WO2009080762A2 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- WO2009080762A2 WO2009080762A2 PCT/EP2008/068051 EP2008068051W WO2009080762A2 WO 2009080762 A2 WO2009080762 A2 WO 2009080762A2 EP 2008068051 W EP2008068051 W EP 2008068051W WO 2009080762 A2 WO2009080762 A2 WO 2009080762A2
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- weight
- lubricant
- tablet
- quinazolin
- piperazin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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Definitions
- the present invention relates to novel pharmaceutical compositions comprising 3-(lW.-indol- 3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione or a pharmaceutically acceptable salt thereof, process for their production and use of the pharmaceutical compositions.
- 3-(lH.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione is water sensitive and poorly water soluble.
- water sensitive drug is meant an active agent which is highly soluble in water and in ethanol with a high powder-liquid ratio, e.g. a ratio of 10mg/ml, and which may convert either to a free base hydrate, a solvate or an amorphous form in the presence of ethanol and/or water.
- compositions comprising 3-(l/-/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione are described in WO2006/092255, the content of which being incorporated herein by reference.
- WO2006/092255 describes a tablet containing the acetate salt of 3-(lH.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4- yl]-pyrrole-2,5-dione.
- Coating may be necessary for example to improve the aesthetic aspect of the tablet or permit to differentiate the available dosage strengths. Coating may also improve patient convenience and acceptance.
- a tablet must have certain physical characteristics, such as hardness and low friability.
- suitable tablets comprising 3-(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole- 2,5-dione, or a pharmaceutically acceptable salt thereof, which are particularly stable, hard and convenient to administer are obtainable when the tablets comprise at least 2% by weight of lubricant, based on the total weight of the tablet core.
- the amount of lubricant contained in a tablet is comprised between 0.5 and 1.5% by weight, based on the total weight of the tablet core.
- the present invention provides an improved tablet comprising 3-(l/-/.-indol-3- yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione, or a pharmaceutically acceptable salt thereof, which is suitable to achieve high drug loads, and thus improve patient compliance.
- the tablet according to the present invention may show a high level of uniformity in the distribution of the drug as well as high stability.
- a tablet comprising from about 5 to about 90%, from about 10 to about 85%, from about 15 to about 80%, from about 20 to about 70%, from about 20 to about 55%, from about 25 to about 52%, from about 35 to about 52% by weight of 3-(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione or a pharmaceutically acceptable salt thereof, based on the total tablet core weight.
- One or more pharmaceutically acceptable carriers or diluents may be present in the tablet, e.g. at least one lubricant, at least one binder, at least one filler; and optionally at least one additional excipient selected from a disintegrant, a glidant; and a surfactant.
- Lubricants according to the invention include e.g. Mg-, Al- or Ca-stearate, PEG 4000-8000, talc, sodium benzoate, glyceryl mono fatty acid, e. g. having a molecular weight of from 200 to 800 Daltons, e. g. glyceryl monostearate (e. g. Danisco, UK), glyceryl dibehenate (e. g. COMPRITOLATTM 0888, Gattefosse France), glyceryl palmito-stearic ester (e. g.
- PRECIROLTM Gattefosse France
- polyoxyethylene glycol PEG, BASF
- hydrogenated cotton seed oil Lubitrab, Edward Mendell Co Inc
- castor seed oil Cutina HR, Henkel
- vinylpyrrolidone-vinyl acetate copolymer e.g. Kollidon
- magnesium stearate is used, either alone or in combination with another lubricant
- composition of the invention contains from 2 to 15, preferably 2 5 to 12 %, more preferably 3 to 10% by weight of a lubricant, based on the total weight of the composition, the total weight of the composition being the total tablet core weight
- the tablet of the invention comprises at least 2% by weight of lubricant, e g at least 2 5% by weight, e g at least 3% by weight, based on the total weight of the tablet core
- a particularly suitable tablet contains as lubricant from 2 to 15, e g 2 5 to 12, e g 3 to 10% by weight of magnesium stearate, based on the total weight of the tablet core
- lubricant is present in an amount of 3-5% by total weight of the tablet core, yet more preferably 3-4%
- Binders according to the invention include starches, e g potato, wheat or corn starch, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, e g hydroxypropylmethyl cellulose-Type 2910 USP, hypromellose, polyvinylpyrrolidone (e g POVIDONE K30), and Copovidone
- hydroxypropylmethyl cellulose, polyvinylpyrrolidone 30 or Copovidone is used
- composition of the invention may contain from 4 to 40% by weight, preferably from 4 to 35%, more preferably 5 to 30, even more preferably 5 to 20% by weight, of a binder based on the total weight of the tablet core
- a particularly suitable tablet according to the invention contains as binder (a) from 5 to 20% by weight of copovidone
- Fillers according to the invention include e g lactose, especially lactose monohydrate, preferably lactose monohydrate (200mesh) or lactose spray dried, microcrystalline cellulose, e g PH 102, PH 101 , microcrystalline silicified cellulose, starch, calcium phosphate, or a saccharide, e g manmtol, maltodextrin or maltose, or a mixture thereof
- lactose spray dried, microcrystalline cellulose or microcrystalline silicified cellulose more preferably lactose spray dried and microcrystalline cellulose or lactose spray dried and microcrystalline silicified cellulose is used
- the composition of the invention preferably contains from 15 to 65%, preferably 35 to 65% by weight of a filler, based on the total weight of the composition, the total weight of the tablet core
- a particularly suitable solid pharmaceutical composition contains as filler (a) from 15 to 35, e.g. from 18 to 30 %by weight of lactose, e.g. lactose spray dried, and from 10 to 35%, e.g. from 15 to 30 % by weight of microcrystalline cellulose, based on the total weight of the tablet core.
- Disintegrants according to the invention include e.g. natural starches, such as maize starch, potato starch, and the like; directly compressible starches, e. g. Sta-RX 1500; partially pregelatinized starch; modified starches, e. g. carboxymethyl starches and sodium starch glycolate; starch derivatives such as amylase, crosslinked polyvinylpyrrolidones, e. g. crospovidones, e. g. Polyplasdone R XL or Kollidon R CL, alginic acid or sodium alginate, methacrylic acid divinylbenzene copolymer salts, e. g.
- natural starches such as maize starch, potato starch, and the like
- directly compressible starches e. g. Sta-RX 1500
- partially pregelatinized starch e. g. carboxymethyl starches and sodium starch glycolate
- starch derivatives such as amylase, crosslinked polyvin
- AMBERLITE 9 IRP-88, or cross- linked sodium carboxymethylcellulose, available as e. g. AC-DI-SOL; COMMAT; PRIMELLOSEF, PHARMACEL, EXPLOCEL, or NYMCEL ZSX.
- a directly compressible starch such as Sta-RX 1500, or a cross-linked polyvinylpyrrolidone, such as crospovidone, is used.
- composition of the invention preferably contains from 3 to 20% by weight, e.g. 5 to 15% by weight of a disintegrant, based on the total tablet core weight.
- a particularly suitable tablet contains as disintegrant from 3 to 20% by weight, e.g. 5 to 15% by weight of a directly compressible starch or a starch derivative, based on the total weight of core weight.
- the tablet may contain from 3 to 20%, e.g. from 3 to 10%, by weight of partially pregelatinized starch, based on the total weight of core weight.
- the tablet of the invention may contain from 0 to 3% of a surfactant based on the total weight of the tablet core.
- surfactants according to the invention include e.g. an anionic, cationic or non-ionic surfactant or a mixture thereof, e.g. sodium lauryl sulfate, cetrimide, a polysorbate or a sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleic, stearic or palmitic acid.
- Glidants according to the invention include e.g. silica, colloidal silica, e. g. colloidal silicon dioxide, e. g. AEROSIL 200, magnesium trisilicate, powdered cellulose, starch and talc.
- colloidal silicon dioxide is used.
- the tablet of the invention preferably contains from 0.5 to 1 % by weight of a glidant, based on the total weight of the tablet core.
- a particularly suitable tablet contains as glidant from 0.5 to 1 % by weight of colloidal silicone dioxide, based on the total tablet core weight.
- the tablet may optionally be coated, for instance with a coating comprising, a polysaccharide, e. g. cellulose, hydroxypropyl-methylcellulose, e.g. HMPC 603, polyoxyethylene glycol, e.g. PEG 6000 or PEG 8000, one or more dyers, carnauba wax, or an aluminium lake.
- a polysaccharide e. g. cellulose, hydroxypropyl-methylcellulose, e.g. HMPC 603
- polyoxyethylene glycol e.g. PEG 6000 or PEG 8000
- dyers e.g. PEG 6000 or PEG 8000
- carnauba wax e.g. auba wax
- aluminium lake e.g. a coating comprising, a polysaccharide, e. g. cellulose, hydroxypropyl-methylcellulose, e.g. HMPC 603, polyoxyethylene glycol, e.g. PEG 6000 or
- 3-(lH.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]- pyrrole-2,5-dione is preferably in form of the acetate salt.
- the tablet of the invention show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics may be determined, e. g. by measuring decomposition products by HPLC analysis after storage for particular time periods, at various temperatures, e. g. 25°, 40° or 60 0 C.
- the tablet of the present invention may be produced by standard processes, for instance by conventional mixing, compacting, granulating, compression, or coating with or without sugar. Procedures which may be used are known in the art, 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 pharmazeutica für für Fine Science, 13th Ed. (Mack Publ., Co. , 1970) or later editions.
- the present invention relates to a process for producing the tablet of the invention, comprising: (a) mixing 3-(l/-/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1 -yl)-quinazolin- 4-yl]-pyrrole-2,5-dione or a pharmaceutically acceptable salt thereof, e.g.
- the tablet of the invention can be prepared by dry compression.
- This method involves the dry treatment of the drug substance, in which the drug is mixed with a part of the excipients, compressed either directly there or after screening and mixing with other suitable excipients.
- the process may be carried out by dry mixing the components.
- the milling step (b) may suitably comprise passing the mixture obtained in (a) through a screen, which preferably has a mesh size of 900 to 1000 ⁇ m.
- the lubricant e. g. magnesium stearate
- the lubricant is preferably pre-screened, e. g. with a 800 to 900 ⁇ m screen, before mixing.
- a wet granulation e.g. aqueous granulation process
- Wet granulation has the advantage of providing an homogeneous material , i.e. granulates having a quite uniform particle size. Obtaining such an uniform material permits to obtain tablets with limited weight variation and uniform content.
- the compound 3-(lH.-indol-3-yl)-4-[2-(4- methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione show high degradation in water, which renders aqueous granulation difficult.
- the filler, binder, and optionally the disintegrant are granulated together using an aqueous solution, e.g. an aqueous solution of the binder, in a high shear mixture.
- the granulates thus obtained are dried, milled and then mixed with a lubricant.
- the tablet of the invention may be used for the treatment or prevention of the diseases for which the active agent it contains, is useful.
- the tablet of the invention may be used in the treatment and/or prevention of diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue ado- or xenografts, atherosclerosis, vascular occlusion due to vacular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g.
- 3-(lH.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione is also useful in the treatment and/or prevention of T-cell mediated acute or chronic inflammatory diseases or disorders or autoimmune diseases, e.g.
- rheumatoid arthritis osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or Il and the disorders associated therewith, respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.
- respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated
- the required dosage will of course vary depending on the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.1 to about 100 mg/kg body weight.
- An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day.
- the tablet of the invention may be administered in conjunction with a co-agent depending on the diseases or disorders to be treated .
- a co-agent depending on the diseases or disorders to be treated .
- it may be administered in conjunction, either simultaneously or in sequence, with other drugs in immunomodulating regimens or other anti-inflammatory agents e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders.
- it may be used in combination with cyclosporines, or ascomycines or their immunosuppressive analogs or derivatives, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281 , ASM 981 ; an mTOR inhibitor, e.g.
- rapamycin 40-O-(2-hydroxy-ethyl)-rapamycin, CCI779, ABT578, biolimus-7, biolimus-9, TAFA-93, AP23573, AP23464 or AP23841 etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; a S1 P receptor modulator, e.g.
- immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC 1 CD2, CD3, CD4, CD 1 1a/CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (
- a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including LFA-1 antagonists, Selectin antagonists and VLA-4 antagonists.
- the tablet of the invention may also be administered in conjunction with, e.g. simultaneously or in sequence, an antiproliferative drug, e.g.
- chemotherapeutic drug e.g. in cancer treatment, or with an anti-diabetic drug in diabetes therapy.
- Dosages of the co-administered immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic agent may vary depending on the type of the co-agent used, on the specific drug employed, on the condition being treated and so forth.
- the present invention further provides:
- a method for preventing or treating disorders or diseases mediated by T lymphocytes and/or PKC, e.g. such as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a tablet as defined above.
- a method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a tablet as defined above.
- a method for preventing or treating disorders or diseases mediated by T lymphocytes and/or PKC, e.g. such as indicated above, in a subject in need of such treatment comprises co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a tablet containing 3-(lH.-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione, as defined above, and a second drug substance, said second drug substance being an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug, e.g. as indicated above.
- a therapeutic combination e.g. a kit, comprising a) a tablet containing 3-(f.H.-indol-3- yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yI]-pyrrole-2,5-dione, as defined above, and b) at least one second agent selected from an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative and anti-diabetic drug.
- Component a) and component b) may be used concomitantly or in sequence.
- the kit may comprise instructions for its administration.
- Example 1 dry compression followed by coating
- the drug substance is mixed with the diluent, binder, disintegrant, glidant (positions 1-6) and mixed in a free fall mixer. This premix is mixed again with the lubricant (Pos 7) and compressed directly into tablets of different strengths.
- Example 1a dry compression followed by coating
- the drug substance is mixed with the diluent, binder, disintegrant, glidant (positions 1-6) and mixed in a free fall mixer. This premix is mixed again with the lubricant (Pos 7) and compressed directly into tablets of different strengths. Examples of three compositions obtainable via this method are shown in Table 1a.
- Example 2 dry compression followed by coating.
- the drug substance is mixed with the diluent, binder, disintegrant, glidant (positions 1-5), mixed together with the lubricant (Position 6), is compressed at first stage into a tablet or into a ribbon, which is screened through a suitable sieve to give a granulation. This granulation is mixed again with another part of diluent, binder, disintegrant and glidant (Pos 7-10) and compressed into tablets after adding a suitable lubricant to the mixture.
- the excipients are granulated together using a solution of the binder in purified water (position 3) in a high shear mixture.
- the granulate is dried, screened and mixed with lubricant (position 5).
- the drug substance (Pos 6) along with excipients (7, 8, 9,10) are added, mixed together, mixed again with the rest of the lubricant (1 1 ) and compressed into tablets. These tablets are then coated with a non-functional coating agent.
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Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ586313A NZ586313A (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition comprising 3-(1.h.-indol-3-yl)-4-[2-(4-methyle-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione and a lubricant |
CA2709909A CA2709909A1 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
JP2010538767A JP5525453B2 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
RU2010129544/15A RU2485951C2 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
BRPI0820839-5A BRPI0820839A2 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical Composition |
EP08865096A EP2240164A2 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
US12/808,905 US20100316713A1 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
CN2008801190561A CN101883558A (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
AU2008340019A AU2008340019B2 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
IL205931A IL205931A0 (en) | 2007-12-21 | 2010-05-24 | Pharmaceutical composition |
TN2010000243A TN2010000243A1 (en) | 2007-12-21 | 2010-05-28 | Pharmaceutical composition |
MA32969A MA31950B1 (en) | 2007-12-21 | 2010-06-29 | PHARMACEUTICAL COMPOSITION |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07150347 | 2007-12-21 | ||
EP07150347.8 | 2007-12-21 |
Publications (2)
Publication Number | Publication Date |
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WO2009080762A2 true WO2009080762A2 (en) | 2009-07-02 |
WO2009080762A3 WO2009080762A3 (en) | 2009-09-11 |
Family
ID=39495348
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2008/068051 WO2009080762A2 (en) | 2007-12-21 | 2008-12-19 | Pharmaceutical composition |
Country Status (21)
Country | Link |
---|---|
US (1) | US20100316713A1 (en) |
EP (1) | EP2240164A2 (en) |
JP (2) | JP5525453B2 (en) |
KR (1) | KR20100103625A (en) |
CN (1) | CN101883558A (en) |
AR (1) | AR069799A1 (en) |
AU (1) | AU2008340019B2 (en) |
BR (1) | BRPI0820839A2 (en) |
CA (1) | CA2709909A1 (en) |
CL (1) | CL2008003823A1 (en) |
CO (1) | CO6382170A2 (en) |
EC (1) | ECSP10010360A (en) |
IL (1) | IL205931A0 (en) |
MA (1) | MA31950B1 (en) |
MY (1) | MY158293A (en) |
NZ (1) | NZ586313A (en) |
PE (1) | PE20091522A1 (en) |
RU (1) | RU2485951C2 (en) |
TN (1) | TN2010000243A1 (en) |
TW (1) | TWI449541B (en) |
WO (1) | WO2009080762A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20091522A1 (en) * | 2007-12-21 | 2009-10-29 | Novartis Ag | SOLID PHARMACEUTICAL COMPOSITION CONTAINING 3- (1.H-INDOL-3-IL) -4- [2- (4-METHYL-PIPERAZIN-1-IL) -QUINAZOLIN-4-IL] -QUINAZOLIN-4-IL] - PIRROL-2,5-DIONA |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003082859A1 (en) * | 2002-04-03 | 2003-10-09 | Novartis Ag | Indolylmaleimide derivatives |
WO2006092255A1 (en) * | 2005-03-01 | 2006-09-08 | Novartis Ag | Pharmaceutical composition comprising an indolylmaleimide derivative |
Family Cites Families (5)
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HU226821B1 (en) * | 1995-11-20 | 2009-11-30 | Lilly Co Eli | The mesylate salt of a macrocyclic bis-indolyl-maleimide derivative, process for its preparation, use thereof and pharmaceutical compositions containing the same |
AU2006252553B2 (en) * | 2005-06-02 | 2012-03-29 | Merck Sharp & Dohme Corp. | Combination of HCV protease inhibitors with a surfactant |
KR20080039876A (en) * | 2005-07-22 | 2008-05-07 | 미리어드 제네틱스, 인크. | High drug load formulations and dosage forms |
US7762932B2 (en) * | 2007-09-17 | 2010-07-27 | Fitness Anywhere, Inc. | Inelastic exercise device having a limited range |
PE20091522A1 (en) * | 2007-12-21 | 2009-10-29 | Novartis Ag | SOLID PHARMACEUTICAL COMPOSITION CONTAINING 3- (1.H-INDOL-3-IL) -4- [2- (4-METHYL-PIPERAZIN-1-IL) -QUINAZOLIN-4-IL] -QUINAZOLIN-4-IL] - PIRROL-2,5-DIONA |
-
2008
- 2008-12-18 PE PE2008002124A patent/PE20091522A1/en not_active Application Discontinuation
- 2008-12-18 AR ARP080105520A patent/AR069799A1/en unknown
- 2008-12-19 NZ NZ586313A patent/NZ586313A/en not_active IP Right Cessation
- 2008-12-19 JP JP2010538767A patent/JP5525453B2/en not_active Expired - Fee Related
- 2008-12-19 MY MYPI2010002374A patent/MY158293A/en unknown
- 2008-12-19 TW TW097149851A patent/TWI449541B/en not_active IP Right Cessation
- 2008-12-19 CA CA2709909A patent/CA2709909A1/en not_active Abandoned
- 2008-12-19 US US12/808,905 patent/US20100316713A1/en not_active Abandoned
- 2008-12-19 KR KR1020107016148A patent/KR20100103625A/en not_active Application Discontinuation
- 2008-12-19 RU RU2010129544/15A patent/RU2485951C2/en not_active IP Right Cessation
- 2008-12-19 EP EP08865096A patent/EP2240164A2/en not_active Withdrawn
- 2008-12-19 WO PCT/EP2008/068051 patent/WO2009080762A2/en active Application Filing
- 2008-12-19 CN CN2008801190561A patent/CN101883558A/en active Pending
- 2008-12-19 CL CL2008003823A patent/CL2008003823A1/en unknown
- 2008-12-19 AU AU2008340019A patent/AU2008340019B2/en not_active Ceased
- 2008-12-19 BR BRPI0820839-5A patent/BRPI0820839A2/en not_active IP Right Cessation
-
2010
- 2010-05-24 IL IL205931A patent/IL205931A0/en unknown
- 2010-05-28 TN TN2010000243A patent/TN2010000243A1/en unknown
- 2010-06-29 MA MA32969A patent/MA31950B1/en unknown
- 2010-07-20 EC EC2010010360A patent/ECSP10010360A/en unknown
- 2010-07-21 CO CO10088697A patent/CO6382170A2/en not_active Application Discontinuation
-
2013
- 2013-11-15 JP JP2013236787A patent/JP2014040477A/en active Pending
Patent Citations (2)
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WO2003082859A1 (en) * | 2002-04-03 | 2003-10-09 | Novartis Ag | Indolylmaleimide derivatives |
WO2006092255A1 (en) * | 2005-03-01 | 2006-09-08 | Novartis Ag | Pharmaceutical composition comprising an indolylmaleimide derivative |
Non-Patent Citations (1)
Title |
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DAVIS P D ET AL: "INHIBITORS OF PROTEIN KINASE C 1. 2,3-BISARYLMALEIMIDES" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 35, no. 1, 1 January 1992 (1992-01-01), pages 177-184, XP000910195 ISSN: 0022-2623 * |
Also Published As
Publication number | Publication date |
---|---|
WO2009080762A3 (en) | 2009-09-11 |
CN101883558A (en) | 2010-11-10 |
AR069799A1 (en) | 2010-02-17 |
ECSP10010360A (en) | 2010-08-31 |
CO6382170A2 (en) | 2012-02-15 |
AU2008340019A1 (en) | 2009-07-02 |
EP2240164A2 (en) | 2010-10-20 |
JP2014040477A (en) | 2014-03-06 |
BRPI0820839A2 (en) | 2015-06-16 |
PE20091522A1 (en) | 2009-10-29 |
KR20100103625A (en) | 2010-09-27 |
TW200940106A (en) | 2009-10-01 |
NZ586313A (en) | 2012-08-31 |
CL2008003823A1 (en) | 2010-01-22 |
CA2709909A1 (en) | 2009-07-02 |
AU2008340019B2 (en) | 2012-05-03 |
MA31950B1 (en) | 2010-12-01 |
MY158293A (en) | 2016-09-30 |
RU2485951C2 (en) | 2013-06-27 |
IL205931A0 (en) | 2010-11-30 |
TWI449541B (en) | 2014-08-21 |
JP2011506576A (en) | 2011-03-03 |
TN2010000243A1 (en) | 2011-11-11 |
US20100316713A1 (en) | 2010-12-16 |
JP5525453B2 (en) | 2014-06-18 |
RU2010129544A (en) | 2012-01-27 |
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