EP1888072A1 - Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)[4-(4-pyridylmethyl)phthalazin-1-yl]and salts thereof - Google Patents
Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)[4-(4-pyridylmethyl)phthalazin-1-yl]and salts thereofInfo
- Publication number
- EP1888072A1 EP1888072A1 EP06762010A EP06762010A EP1888072A1 EP 1888072 A1 EP1888072 A1 EP 1888072A1 EP 06762010 A EP06762010 A EP 06762010A EP 06762010 A EP06762010 A EP 06762010A EP 1888072 A1 EP1888072 A1 EP 1888072A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pyridylmethyl
- weight
- range
- formulation
- phthalazin
- 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.)
- Withdrawn
Links
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- 239000012729 immediate-release (IR) formulation Substances 0.000 title abstract description 13
- -1 (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-1-yl] Chemical class 0.000 claims abstract description 64
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- 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
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- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to immediate-release and high-drug-load solid pharmaceutical formulations comprising (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin- 1-yl] as well as pharmaceutically acceptable salts thereof.
- vascular systems Two processes, namely the de novo formation of vessels from differentiating endothelial cells or angioblasts in the developing embryo (vasculogenesis) and the growth of new capillary vessels from existing blood vessels (angiogenesis), are involved in the development of the vascular systems of animal organs and tissues.
- Transient phases of new vessel formation also occur in the adult body, for example during the menstrual cycle, during pregnancy or during wound healing.
- angiogenesis a number of diseases are known to be associated with deregulated angiogenesis, for example retinopathies, psoriasis, haemangioblastoma, haemangioma, and neoplastic diseases (solid tumours).
- retinopathies for example retinopathies, psoriasis, haemangioblastoma, haemangioma, and neoplastic diseases (solid tumours).
- vasculogenesis and angiogenesis have been found to involve a whole range of molecules, especially angiogenic growth factors and their endothelial receptors, as well as cell adhesion molecules.
- VEGF Vascular Endothelial Growth Factor
- VEGF is a dimeric, disulfide-linked 46 kDa glycoprotein and is structurally related to "Platelet-Derived Growth Factor” (PDGF). It is produced by normal cell lines and tumour cell lines.
- PDGF Platinum-Derived Growth Factor
- VEGF is an endothelial cell-specific mitogen and shows angiogenic activity in in vivo test systems (e.g. rabbit cornea).
- VEGF is chemotactic for endothelial cells and monocytes, and induces plasminogen activators in endothelial cells, which are then involved in the proteolytic degradation of the extracellular matrix during formation of capillaries.
- VEGF-A A number of splice variants of VEGF-A are known which show comparable biological activity, but which differ in the type of cells that secrete them and in their heparin-binding capacity.
- PLGF Percental Growth Factor
- VEGF-B vascular endothelial growth factor-B
- VEGF-C vascular endothelial growth factor-D
- tumours especially gliomas and carcinomas
- VEGF variants and their receptors express high levels of the VEGF variants and their receptors. This has led to the hypothesis that the VEGF released by tumour cells could stimulate the growth of blood capillaries and the proliferation of tumour endothelium in a paracrine manner and thus, through the improved blood supply, accelerates tumour growth. Increased VEGF expression could explain the occurrence of cerebral oedema in patients with glioma. Direct evidence of the role of VEGF as a tumour angiogenesis factor in vivo has been obtained from studies in which VEGF expression or VEGF activity was inhibited.
- VEGFR receptors There are three VEGFR receptors with different affinities to the ligands.
- VEGF-A binds to VEGFRl and VEGFR2;
- VEGF-B and Placental Growth Factor bind to VEGFRl;
- VEGF-A and processed forms of VEGF-C and VEGF-D bind to VEGFR-2;
- VEGF-C and VEGF-D bind to VEGFR-3.
- VEGFR-3 is especially important for the growth of lymphatic vessels which play a role in tumour and metastases formation. Also in another diseases state, asthma, the lymphatic tissue is of major importance as it does remain in the alveoli after an acute inflammation and does not resolve like the blood vessels. This leads to the continuing susceptibility to stimulation by foreign agents.
- the signal of the VEGF variants is transmitted via the dimerisation of two receptor molecules inducing thereby an activation of the enzymatic activity at the intracellular C-terminal end.
- the enzymatic activity is a signal kinase, which transfers phosphates from ATP to itself (autophosphorylation) and to downstream signal molecules. This allows for interaction with an entire intracellular signal cascade eventually leading to endothelial cell proliferation and migration. The macroscopic result is the formation of new vessels.
- WO 98/35958 describes generically a series of phthalazine derivatives with angiogenesis inhibiting activity and specifically (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], including salts thereof, in particular the succinic acid salt thereof, as an interesting candidate for treatment of tumours.
- This compound is an inhibitor of all three VEGFR kinases. The inhibition is not dependent on a specific ligand, but blocks all the signals.
- the drug substance Since the drug substance is absorbed in the small intestine, where the pH is usually above 5, it is of utmost importance that essentially all of the drug substance is dissolved before entering the small intestine, i.e. essentially all of the drug substance should be dissolved in the gastric juice. Evidently, in order to obtain satisfactory absorption of the drug substance, the drug substance must be administered in an immediate-release formulation.
- micronization has been used for the purpose of ensuring adequate release of a drug substance.
- a number of well-known manufacturing problems such as agglomeration of the micronized particles, adherence of the micronized particles to production equipment, etc., may arise for the micronized drug substance.
- pynasunate is classified as being hazardous with an internal workspace limit of 0.1 mg/m 3 , i.e. handling of the drug substance must be under contained conditions and the use of e.g. high shear mixing granulation implies many product transfers and non-contained handlings of the drug substance.
- a formulation as described herein can be prepared with a robust prodcution process and which has a high load of non-micronized drug substance, an immediate-release profile and which contains a minimum of pharmaceutical excipients.
- the object of the present invention is to provide a high-load solid pharmaceutical formulation of non-micronized (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or pharmaceutically acceptable salts thereof, which exhibits a reproducible immediate-release of the drug substance.
- the present invention relates to a solid pharmaceutical formulation
- a solid pharmaceutical formulation comprising at least 50% by weight of the total formulation of non-micronized (4- chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, wherein at least 70% of said (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l- yl], or a pharmaceutical acceptable salt thereof, is dissolved from said solid pharmaceutical formulation within 30 minutes as determined by the USP 28 Paddle Method using 0.05 M KH 2 PCVHCI buffer adjusted to pH 3.0 at 37°C as the dissolution media and 50 rpm as the stirring rate.
- the present invention relates to a solid dosage form, in particular a solid unit dosage form, comprising the solid pharmaceutical formulation of the invention.
- the present invention relates to a composition of non-micronized particles of (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, having a d 90 value in the range of 50-300 ⁇ m and a d 50 value in the range of 15-100 ⁇ m, when determined as described herein.
- the present invention relates to the formulation of the invention, the dosage form of the invention, or the composition of the invention, for use as a medicament.
- the present invention relates to the use of the formulation of the invention, the dosage form of the invention, or the composition of the invention, for the manufacture of a medicament for the treatment of cancer.
- the present invention relates to a method of treating cancer, said method comprising administering a therapeutically effective amount of the formulation of the invention, the dosage form of the invention, or composition of the invention, to a patient in need thereof.
- Fig. 1 shows a particle size volume distribution of pynasunate prepared according to Example 1.
- Fig. 2 shows a particle size volume distribution of pynasunate prepared according to Example 2.
- Fig. 3 shows a particle size volume distribution of pynasunate prepared according to Example 3.
- Fig. 4 shows a particle size volume distribution of pynasunate prepared according to Example 4.
- Fig. 5 shows the relationship between compression force and hardness of the tablets prepared in Example 6.
- the present invention provides an immediate-release and high-load solid pharmaceutical formulation comprising the drug substance (4-chlorophenyl)[4-(4- pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, in non- micronized form.
- Solid pharmaceutical formulation comprising the drug substance (4-chlorophenyl)[4-(4- pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, in non- micronized form.
- non-micronized is intended to mean that the particle size distribution is so that at least 90% of the particles have a particle diameter of more than 50 ⁇ m (calculated from the volume distribution curve under the presumption of spherical particles using laser diffraction methods), i.e. a d 90 value of at least 50 ⁇ m. It is well- known to the skilled person that parameters used to describe a given particle size distribution may vary considerably dependent on the specific equipment and settings used. Therefore, it is important to note that whenever the terms “particle size distribution”, “particle diameter”, "d 50 “, “d 90 “, “d 95 “, “d 99 “, etc.
- the d 90 value of (4-chlorophenyl)[4-(4-pyridylmethyl)- phthalazin-1-yl], or a pharmaceutically acceptable salt thereof is at least 60 ⁇ m, such as at least 70 ⁇ m, e.g. at least 80 ⁇ m, or at least 90 ⁇ m.
- the d 90 value is at least 100 ⁇ m, such as at least 110 ⁇ m, e.g. at least 120 ⁇ m, more preferably at least 130 ⁇ m, such as at least 140 ⁇ m.
- the d 50 value of (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof should preferably be at least 15 ⁇ m, in particular at least 20 ⁇ m, such as at least 25 ⁇ m, e.g. at least 30 ⁇ m, most preferably at least 35 ⁇ m.
- the present invention is, at least in part, based on the surprising discovery that stable, immediate-release formulations may be prepared even without micronizing the drug substance.
- the particle size of the drug substance should not be too large as the dissolution properties are then impeded. Accordingly, the d 90 value of (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, will typically be in the range of 50-300 ⁇ m.
- the d 90 value is in the range of 60-250 ⁇ m, such as in the range of 70-200 ⁇ m, e.g. in the range of 80-200 ⁇ m, more preferably in the range of 90- 200 ⁇ m, such as in the range of 100-200 ⁇ m, e.g. in the range of 110-190 ⁇ m, most preferably in the range of 120-180 ⁇ m, such as in the range of 130-170 ⁇ m, e.g. in the range of 140-160 ⁇ m.
- the d 50 value of (4-chlorophenyl)[4-(4-pyridylmethyl)- phthalazin-1-yl], or a pharmaceutically acceptable salt thereof will typically be in the range of 15-100 ⁇ m, in particular in the range of 20-90 ⁇ m, such as in the range of 25-80 ⁇ m, e.g. in the range of 30-70 ⁇ m.
- the terms "fast-release” or “immediate-release” mean that at least 70% of the drug substance (i.e. (4-chlorophenyl) [4-(4-pyridylmethyl)-phthalazin-l-yl] or a pharmaceutically acceptable salt thereof) is dissolved from the solid pharmaceutical formulation within 30 minutes as determined by the USP 28 Paddle Method using 0.05 M KH 2 PO 4 /HCI buffer adjusted to pH 3.0 at 37°C as the dissolution media and 50 rpm as the stirring rate. In a preferred embodiment of the invention at least 75%, more preferably at least 80%, of the drug substance is dissolved from the solid pharmaceutical formulation within 30 minutes as determined by the USP 28 Paddle Method described herein.
- the solid pharmaceutical formulation contains a "high-load” of drug substance due to the relative large amount of drug substance needed for administration to patients.
- the term "high-load” or “high-drug-load” means that the solid pharmaceutical formulation contains at least 50% by weight, calculated on the basis of the total weight of the formulation, of the drug substance (i.e. (4-chlorophenyl) [4-(4- pyridylmethyl)-phthalazin-l-yl] or a pharmaceutically acceptable salt thereof).
- the solid pharmaceutical formulation comprises at least 55% by weight, such as at least 60% by weight, e.g.
- the solid pharmaceutical formulation typically comprises 50-95% by weight of the drug substance (i.e. (4-chlorophenyl) [4-(4-pyridylmethyl)-phthalazin-l-yl] or a pharmaceutically acceptable salt thereof), calculated on the basis of the total weight of the formulation.
- the solid pharmaceutical formulation comprises 50-70% by weight or 70-90% by weight, such as 55-65% by weight or 85-95% by weight of the drug substance, calculated on the basis of the total weight of the formulation.
- the drug substance itself may be the free base, i.e. (4-chlorophenyl)[4-(4-pyridylmethyl)- phthalazin-1-yl] or a pharmaceutically acceptable salt thereof, in particular an acid addition salt.
- Such salts may be formed from suitable inorganic or organic acids.
- suitable inorganic acids include the halogen acids, such as hydrochlorid acid; sulfuric acid; and phosphoric acid.
- suitable organic acids include carboxylic, phosphonic, sulfonic or sulfamic acids, such as acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid; amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetyl- asparagine and N-acetylcysteine; pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3- glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-
- the drug substance is the succinate salt of (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl].
- the term “pynasunate” refers to the succinate salt of (4-chlorophenyl)[4-(4- pyridylmethyl)-phthalazin-l-yl], i.e. (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l- yl]ammonium hydrogen succinate. Pynasunate is described in WO 98/35958.
- the solid pharmaceutical formulation of the invention may, in addition to non-micronized (4-chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, contain at least one pharmaceutically acceptable excipient.
- excipients may, e.g., be selected from the group consisting of fillers, binders, surfactants, disintegrants, glidants and lubricants.
- Inert diluents or fillers such as sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches, polysaccharides, carragenan, lamda-carragenan, kappa-carragenan, iota-carragenan, sodium chloride, sodium phosphate, calcium carbonate, calcium phosphate, calcium sulfate or lactose, e.g. lactose monohydrate.
- the inert diluent or filler is typically present in an amount from 1-50% by weight of the total formulation.
- the inert diluent or filler is present in an amount from 1-40% by weight of the total formulation.
- the inert diluent or filler is present in an amount from 1-20% by weight of the total formulation, preferably in an amount from 1-10% by weight of the total formulation, more preferably in an amount from 1-7.5% by weight of the total formulation, most preferably in an amount from 1-5% by weight of the total formulation.
- the inert diluent or filler is present in an amount from 20-40% by weight of the total formulation, preferably in an amount from 25-35% by weight of the total formulation, more preferably in an amount from 30-35% by weight of the total formulation.
- the inert filler or diluent is lactose, in particular lactose monohydrate.
- Binders such as sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatine, starch, pregelatinised starch, microcrystalline cellulose, polysaccharides, carragenan, lamda- carragenan, kappa-carragenan, iota-carragenan, magnesium aluminium silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethylcellulose, hydroxy- propylmethylcellulose (HPMC), polyvinylacetate, polyethylene glycol or polyvinylpyrrolidone, e.g.
- CMC sodium carboxymethylcellulose sodium
- HPMC hydroxy- propylmethylcellulose
- polyvinylacetate polyethylene glycol or polyvinylpyrrolidone, e.g.
- the binder is typically present in an amount from 0.5-15% by weight of the total formulation.
- the binder is present in an amount from 1- 10% by weight of the total formulation, more preferably in an amount from 1-5% by weight of the total formulation.
- the binder is HPMC, in particular HPMC having viscosity grade 3.
- Lubricants including glidants and antiadhesives, such as magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils or talc.
- the lubricant is typically present in an amount from 0.1-10% by weight of the total formulation.
- the lubricant is present in an amount from 0.2-5% by weight of the total formulation, such as from 0.5-5% by weight of the total formulation, e.g. from 1-5% by weight of the total formulation, more preferably in an amount from 1-3% by weight of the total formulation.
- the lubricant is magnesium stearate.
- Disinteg rants such as croscarmellose sodium, cross-linked povidone, sodium starch glycolate, maize starch or potato starch.
- the disintegrant is typically present in an amount from 1-20% by weight of the total formulation.
- the disintegrant is present in an amount from 1-15% by weight of the total formulation, such as from 1-10% by weight of the total formulation, e.g. from 1-7.5% by weight of the total formulation, more preferably from 1- 5% by weight of the total formulation.
- the disintegrant is croscarmellose sodium. Croscarmellose sodium is commercially available under the trademark Ac-Di-Sol ® .
- - Surfactants and wetting agents such as naturally occurring phosphatides, e.g. lechitin or soybean lechitin; condensation products of ethylene oxide with e.g. a fatty acid, a long chain fatty alcohol, or a partial ester derived from fatty acids and a hexitol or a hexitol anhydride, for example polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, etc.; or salts of long-chain aliphatic phosphates, such as sodium lauryl sulphate.
- naturally occurring phosphatides e.g. lechitin or soybean lechitin
- condensation products of ethylene oxide with e.g. a fatty acid, a long chain fatty alcohol, or a partial ester derived from fatty acids and a hexitol or a hexitol anhydride for example polyoxyethylene stearate, polyoxyethylene
- Examples of other pharmaceutically acceptable excipients which may be incorporated in the solid pharmaceutical formulation of the invention include colorants, flavouring agents, plasticizers, humectants, buffering agents, etc.
- the solid pharmaceutical formulations of the invention may also contain further drug substances, such as anti-cancer agents.
- the unit dosage form is adapted for oral administration and may be provided with a coating, such as a film coating, a sugar coating, or the like.
- a suitable coating for the solid unit dosage form according to the invention may, for example, be a sugar coating or a film coating based on one or more of the ingredients: Hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, acrylate polymers (e.g. Eudragit ® ), polyethylene glycols or polyvinylpyrrolidone.
- the coating is a film coating based on HPMC.
- the coated or uncoated tablet typically has a weight in the range from 500-700 mg, such as in the range of 525-675 mg, e.g. in the range of 525-650 mg.
- the coated or uncoated tablet has a weight in the range of 525-575 mg, such as about 550 mg if uncoated or about 562 mg if coated.
- the coated or uncoated tablet has a weight in the range of 610-650 mg, such as about 627 mg if uncoated or about 640 mg if coated.
- the amount of active drug substance, in particular (4-chlorophenyl)[4-(4-pyridylmethyl)- phthalazin-l-yl]ammonium hydrogen succinate, present in the tablet will typically be in the range from 300-600 mg.
- the tablet comprises 300-350 mg, such as 310-350 mg, e.g. 320-350 mg, preferably 330-340 mg, more preferably about 335 mg drug substance.
- the tablet comprises 500-600 mg, such as 510-600 mg, e.g. 520-600 mg, preferably 530-590 mg, such as 540-580 mg, e.g. 550-570, more preferably 555-565 mg, such as about 558.3 mg drug substance.
- the uncoated tablets contain the following ingredients:
- Drug substance e.g. pynasunate
- Filler e.g. lactose monohydrate, mannitol
- Binder e.g. HPMC, microcrystalline cellulose 1-10
- Disintegrant e.g. croscamellose sodium 1-20
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients: Ingredient % %
- Drug substance e.g. pynasunate 50-70 70-90
- Filler e.g. lactose monohydrate, mannitol 20-40 1-20
- Binder e.g. HPMC, microcrystalline cellulose 1-5 1-5
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients:
- Drug substance e.g. pynasunate
- Filler e.g. lactose monohydrate, mannitol
- Binder e.g. HPMC, microcrystalline cellulose
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients:
- Drug substance e.g. pynasunate
- Filler e.g. lactose monohydrate, mannitol
- Binder e.g. HPMC, microcrystalline cellulose
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearatel IJJ 1.8 1.8 1.8
- the respective uncoated tablets may be coated.
- the uncoated tablets may, in a typical embodiment of the invention, contain the following ingredients:
- Drug substance e.g. pynasunate 300-600
- Binder e.g. HPMC, microcrystalline cellulose 5-50
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients: Ingredient Amount (mo) Amount ( ⁇ Q)
- Drug substance e.g. pynasunate 300-350 500-600 Filler (e.g. lactose monohydrate, mannitol) 110-220 1-50 Binder (e.g. HPMC, microcrystalline cellulose) 5-30 5-30 Disintegrant (e.g. croscamellose sodium) 5-35 5-35 Lubricant (e.g. magnesium stearate) 1-20 1-20
- Filler e.g. lactose monohydrate, mannitol
- Binder e.g. HPMC, microcrystalline cellulose
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients:
- Drug substance e.g. pynasunate
- Filler e.g. lactose monohydrate, mannitol
- Binder e.g. HPMC, microcrystalline cellulose
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients:
- Drug substance e.g. pynasunate 330-340 555-565
- Binder e.g. HPMC, microcrystalline cellulose 10-20 10-20
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients:
- Drug substance e.g. pynasunate 332-337 557-560
- Filler e.g. lactose monohydrate, mannitol
- Binder e.g. HPMC, microcrystalline cellulose
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective uncoated tablets may be coated.
- the uncoated tablets contain the following ingredients:
- Binder e.g. HPMC, microcrystalline cellulose
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate 10 11.5
- the respective uncoated tablets may be coated.
- granules contain ingredients according to anyone of the preceding compositions wherein the lubricant is left out.
- the granule is shaped to pellets, whereas the respective granule contains the following ingredients:
- Binder e.g. HPMC, microcrystalline cellulose, carragenan 5.0 96
- Disintegrant e.g. croscamellose sodium
- Disintegrant e.g. croscamellose sodium
- Lubricant e.g. magnesium stearate
- the respective pellets may be coated.
- the solid pharmaceutical formulation and the solid unit dosage form of the invention is typically prepared by means of a granulation process, i.e. the non-micronized drug substance, together with appropriate excipients, is subjected to a granulation process, preferably a wet granulation process, such as a fluid bed granulation process. After the granulation process, the granules are processed further into the final solid unit dosage form. In one embodiment of the invention the granules may be filled in capsules, such as hard gelatine capsules. However, in a preferred embodiment of the invention the granules are processed into tablets by compression and subsequently film-coated.
- the present invention is also directed to a process for the preparation of granules comprising at least 50% by weight of the total granule of non-micronized (4- chlorophenyl)[4-(4-pyridylmethyl)-phthalazin-l-yl], or a pharmaceutically acceptable salt thereof, said process comprising the steps of i) preparing a liquid medium comprising the binder
- the present invention is also directed to a process for the preparation of a solid unit dosage form according to the invention, said process comprising the steps of
- the liquid medium typically comprises a binder.
- the liquid does not contain a disintegrant and/or a lubricant.
- the disintegrant and/or the lubricant is added during the granulation process, in particular at the end of the granulation process.
- the liquid medium is preferably water.
- the powder blend typically comprises at least 55% by weight of the components of the medium, excluding liquid, of non-micronized (4-chlorophenyl)[4-(4-pyridylmethyl)- phthalazin-1-yl], or a pharmaceutically acceptable salt thereof.
- the powder blend comprises at least 60% by weight, such as at least 65% by weight, e.g. at least 70% by weight, preferably at least 75% by weight, such as at least 80% by weight, e.g.
- micronized particles of the pynasunate raw material led to considerably manufacturing problems. Compression of the granules formed from the micronized pynasunate particles was not possible as the thereby formed tablets exhibited sticking to the punches and decreased physical stability. In addition, it was observed that the granules prepared from micronized pynasunate particles were less coarse, i.e. the lower the particle size of the micronized pynasunate particles, the lower the amount (in percentage) of granules having a particle size above 300 ⁇ m.
- Non-micronized particles of pynasunate exhibited good to excellent compressibility properties. Only few or no problems with respect to sticking to the punches were encountered. Furthermore, tablets prepared from non-micronized pynasunate particles showed satisfactory physical stability and satisfactory immediate-release of pynasunate. However, the particle size of the granules should not be too large as the release properties are then impeded.
- the granules obtainable by the process described herein are so that least 25% of the granules are coarser than 250 ⁇ m as determined by sieve analysis in accordance with Ph. Eur. Method 2.9.12 using a sieve with a mean mesh width of 250 ⁇ m.
- at least 30% of the granules, such as at least 35% of the granules, e.g. at least 40% of the granules are coarser than 250 ⁇ m. More preferably, 25-70% of the granules are coarser than 250 ⁇ m as determined by sieve analysis in accordance with Ph. Eur. Method 2.9.12 using a sieve with a mean mesh width of 250 ⁇ m.
- the granules such as 35-70% of the granules, e.g. 40- 70% of the granules, most preferably 40-65% of the granules, such as 40-60% of the granules are coarser than 250 ⁇ m.
- non-micronized pynasunate exhibits excellent manufacturing properties allowing high-load solid pharmaceutical formulations to be prepared. Accordingly, the present invention is also directed to a composition of non-micronized (4-chlorphenyl)[4-(4-pyridylmethyl)- phtalazin-l-yl]ammonium hydrogen succinate particles having a d 90 value in the range of 50-300 ⁇ m and a d 50 value in the range of 15-100 ⁇ m, when determined as described herein.
- the d 90 value is in the range of 100-200 ⁇ m and the d 50 value is in the range of 30-70 ⁇ m, when determined as described herein.
- composition of non-micronized (4- chlorphenyl)[4-(4-pyridylmethyl)-phtalazin-l-yl]amrnonium hydrogen succinate particles has the following d 50 , d 90/ d 95 and d 99 values: Composition Cj 52 Ci 22 Ci 25-
- composition of non-micronized (4-chlorphenyl)[4-(4-pyridylmethyl)-phtalazin-l-yl]ammonium hydrogen succinate particles has the d 50 , d 90 , d 95 and d 99 values shown in Example 1, Example 2 or Example 3 herein.
- the present invention provides means and methods for treating certain cancers or tumours or tumour angiogenesis, in any suitable animal, preferably in a mammal, and in particular in a human being.
- solid malignant tumor is intended to indicate an abnormal malignant mass of tissue that is not inflammatory, which arises without obvious cause from cells of preexistent tissue, which possesses no physiologic function and which has the ability to invade normal cells and spread throughout the body.
- typical solid malignant tumours include breast carcinoma, non-small cell lung cancer, colon carcinoma, renal cell carcinoma and malignant melanoma.
- epithelial tissue covers or lines the body surfaces inside and outside the body. Examples of epithelial tissue are the skin and the mucosa and serosa that line the body cavities and internal organs, such as intestines, urinary bladder, uterus, etc. Epithelial tissue may also extend into deeper tissue layers to from glands, such as mucus-secreting glands.
- sarcoma is intended to indicate a malignant tumour growing from connective tissue, such as cartilage, fat, muscles, tendons and bones.
- leukaemia is intended to indicate a blood cancer, i.e. a cancer that originates from the bone marrow and which keeps the marrow from producing normal red and white blood cells and platelets.
- leuka refers to a cancer that originates in the nodes or glands of the lymphatic system.
- glioma when used herein, is intended to cover a malignant tumor originating from glial cells.
- the term “inhibition” or “inhibit” as used in connection with treatment of solid tumours is intended to cover the delayed appearance of primary or secondary tumours, slowed development of primary or secondary tumours, decreased occurrence of primary or secondary tumours, slowed or decreased severity of secondary effects of disease, arrested tumour growth and regression of tumours.
- the term “reduction” or “reducing” in connection with tumour size is covered by the term “inhibition” or “inhibit”.
- the reduction of the solid tumour refers to a reduction of the tumour volume. For example, a 10% reduction of a solid tumour means that the volume of the treated tumour has been reduced with 10%.
- An important aspect of the present invention lies in the therapeutic application of the solid pharmaceutical formulation of the invention.
- the present invention is also directed to a solid pharmaceutical formulation of the invention for use as a medicament.
- the present invention is directed to use of the solid pharmaceutical formulation of the invention for the manufacture of a medicament for treatment of cancer.
- the present invention is directed to a method of treating cancer, said method comprising administering a therapeutically effective amount of the solid pharmaceutical formulation of the invention to a patient in need thereof.
- treatment of a cancer or "treating a mammal having a cancer” is intended to mean that the solid pharmaceutical formulation described herein is administered in a therapeutically effective amount which is sufficient to i) inhibit growth of the tumour, Ii) facilitate tumour regression, i.e. reduce the size of the tumour, Hi) remove the tumour and/or Iv) inhibit cancer cell metastasis.
- the solid pharmaceutical formulation will be administered to patients in a "therapeutically effective" dose, i.e. in a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered.
- a dose will depend on the cancer form to be treated, and will be ascertainable by one skilled in the art using known techniques.
- a suitable dose of the drug substance, in particular pynasunate is contemplated to be in the range of about 1-2 g/patient/day, such as 1-1.5 g/patient/day, e.g. 1.3-1.4 g/patient/day, in particular 1.34 g/patient/day.
- said cancer is a carcinoma, such as a carcinoma selected from the group consisting of malignant melanoma, basal cell carcinoma, ovarian carcinoma, breast carcinoma, non-small cell lung cancer, renal cell carcinoma, bladder carcinoma, recurrent superficial bladder cancer, stomach carcinoma, prostatic carcinoma, pancreatic carcinoma, lung carcinoma, cervical carcinoma, cervical dysplasia, laryngeal papillomatosis, colon carcinoma, colorectal carcinoma and carcinoid tumours, in particular selected from the group consisting of malignant melanoma, non- small cell lung cancer, breast carcinoma, colon carcinoma and renal cell carcinoma.
- a carcinoma such as a carcinoma selected from the group consisting of malignant melanoma, basal cell carcinoma, ovarian carcinoma, breast carcinoma, non-small cell lung cancer, renal cell carcinoma, bladder carcinoma, recurrent superficial bladder cancer, stomach carcinoma, prostatic carcinoma, pancreatic carcinoma, lung carcinoma, cervical carcinoma, cervical dysplasia, laryngeal papillomatosis, colon carcinoma, colorectal carcinoma and carcinoi
- said cancer is malignant melanoma, such as superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral melagnoma, amelanotic melanoma or desmoplastic melanoma.
- said cancer is non-small cell lung cancer.
- said cancer is breast carcinoma.
- said cancer is colon carcinoma.
- said cancer is renal cell carcinoma.
- said cancer is a sarcoma, such as a sarcoma selected from the group consisting of osteosarcoma, Ewing's sarcoma, chondrosarcoma, malignant fibrous histiocytoma, fibrosarcoma and Kaposi's sarcoma.
- a sarcoma such as a sarcoma selected from the group consisting of osteosarcoma, Ewing's sarcoma, chondrosarcoma, malignant fibrous histiocytoma, fibrosarcoma and Kaposi's sarcoma.
- said cancer is a glioma.
- cancer types i.e. carcinomas, sarcomas and gliomas
- carcinomas i.e. carcinomas, sarcomas and gliomas
- said cancer is a lymphoma, such as a lymphoma selected from the group consisting of Hodgkin's disease, non- Hodgkin's disease, B-cell lymphoma, T-cell lymphoma, follicular lymphoma, Burkitt's lymphoma and mycosis fungoides.
- a lymphoma selected from the group consisting of Hodgkin's disease, non- Hodgkin's disease, B-cell lymphoma, T-cell lymphoma, follicular lymphoma, Burkitt's lymphoma and mycosis fungoides.
- said cancer is a myeloma, such as multiple myeloma.
- the formulation of the invention can be used for other diseases characterised by overshooting angiogenesis, like macular degeneration due to vessel in-growth, corneal transplatation due to lymphatic vessel ingrowth and thereby breakage of the immune privilege. It is helpful in diseases like rheumatoid arthritis with vessels growing ectopically towards the joints. As mentioned above it is effective in asthma. Also diseases with female cycle associated vessel growth are influenced beneficially as is the case for endometriosis. It will be understood that an even more effective treatment of the various cancer forms may be obtained by combination therapy where the solid pharmaceutical formulation of the invention is combined with a suitable chemotherapeutic agent and/or is combined with radiotherapy and/or is combined with surgery.
- a further aspect of the present invention relates to the use of a solid pharmaceutical formulation of the invention for the manufacture of a medicament for treatment of cancer in combination with a chemotherapeutic agent.
- a further aspect of the present invention relates to a method of treating cancer, said method comprising administering a therapeutically effective amount of the solid pharmaceutical formulation of the invention and a chemotherapeutic agent to a patient in need thereof.
- chemotherapeutic agents include chemotherapeutic agents selected from the group consisting of adrenocorticosteroids, such as prednisone, dexamethasone or decadron; altretamine (hexalen, hexamethylmelamine (HMM)); amifostine (ethyol); aminoglutethimide (cytadren); amsacrine (M-AMSA); anastrozole (arimidex); androgens, such as testosterone; asparaginase (elspar); bacillus calmette- gurin; bicalutamide (casodex); bleomycin (blenoxane); busulfan (myleran); carboplatin (paraplatin); carmustine (BCNU, BiCNU); chlorambucil (leukeran); chlorodeoxyadenosine (2-CDA, cladribine, leustatin); cisplatin (platinol); cytosine arabinoside
- chemotherapeutic agents which may be useful for the purposes described herein include the chemotherapeutic agents mentioned in column 12, line 62 to column 13, line 42 of US 6,482,802.
- chemotherapeutic agents see The Merck Index, 12 th edition, pp. THER 13-14.
- the chemotherapeutic agent is selected under due consideration of the actual cancer form.
- the following chemotherapeutic agents are used (together with the solid pharmaceutical formulation described herein) for treatment of the following specific cancer forms: malignant melanoma and cisplatin; malignant melanoma and IL-2; renal cell carcinoma and doxorubicin; renal cell carcinoma and IL-2; breast carcinoma and doxorubicin; breast carcinoma and taxol; colon carcinoma and 5-fluorouracil; colon carcinoma and cisplatin; and non-small cell lung cancer and cisplatin.
- Dispersion system Aerial dry dispersion using Sympatec Rodos module
- Measurement time 2 seconds
- Optical model Fraunhofer under the presumption of spherical particles.
- Sample preparation Conditioning run, dosing of 25 ml sample, weighing of sample Sample run: Conditioning run and measurement run at 100 mm/s tip speed. 8 times repetition
- Example 1 Drug substance with a small particle size
- Example 2 Drug substance with a medium particle size
- Example 3 Drug substance with a large particle size
- Example 5 Manufacturing of high-load pynasunate tablets Tablets were prepared from the following ingredients:
- HPMC Hydroxypropylmethylcellulose
- 44 kg of granules were obtained by the following process: Lactose and pynasunate were charged into a fluid bed granulator. The granulation process was started and the binder solution, prepared by dissolving HPMC in water, was spray on the fluidised bed. At the end of the granulation process croscarmellose sodium and magnesium stearate were added to the fluid bed granulator and blended with the granules.
- the granules were compressed to oblong tablets (17.6 x 7 curvature 4 mm) of 550 mg containing the following ingredients:
- the tablets were film-coated with a dispersion containing the following ingredients: In ⁇ redient Amount (kq)
- HPMC Hydroxypropylmethylcellulose
- Iron oxide yellow pigment, talc and titanium dioxide were suspended in water II and added to a solution of HPMC in water I. Additional water was added to a final weight of 23.994 kg. The dispersion was homogenised in a colloidal mill and subsequently sprayed onto the tablets. Coating was performed until the film-coated tablets had reached a weight of 562 mg each.
- Example 6 Manufacturing of very high-load pynasunate tablets Tablets were prepared from the following ingredients:
- HPMC Hydroxypropylmethylcellulose
- 44 kg of granules were obtained by the following process: Lactose and pynasunate were charged into a fluid bed granulator. The granulation process was started and the binder solution, prepared by dissolving HPMC in water, was spray on the fluidised bed. At the end of the granulation process croscarmellose sodium and magnesium stearate were added to the fluid bed granulator and blended with the granules.
- HPMC Hydroxypropylmethylcellulose
- the tablets from were film-coated with a dispersion containing the following ingredients:
- HPMC Hydroxypropylmethylcellulose
- Iron oxide yellow pigment, talc and titanium dioxide were suspended in water II and added to a solution of HPMC in water I. Additional water was added to a final weight of 23.994 kg. The dispersion was homogenised in a colloidal mill and subsequently sprayed onto the tablets. Coating was performed until the film-coated tablets had reached a weight of 640 mg each.
- the very high-load film-coated pynasunate tablets exhibited excellent physical stability, cf. the compression force vs. hardness data shown in Fig. 5.
- Example 7 Optimised high-load film-coated pynasunate tablet
- Pynasunate particles having a d 50 of 64 ⁇ m and a d 90 of 173 ⁇ m were processed to granules as described in Example 5. 47% of the granules were coarser than 250 ⁇ m. The compression process showed no sticking of the granules to the punches and the resulting tablets showed excellent physical stability and no capping. The film-coated tablets released 85.8% of the pynasunate after 30 minutes using the USP 28 Paddle Method described above.
- 1675g of of homogenised, non-micronized, pynasunate was mixed with 52g of mannitol and 96g of microcrystalline cellulose. To this blend 1130ml of water was added. The mixture was given into an extruder and extruded through an 1000 ⁇ m round shaped grid. The extrudates were shaped to round pellets on a spheronizer and then dried to equilibrium in an fluid bed drier at an inlet air temperature of 60 0 C. After that the pellets were conditioned to ambient conditions by open storage for 12 hours. The pellets released 89.9% of the pynasunate after 30 minutes using the USP 28 Paddle Method described above.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06762010A EP1888072A1 (en) | 2005-06-07 | 2006-06-06 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)[4-(4-pyridylmethyl)phthalazin-1-yl]and salts thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05090166A EP1731153A1 (en) | 2005-06-07 | 2005-06-07 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)¬4-(4-pyridylmethyl)phthalazin-1-yl| and salts thereof |
PCT/EP2006/005600 WO2006131393A1 (en) | 2005-06-07 | 2006-06-06 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)[4-(4-pyridylmethyl)phthalazin-1-yl] and salts thereof |
EP06762010A EP1888072A1 (en) | 2005-06-07 | 2006-06-06 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)[4-(4-pyridylmethyl)phthalazin-1-yl]and salts thereof |
Publications (1)
Publication Number | Publication Date |
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EP1888072A1 true EP1888072A1 (en) | 2008-02-20 |
Family
ID=34938467
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05090166A Withdrawn EP1731153A1 (en) | 2005-06-07 | 2005-06-07 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)¬4-(4-pyridylmethyl)phthalazin-1-yl| and salts thereof |
EP06762010A Withdrawn EP1888072A1 (en) | 2005-06-07 | 2006-06-06 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)[4-(4-pyridylmethyl)phthalazin-1-yl]and salts thereof |
Family Applications Before (1)
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EP05090166A Withdrawn EP1731153A1 (en) | 2005-06-07 | 2005-06-07 | Immediate-release and high-drug-load pharmaceutical formulations of non-micronised (4-chlorophenyl)¬4-(4-pyridylmethyl)phthalazin-1-yl| and salts thereof |
Country Status (21)
Country | Link |
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EP (2) | EP1731153A1 (en) |
JP (1) | JP2008542420A (en) |
KR (1) | KR20080031005A (en) |
CN (1) | CN101242840A (en) |
AR (1) | AR053889A1 (en) |
AU (1) | AU2006256852A1 (en) |
BR (1) | BRPI0613393A2 (en) |
CA (1) | CA2610975A1 (en) |
CR (1) | CR9563A (en) |
DO (1) | DOP2006000127A (en) |
EC (1) | ECSP078038A (en) |
GT (1) | GT200600242A (en) |
IL (1) | IL187905A0 (en) |
MX (1) | MX2007015494A (en) |
NO (1) | NO20080065L (en) |
PE (1) | PE20070319A1 (en) |
RU (1) | RU2007147951A (en) |
TW (1) | TW200716115A (en) |
UY (1) | UY29582A1 (en) |
WO (1) | WO2006131393A1 (en) |
ZA (1) | ZA200800112B (en) |
Families Citing this family (2)
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EP1958616A1 (en) * | 2007-02-13 | 2008-08-20 | Bayer Schering Pharma Aktiengesellschaft | Pharmaceutical formulations of 1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine or salts thereof |
AR101476A1 (en) | 2014-08-07 | 2016-12-21 | Acerta Pharma Bv | METHODS TO TREAT CANCER, IMMUNE AND AUTO-IMMUNE DISEASES, AND INFLAMMATORY DISEASES BASED ON THE OCCUPATION RATE OF THE BRUTON TYPOSIN QUINASE (BTK) AND THE RESULTS OF THE TIROSIN QUINASK (TUTOSIN QUINASK) |
Family Cites Families (1)
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CO4950519A1 (en) * | 1997-02-13 | 2000-09-01 | Novartis Ag | PHTHALAZINES, PHARMACEUTICAL PREPARATIONS THAT UNDERSTAND THEM AND THE PROCESS FOR THEIR PREPARATION |
-
2005
- 2005-06-07 EP EP05090166A patent/EP1731153A1/en not_active Withdrawn
-
2006
- 2006-06-06 EP EP06762010A patent/EP1888072A1/en not_active Withdrawn
- 2006-06-06 PE PE2006000619A patent/PE20070319A1/en not_active Application Discontinuation
- 2006-06-06 CN CNA2006800294742A patent/CN101242840A/en active Pending
- 2006-06-06 JP JP2008515151A patent/JP2008542420A/en active Pending
- 2006-06-06 BR BRPI0613393-2A patent/BRPI0613393A2/en not_active IP Right Cessation
- 2006-06-06 KR KR1020087000236A patent/KR20080031005A/en not_active Application Discontinuation
- 2006-06-06 WO PCT/EP2006/005600 patent/WO2006131393A1/en active Application Filing
- 2006-06-06 MX MX2007015494A patent/MX2007015494A/en not_active Application Discontinuation
- 2006-06-06 TW TW095120062A patent/TW200716115A/en unknown
- 2006-06-06 RU RU2007147951/15A patent/RU2007147951A/en not_active Application Discontinuation
- 2006-06-06 CA CA002610975A patent/CA2610975A1/en not_active Abandoned
- 2006-06-06 AU AU2006256852A patent/AU2006256852A1/en not_active Abandoned
- 2006-06-06 GT GT200600242A patent/GT200600242A/en unknown
- 2006-06-07 UY UY29582A patent/UY29582A1/en not_active Application Discontinuation
- 2006-06-07 AR ARP060102363A patent/AR053889A1/en unknown
- 2006-06-07 DO DO2006000127A patent/DOP2006000127A/en unknown
-
2007
- 2007-12-05 IL IL187905A patent/IL187905A0/en unknown
- 2007-12-06 CR CR9563A patent/CR9563A/en not_active Application Discontinuation
- 2007-12-19 EC EC2007008038A patent/ECSP078038A/en unknown
-
2008
- 2008-01-04 ZA ZA200800112A patent/ZA200800112B/en unknown
- 2008-01-04 NO NO20080065A patent/NO20080065L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO2006131393A1 * |
Also Published As
Publication number | Publication date |
---|---|
GT200600242A (en) | 2007-02-09 |
CA2610975A1 (en) | 2006-12-14 |
AU2006256852A8 (en) | 2006-12-14 |
BRPI0613393A2 (en) | 2011-01-11 |
IL187905A0 (en) | 2008-03-20 |
NO20080065L (en) | 2008-03-06 |
CR9563A (en) | 2008-02-20 |
RU2007147951A (en) | 2009-07-20 |
WO2006131393A1 (en) | 2006-12-14 |
CN101242840A (en) | 2008-08-13 |
TW200716115A (en) | 2007-05-01 |
AR053889A1 (en) | 2007-05-23 |
ECSP078038A (en) | 2008-01-23 |
DOP2006000127A (en) | 2006-12-15 |
UY29582A1 (en) | 2007-01-31 |
EP1731153A1 (en) | 2006-12-13 |
ZA200800112B (en) | 2010-06-30 |
PE20070319A1 (en) | 2007-04-12 |
JP2008542420A (en) | 2008-11-27 |
AU2006256852A1 (en) | 2006-12-14 |
MX2007015494A (en) | 2008-02-22 |
KR20080031005A (en) | 2008-04-07 |
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