulose, one or more glidant, e.g. colloidal silicon dioxide, and mixing, e.g. in a diffusion mixer;
  • (iv) adding pharmaceutically acceptable excipients such as one or more lubricant e.g. magnesium stearate, sieving, e.g. hand-sieving, e.g. at 900 μm, and mixing, e.g. in a diffusion mixer;
  • (v) tabletting the mixture obtained in step (iv) by compression, e.g. in a conventional tablet press, e.g. in an EK-0 Korsch eccentric tabletting machine or a rotary tabletting machine, preferably a rotary machine and
  • (vi) coating, e.g. in a pan coater, e.g. Glatt, Accela.
  • By “core” is meant the granulate phase (steps (i) and (ii)) including the active drug Compound I and the outer phase consisting of the excipients.
  • By “total weight of the tablet” is meant the weight of a tablet being the inner and the outer phases and the coating (if any).
  • According to the invention, the coating process may be performed at low temperature, e.g. between 30 and 40° C., preferably between 32 and 39° C., most preferably at a temperature ranging from around 35 to around 38° C. The coating process may be performed with a spray rate preferably in the range of 30 to 105 g of coating dispersion per kg of cores per hour, preferably of 35 to 105 g. It has surprisingly been found that swelling of the disintegrants, e.g. Crospovidone®, nor sticking of the cores occurred during spraying of the coating mixture, as it would be expected by the person skilled in the art by processing at low temperatures.
  • Moreover, the tablets exhibit improved abrasion resistance. The physical and chemical stability may be tested in conventional manner, e.g. the tablets may be tested as such by measurement of dissolution, friability, disintegration time, assay for Compound I degradation products, appearance and/or microscopy, e.g. after storage at room temperature, i.e. 25° C., and/or storage at 40° C.
  • The tablet cores may vary in shape and be, for example, round, oval, oblong, cylindrical or any other suitable shape. A characteristic of tablets according to the invention is their small size having regard to the amount of Compound I or Compound I salt contained therein.
  • In a preferred embodiment of the invention tablets obtained by the compression method described above are round or oval. The edges of the tablets may be beveled or rounded. Most preferably, the tablets are ovaloid and/or round. The tablets according to the invention may be scored. The ovaloid tablet may be small in dimension e.g. 10 to 20 mm in length, preferably 15 to 20 mm, most preferably 17 to 19 mm; 5 to 10 mm in width, preferably 6.5 to 8 mm. The thickness of the tablet is from 4 to 8 mm, preferably 6 to 8 mm. Compression forces of between 10 to 20 kN are used to prepare the compressed tablet, preferably, 12 to 18 kN. Preferably, the ovaloid tablet contains 400 mg of Compound I. The round tablet may be of the following dimensions, e.g. 5 to 15 mm in diameter, preferably 7 to 10 mm, most preferably about 9 mm. The thickness of the tablet may be from 2 to 5 mm, preferably 2.5 to 4 mm. Compression forces of between 6 to 18 kN are used to prepare the compressed tablet, preferably, 8 to 14 kN. Preferably, the round tablet contains 100 mg of Compound I. Preferably the 100 mg tablet is a scored tablet, most preferably the tablet has a break score on one side.
  • The tablets of the invention comprising about 100 mg of Compound I may furthermore have a hardness of from about 30 to 140 N, e.g. 40 to 140 N, 30 to 100 N, 40 to 100 N, preferably 50 to 80 N. The tablets of the invention comprising about 400 mg of Compound I may have a hardness of 100 to 270 N, e.g. 100 to 250 N, 160 to 270 N, 160 to 250 N, preferably 195 to 235 N.
  • The disintegration time of the tablet may be of about 20 min or less. Preferably, for the 100 mg Compound I tablet, the disintegration time is ranging from about 2 to 10 min, preferably 4 to 10 min, e.g. 4 to 8 min. For the 400 mg Compound I tablet, the disintegration time is, preferably ranging from about 7 to 15 min, preferably 8 to 15 min, e.g. 8 to 14 min.
  • The friability of the tablets is measured according to the US Pharmacopeia. The friability of the tablets according to the invention monitored following the recommendation of the US Phramacopeia is 0%.
  • The tablets of the invention may furthermore be colored and/or the tablets or coating marked so as to impart an individual appearance and to make them instantly recognizable. The use of dyes can serve to enhance the appearance as well as to identify the tablets. Dyes suitable for use in pharmacy typically include carotinoids, iron oxides of chlorophyll. The tablets of the invention may be marked using an imprint code.
  • Procedures which may be used may be conventional or known in the art or based on such procedures e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions.
  • The tablets of the invention are useful for human indication of Compound I, e.g. anti-tumor treatment, as indicated by standard tests. The activity and characteristics of the tablets of the invention may be indicated in standard clinical trials and/or animal trials.
  • The tablets of the invention are particularly useful for, e.g. treatment of non-malignant and malignant proliferative disorders, e.g. leukemia, gliomas, sarcomas, prostate-, breast-, gastro-intestinal lung-, ovary tumors.
  • The tablets of the invention comprising a pharmacologically effective amount of Compound I or Compound I salt may be administered as the sole active drug or with another active drug may be envisaged, e.g. together with simultaneous or separate administration of other drugs.
  • Furthermore, the tablets of the invention obtained are stable both to the production process and during storage, e.g. for 2 years or even 3 years in conventional packaging, e.g. sealed aluminium blister packs. Less than about 5%, e.g. 2 or 3% or less of Compound I or Compound I salt may degrade daring this time as determined in conventional tests.
  • The tablets of the invention, e.g. the 100 and 400 mg tablets, are bioequivalent with the marketed hard gelatine capsules (100 mg) of Compound I. The administration of 400 mg of Compound I in hard gelatine capsules (4×100 mg) in the form of a single film coated tablet is well tolerated.
  • Depending on age, individual condition, mode of administration, and the clinical picture in question, effective doses, for example daily dosing of tablets of the invention comprising, e.g. 100-1000 mg, e.g. 100 to 800 mg, preferably 100 to 600 mg, especially 400 mg of Compound I, are administered to patients of about 70 kg bodyweight.
  • The invention relates also to a method for administering to a human subject in need of such a treatment, Compound I or a pharmaceutically acceptable salt thereof in the form of a tablet, once daily for a period, exceeding 3 months. The invention plates especially to such method wherein a daily dose of 100 to 1000 mg, preferably 100 to 800 mg, especially 200 to 600 mg, preferably 400 mg, of Compound I is administered to an adult. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the age, the body weight, general health, drug combination with one or more active drugs, type and severity of the disease.
  • Accordingly in a further aspect the present invention provides a method of treating a subject which comprises administering a tablet according to the invention comprising a pharmacologically effective amount of Compound I salt to a subject in need of such a treatment, optionally with the simultaneous, sequential or separate administration of another drug e.g. a cyclosporin, a rapamycin, an ascomycin, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid and/or mycophenolate mofetil.
  • When the tablets of the invention are co-administered within a combined therapy the dosages of the Compound I mesylate may be reduced e.g. to one-half to one-third their dosages when used alone.
  • The medicament package comprises tablets according to the invention and printed instructions directing that one or more tablets of Compound I be administered orally.
  • Following non-limitative examples illustrate the invention.
    • EXAMPLE 1 Tablet Formulation (100 mg Tablet)
  • Composition Per Dosage Form Unit and Quantity Per Batch
  • Composition Quantity
    Component per unit (mg) per batch (kg)
    Compound I mesylate 1 2119.500 167.300
    Microcrystalline cellulose 1 (1.1) 25.000 35.000
    Hypromellose/Hydroxypropyl (1.1) 2.500 3.500
    methylcellulose 1
    Microcrystalline cellulose 3(1.1) 9.850 13.790
    Crospovidone (1.2) 28.000 39.200
    Silica, colloidal anhydrous/ (1.3) 1.250 1.750
    Colloidal silicon dioxide
    Magnesium stearate (1.4) 1.400 1.960
    Basic coating premix yellow (1.5) 7.125 8.5504 9.975 14.3644
    Basic coating premix red (1.5) 0.375 0.4504 0.525 0.7564
    Total weight 195.000 196.500 273.000 =275.000
    Units/batch 1'400'000
    1 Components of the granulate,
    2119.5 mg Compound I mesylate equals 100 mg Compund I free base,
    3Microcrystalline cellulose is added in the outer phase as a dry binder,
    4a 20% manufacturing overage of the coating dispersion is included to cover spray losses during the coating process step.
  • Tablets of 100 mg of Compound I free base according to the invention and of the above tablet were prepared by wet granulation of a mixture of Compound I salt with (1.1), mixing with 3(1.1), (1-2), (1.3) and (1.4), compressing and coating the resultant tablets with an aqueous dispersion of the coating mixture (1.5).
  • The coating process may be performed at low temperature, e.g. ranging from around 35 to around 38° C. The coating process may be performed with a spray rate preferably in the range of 30 to 105 g of coating dispersion per kg of cores (“core” corresponds to the compressed inner and outer phase) per hour, e.g. 35 to 105 g per kg of cores per h.
    • EXAMPLE 2 Tablet Formulation (400 mg Tablet)
  • Tablets of 400 mg of Compound I according to the invention and of the following tablet were prepared by wet granulation of a mixture of Compound I salt with (1.1), mixing with 3(1.1), (1.2), (1.3) and (1.4), compressing and coating the resultant tablets with an aqueous dispersion of the coating mixture (1.5).
  • Composition Per Dosage Form Unit and Quantity Per Batch
  • Composition Quantity
    Component per unit (mg) per batch (kg)
    Compound I mesylate 1 2478.000 167.300
    Microcrystalline cellulose 1 (1.1) 100.000 35.000
    Hypromellose/Hydroxypropyl (1.1) 10.000 3.500
    methylcellulose 1
    Microcrystalline cellulose 3(1.1) 39.400 13.790
    Crospovidone (1.2) 112.000 39.200
    Silica, colloidal anhydrous/ (1.3) 5.000 1.750
    Colloidal silicon dioxide
    Magnesium stearate (1.4) 5.600 1.960
    Basic coating premix yellow (1.5) 17.100 20.4254 5.985 8.5884
    Basic coating premix red (1.5) 0.900 1.0754 0.315 0.4524
    Total weight 768.000 771.500 268.800 =270.000
    Units/batch 350'000
    1 Components of the granulate,
    2478 mg Compound I mesylate equals 400 mg Compound I free base,
    3Microcrystalline cellulose is added in the outer phase as a dry binder,
    4a 20% manufacturing overage of the coating dispersion is included to cover spray losses during the coating process step.
  • The coating process may be performed at low temperature, e.g. ranging from around 35 to around 38° C. The coating process may be performed with a spray rate preferably in the range of 30 to 105 g of coating dispersion per kg of cores (“core” corresponds to the compressed inner and outer phase) per hour, e.g. 35 to 105 g per kg of cores per h.
    • EXAMPLE 3 Dimensions of the Tablets
  • Compound I free
    base/tablet Shape and Dimensions
    100 mg Round, 9.1-9.3 mm diameter, curved, bevelled edges,
    thickness: 2.8-3.4 mm break score on one side
    400 mg Ovaloid, 18.1-18.3 × 7.2-7.4 mm, curved, bevelled
    edges, thickness: 6.6-7.2 mm
  • Compound I free
    base/tablet Shape and Dimensions
    100 mg Round, 9.1-9.4 mm diameter, curved, bevelled edges,
    thickness: 2.8-3.4 mm break score on one side
    400 mg Ovaloid, 18.1-18.4 × 7.2-7.5 mm, curved, bevelled
    edges, thickness: 6.6-7.2 mm

Claims (11)

1. A small tablet comprising a pharmacologically effective amount of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide of formula (1) in the form of a monomesylate salt as the sole active drug:
Figure US20160101105A1-20160414-C00003
in an amount from 30% to 80% by weight of the active moiety based on the total weight of the small tablet; and at least one disintegrant, wherein the at least one disintegrant is cross-linked polyvinlypyrrolidinone, wherein the small tablet is either
a small ovaloid tablet that is 10 to 20 mm in length, 5 to 10 mm in width and 4 to 8 mm in thickness or
a small round tablet that is 5 to 15 mm in diameter and 2 to 5 mm in thickness
and wherein the pharmacologically effective amount of the sole active moiety 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide is from 50 mg to 600 mg.
2. A small tablet according to claim 1, wherein the sole active moiety is present in an amount from 50% to 80% of the active moiety by weight based on the weight of the small tablet.
3. A small tablet according to claim 1 wherein the 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide monomesylate salt is in the alpha crystalline form thereof.
4. A small tablet according to claim 1 wherein 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide monomesylate is in the beta crystalline form thereof.
5. A small tablet according to claim 1 further comprising at least one binder.
6. The small tablet according to claim 1 further comprising:
at least one binder in an amount of 1% to 25% in weight based on the total weight of the small tablet;
at least one glidant in an amount of 0.5% to 3% in weight based on the total weight of the small tablet; and wherein the small ovaloid tablet comprises 400 mg of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide and the small round tablet comprises 100 mg of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide.
7. A small tablet according to claim 6 wherein the binder is selected from: microcrystalline cellulose, hydroxypropylcellulose and mixtures thereof.
8. A small tablet according to claim 6 wherein the glidant is selected from: colloidal silicon dioxide, colloidal anhydrous silica and mixtures thereof.
9. A small tablet according to claim 6 wherein the lubricant is magnesium stearate.
10. A process for the preparation of a small tablet according to claim 5, which process comprises
(a) forming an inner phase comprising
(i) mixing the sole active drug 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide of formula (1)) in the form of monomesylate salt and at least one binder, wherein active moiety of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide is 30 to 80% on the total weight of the small tablet;
(ii) wet-granulating;
(b) forming an outer phase comprising
(iii) mixing with at least one disintegrant, wherein the at least one disintegrant is cross-linked polyvinlypyrrolidinone;
to form a mixture; and
(c) forming a tablet by
(iv) compressing the mixture obtained in step (iii).
11. The process of claim 10 further comprising coating the tablet formed in (iv) at a low temperature of between 30 and 40 degrees C.
US14/974,658 2002-04-23 2015-12-18 High drug load tablet Abandoned US20160101105A1 (en)

Priority Applications (1)

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Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
GB0209265A GB0209265D0 (en) 2002-04-23 2002-04-23 Organic compounds
GB0209265.8 2002-04-23
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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0209265D0 (en) 2002-04-23 2002-06-05 Novartis Ag Organic compounds
HUE028884T2 (en) 2004-02-11 2017-01-30 Natco Pharma Ltd Novel polymorphic form of imatinib mesylate and a process for its preparation
WO2006040779A2 (en) * 2004-10-11 2006-04-20 Natco Pharma Limited Controlled release gastric floating matrix formulation containing imatinib
ATE482693T1 (en) 2005-03-07 2010-10-15 Bayer Schering Pharma Ag PHARMACEUTICAL COMPOSITION CONTAINING AN OMEGA CARBOXYARYL SUBSTITUTED DIPHENYL UREA FOR THE TREATMENT OF CANCER
MY148074A (en) * 2005-05-10 2013-02-28 Novartis Ag Pharmaceutical compositions comprising imatinib and a release retardant
RU2398586C3 (en) 2005-05-26 2017-10-04 Сумитомо Дайниппон Фарма Ко., Лтд. PHARMACEUTICAL COMPOSITION
DE502006005084D1 (en) 2005-08-15 2009-11-26 Siegfried Generics Int Ag Film-coated tablet or granules containing a pyridylpyrimidine
US20090324718A1 (en) * 2006-09-01 2009-12-31 Ilan Zalit Imatinib compositions
JP5735742B2 (en) 2006-09-22 2015-06-17 ノバルティス アーゲー Methods for optimizing treatment of Philadelphia positive leukemia with ABL tyrosine kinase inhibitors
EP1920767A1 (en) 2006-11-09 2008-05-14 Abbott GmbH & Co. KG Melt-processed imatinib dosage form
US20090087489A1 (en) * 2007-09-25 2009-04-02 Bella Gerber Imatinib compositions
PL2217205T3 (en) 2007-11-06 2015-07-31 Novartis Ag Dual-acting pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (arb) and neutral endopeptidase (nep) inhibitor
TWI508728B (en) 2008-06-27 2015-11-21 Univ Indiana Res & Tech Corp Materials and methods for suppressing and/or treating neurofibroma and related tumors
WO2010065433A1 (en) 2008-12-01 2010-06-10 Novartis Ag Method of optimizing the treatment of philadelphia-positive leukemia with imatinib mesylate
PL389357A1 (en) 2009-10-22 2011-04-26 Tomasz Koźluk Tartaric acids derivatives imatinib salts and process for the preparation thereof
PL390611A1 (en) 2010-03-04 2011-09-12 Tomasz Koźluk Process for the preparation of polymorphic alpha form and new polymorphic form of imatinib mesylate
EP2582362A1 (en) * 2010-06-21 2013-04-24 Zaklady Farmaceutyczne "Polpharma" S.A. Pharmaceutical compositions comprising imatinib or pharmaceutically acceptable salt thereof and processes for the manufacture thereof
WO2011161689A1 (en) * 2010-06-21 2011-12-29 Suven Nishtaa Pharma Pvt Ltd Imatinib mesilate pharmaceutical tablet
EP2603288A1 (en) 2010-08-11 2013-06-19 Synthon BV Pharmaceutical granulate comprising imatinib mesylate
TR201010618A2 (en) 2010-12-20 2012-07-23 Bi̇lgi̇ç Mahmut An oral dosage form comprising imatinib and the manufacture of an oral dosage form
CN102552268A (en) * 2010-12-23 2012-07-11 天津泰普药品科技发展有限公司 Medicinal preparation containing crystal form a imatinib mesylate
PL394169A1 (en) 2011-03-09 2012-09-10 Adamed Spółka Z Ograniczoną Odpowiedzialnością The pharmaceutical composition of imatinib mesylate for filling unit dosage forms and the method for its preparation
US9750700B2 (en) 2011-06-22 2017-09-05 Natco Pharma Limited Imatinib mesylate oral pharmaceutical composition and process for preparation thereof
CN102349874B (en) * 2011-08-26 2013-04-17 石药集团中奇制药技术（石家庄）有限公司 Imatinib mesylate composition and preparation method thereof
CN102349875A (en) * 2011-10-11 2012-02-15 浙江华海药业股份有限公司 Preparation method of methylsulfonic acid imatinib tablet
JP2014532647A (en) 2011-10-28 2014-12-08 ノバルティス アーゲー How to treat gastrointestinal stromal tumors
WO2013063003A1 (en) 2011-10-28 2013-05-02 Novartis Ag Method of treating gastrointestinal stromal tumors
BR112014012400A2 (en) 2011-11-24 2017-06-13 Imuneks Farma Ilaç Sanayi Ve Ticaret A S reconstituted solid dosage forms of imatinib just prior to use
KR101428149B1 (en) * 2011-12-23 2014-08-08 씨제이헬스케어 주식회사 Granules containing imatinib mesylate, immediate-release tablet composition for oral use comprising said granules and method for preparing thereof
WO2013124774A1 (en) 2012-02-21 2013-08-29 Ranbaxy Laboratories Limited Stable dosage forms of imatinib mesylate
GB201204810D0 (en) 2012-03-20 2012-05-02 Pharos Pharmaceutical Oriented Services Ltd Pharmaceutical compositions
JP5928159B2 (en) * 2012-05-28 2016-06-01 ニプロ株式会社 Pharmaceutical composition
US20150202203A1 (en) 2012-07-11 2015-07-23 Novartis Ag Method of Treating Gastrointestinal Stromal Tumors
RU2517216C2 (en) * 2012-08-22 2014-05-27 Закрытое Акционерное Общество "БИОКАД" (ЗАО "БИОКАД") Pharmaceutical composition of imatinib or its pharmaceutically acceptable salt, method for preparing it and method(s) of treating
GB201304699D0 (en) 2013-03-15 2013-05-01 Remedica Ltd Pharmaceutical compositions
KR101520792B1 (en) * 2013-04-10 2015-05-15 보령제약 주식회사 High load imatinib tablet
ES2683361T3 (en) 2013-05-14 2018-09-26 Hetero Research Foundation Imatinib compositions
CN104749226A (en) * 2013-12-25 2015-07-01 辰欣药业股份有限公司 Method for determining imatinib mesylate content by potentiometric titration
WO2017078647A1 (en) 2015-11-05 2017-05-11 Koçak Farma Ilaç Ve Kimya Sanayi Anonim Şirketi Pharmaceutical compositions of imatinib
CA2937365C (en) 2016-03-29 2018-09-18 F. Hoffmann-La Roche Ag Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same
EP3257499A1 (en) 2016-06-17 2017-12-20 Vipharm S.A. Process for preparation of imatinib methanesulfonate capsules
WO2019016673A2 (en) 2017-07-20 2019-01-24 Kashiv Pharma Llc A stable oral pharmaceutical composition of imatinib
BR112022000571A2 (en) 2019-07-15 2022-03-15 Intas Pharmaceuticals Ltd Pharmaceutical composition and process for preparing a pharmaceutical composition comprising imatinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients in powder form
CN116528853A (en) * 2020-12-01 2023-08-01 株式会社Lg化学 Oral formulations comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and methods for their preparation
AR126164A1 (en) * 2021-06-17 2023-09-27 Lg Chemical Ltd COMPOUND FORMULATION FOR ORAL DOSAGE COMPRISING 1-(3-CYANO-1-ISOPROPYL-INDOL-5-IL)PYRAZOLE-4-CARBOXYLIC ACID

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3751277A (en) * 1971-03-24 1973-08-07 Dow Chemical Co Tablet coating process and composition
US4992278A (en) * 1987-01-14 1991-02-12 Ciba-Geigy Corporation Therapeutic system for sparingly soluble active ingredients
US6468563B1 (en) * 1997-12-18 2002-10-22 Lichter Pharma Ag Method and device for producing pharmaceutical formulations containing an extract
WO2003084543A1 (en) * 2002-04-10 2003-10-16 Virginia Commonwealth University Combination of glivec(sti571) with a cyclin-dependent kinase inhibitor, especially flavopiridol in the treatment of cancer

Family Cites Families (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH176497A (en) 1934-09-14 1935-04-15 Schmid Ernst Alarm device.
US3453368A (en) * 1966-01-13 1969-07-01 Hoffmann La Roche Smaller high potency compressed tablets of ascorbic acid
US4562024A (en) 1982-07-06 1985-12-31 Sterling Drug Inc. Process for preparing granulate containing poorly compressible medicinally active matter
US4639458A (en) 1985-01-22 1987-01-27 Merck & Co., Inc. Tablet and formulation
US4666705A (en) * 1985-06-03 1987-05-19 E. R. Squibb & Sons, Inc. Controlled release formulation
US4861598A (en) 1986-07-18 1989-08-29 Euroceltique, S.A. Controlled release bases for pharmaceuticals
JPS63267731A (en) * 1987-04-23 1988-11-04 Asahi Chem Ind Co Ltd tablet composition
WO1989000424A1 (en) 1987-07-22 1989-01-26 Leo Pharmaceutical Products B.V. Fusidic acid useful in the treatment of aids
YU120988A (en) 1988-06-23 1990-06-30 Lek Tovarna Farmacevtskih Process for preparing new dispersion pills of cimetidine
US5368864A (en) 1988-11-25 1994-11-29 Henning Berlin Gmbh Chemie- Und Pharmawerk Formulation of oxypurinol and/or its alkali and alkaline earth salts
US4911921A (en) 1989-02-02 1990-03-27 Mallinckrodt, Inc. High ibuprofen content granulations
DE4031881C2 (en) 1990-10-08 1994-02-24 Sanol Arznei Schwarz Gmbh Solvent-free, oral sustained-release pharmaceutical preparation and process for its preparation
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
TW225528B (en) * 1992-04-03 1994-06-21 Ciba Geigy Ag
IL109770A0 (en) 1993-05-29 1994-11-28 Smithkline Beecham Corp Thermal infusion process for preparing controlled release solid dosage forms of medicaments for oral administration and controlled release solid dosage forms of medicaments prepared thereby
US5635208A (en) 1993-07-20 1997-06-03 Mcneil-Ppc, Inc. Granulation process for producing an acetaminophen and diphenhydramine hydrochloride composition and composition produced by same
US5506248A (en) * 1993-08-02 1996-04-09 Bristol-Myers Squibb Company Pharmaceutical compositions having good dissolution properties
US5543520A (en) 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
DE69430921T2 (en) 1993-10-12 2003-02-13 Mitsubishi Pharma Corp., Osaka TABLET CONTAINING COLONIFULAR GRANULATES
US5605889A (en) 1994-04-29 1997-02-25 Pfizer Inc. Method of administering azithromycin
JP4334616B2 (en) * 1994-09-22 2009-09-30 ナームローゼ・フエンノートチヤツプ・オルガノン Method for producing a dosage unit by wet granulation
ES2079327B1 (en) 1994-12-13 1996-08-01 Lilly Sa PHARMACEUTICAL FORMULATIONS OF CEFACLOR.
US6106865A (en) 1995-01-09 2000-08-22 Edward Mendell Co., Inc. Pharmaceutical excipient having improved compressibility
GB9501127D0 (en) 1995-01-20 1995-03-08 Wellcome Found Tablet
US5994348A (en) 1995-06-07 1999-11-30 Sanofi Pharmaceutical compositions containing irbesartan
TW442301B (en) 1995-06-07 2001-06-23 Sanofi Synthelabo Pharmaceutical compositions containing irbesartan
US5805889A (en) * 1995-10-20 1998-09-08 Sun Microsystems, Inc. System and method for integrating editing and versioning in data repositories
US6123964A (en) 1995-10-27 2000-09-26 Merck & Co., Inc. Wet granulation formulation of a growth hormone secretagogue
EP0890359B1 (en) 1996-02-29 2002-05-02 Fujisawa Pharmaceutical Co., Ltd. Tablets containing beta-lactam antibiotic and process for producing the same
GB9613470D0 (en) 1996-06-27 1996-08-28 Ciba Geigy Ag Small solid oral dosage form
US20030124187A1 (en) * 1997-02-14 2003-07-03 Smithkline Beecham Laboratoires Pharmaceutiques, Pharmaceutical formulations comprising amoxycillin and clavulanate
JP3212531B2 (en) * 1997-03-21 2001-09-25 信越化学工業株式会社 Low-substituted hydroxypropylcellulose, low-substituted hydroxypropylcellulose disintegrant and production method thereof
CO4940418A1 (en) * 1997-07-18 2000-07-24 Novartis Ag MODIFICATION OF A CRYSTAL OF A DERIVATIVE OF N-PHENYL-2-PIRIMIDINAMINE, PROCESSES FOR ITS MANUFACTURE AND USE
FI109088B (en) 1997-09-19 2002-05-31 Leiras Oy Tablet and process for its preparation
PL340587A1 (en) 1997-11-17 2001-02-12 Smithkline Beecham Corp Oral preparations of high therapeutic substance content with instantaneous or modifiable release of such substance and methods of obtaining them
EP1058538B9 (en) 1998-03-06 2013-01-02 Aptalis Pharma S.r.l. Fast disintegrating tablets
UA72207C2 (en) 1998-04-07 2005-02-15 Брістол- Майєрс Сквібб Фарма Компані Pharmaceutical formulations of efavirenz and disintegrants providing for increasing dissolution rate and process of manufacturing such tablets or capsules
US20010014352A1 (en) 1998-05-27 2001-08-16 Udit Batra Compressed tablet formulation
CA2239931A1 (en) 1998-07-15 2000-01-15 Bernard Charles Sherman Pharmaceutical tablet comprising norfloxacin
US7041313B1 (en) * 1998-08-12 2006-05-09 Altana Pharma Ag Oral administration form for pyridin-2-ylmethylsulfinyl-1H-benzimidazoles
FR2785538B1 (en) 1998-11-06 2004-04-09 Prographarm Laboratoires PERFECTED QUICK DELIVERY TABLET
UA72483C2 (en) 1998-11-10 2005-03-15 Moxifloxacin-containing pharmaceutical preparation and method for its manufacture
US6498153B1 (en) * 1998-12-31 2002-12-24 Akzo Nobel N.V. Extended release growth promoting two component composition
IT1311907B1 (en) 1999-04-06 2002-03-20 Zambon Spa DEGLUTABLE TABLETS WITH HIGH CONTENT OF N-ACETYLCISTEIN.
DK1200090T3 (en) 1999-08-03 2013-11-25 Icos Corp Pharmaceutical formulation comprising a beta-carboline and its use in the treatment of sexual dysfunction
US6294198B1 (en) * 1999-08-24 2001-09-25 Purepac Pharmaceutical Co. Pharmaceutical tablet formulation containing gabapentin with improved physical and chemical characteristics and method of making the same
US6264983B1 (en) 1999-09-16 2001-07-24 Rhodia, Inc. Directly compressible, ultra fine acetaminophen compositions and process for producing same
US6582721B1 (en) 1999-09-17 2003-06-24 Alcon, Inc. Stable carotene-xanthophyll beadlet compositions and methods of use
JP2001139462A (en) 1999-11-10 2001-05-22 Dai Ichi Seiyaku Co Ltd New preparation
BR0008059A (en) * 1999-12-08 2002-03-26 Pharmacia Corp Compositions of valdecoxib
US8124124B2 (en) 1999-12-09 2012-02-28 Reckitt Benckiser Healthcare (Uk) Limited Compressed tablet formulation comprising non-steroidal anti-inflammatory drugs and methods
ITMI992711A1 (en) * 1999-12-27 2001-06-27 Novartis Ag ORGANIC COMPOUNDS
DE10003757A1 (en) * 2000-01-28 2001-08-02 Knoll Ag Ibuprofen drug preparation
CA2400950A1 (en) 2000-03-03 2001-09-07 Ranbaxy Laboratories Limited Orally administered controlled delivery system for once daily administration of ciprofloxacin
PT1265608E (en) 2000-03-22 2008-12-15 Pharmacia & Upjohn Co Llc Oxazolidinone tablet formulation
DE10015479A1 (en) 2000-03-29 2001-10-11 Basf Ag Solid oral dosage forms with delayed release of active ingredient and high mechanical stability
PL365696A1 (en) 2000-04-12 2005-01-10 Novartis Ag Combination of organic compounds
AU8576801A (en) 2000-06-22 2002-01-02 Novartis Ag Pharmaceutical compositions
JP4698000B2 (en) 2000-06-27 2011-06-08 旭化成ケミカルズ株式会社 Easily water-soluble drug-containing tablets
JP4121372B2 (en) 2001-02-27 2008-07-23 千寿製薬株式会社 Biodegradable polymer-type drug release system
GB0209265D0 (en) 2002-04-23 2002-06-05 Novartis Ag Organic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3751277A (en) * 1971-03-24 1973-08-07 Dow Chemical Co Tablet coating process and composition
US4992278A (en) * 1987-01-14 1991-02-12 Ciba-Geigy Corporation Therapeutic system for sparingly soluble active ingredients
US6468563B1 (en) * 1997-12-18 2002-10-22 Lichter Pharma Ag Method and device for producing pharmaceutical formulations containing an extract
WO2003084543A1 (en) * 2002-04-10 2003-10-16 Virginia Commonwealth University Combination of glivec(sti571) with a cyclin-dependent kinase inhibitor, especially flavopiridol in the treatment of cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Gordon et al. Journal of Pharmaceutical Sciences 1993 82(2):220-226 *

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