Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0031—Rectum, anus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • 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
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to novel indications for direct thrombin inhibitors (DTI), processes for preparing pharmaceutical compositions for treating said diseases and methods of treating them.
• DTI direct thrombin inhibitors
• Direct thrombin inhibitors include
• Preferred direct thrombin inhibitors are dabigatran, dabigatran etexilate and 1 - methyl-2-[4-( ⁇ /-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl- carboxylic acid-( ⁇ /-2-pyhdyl- ⁇ /-2-ethoxycarbonylethyl)-amide, and the tautomers, racemates, enantiomers, diastereomers, pharmacologically acceptable acid addition salts, solvates, hydrates and prodrugs thereof.
• dabigatran and dabigatran etexilate More preferred are dabigatran and dabigatran etexilate, and the tautomers, racemates, enantiomers, diastereomers, pharmacologically acceptable acid addition salts, solvates, hydrates and prodrugs thereof.
• dabigatran etexilate and the tautomers, racemates, enantiomers, diastereomers, pharmacologically acceptable acid addition salts, solvates, hydrates and prodrugs thereof, particularly its acid addition salt with methanesulfonic acid.
• the active compounds (1 ) to (3) are disclosed in the prior art, e.g. in WO 98/37075 and WO 04/014894.
• the acid addition salt of dabigatran etexilate with methanesulfonic acid is described in WO 03/074056. Additional salts of dabigatran etexilate are mentioned in the experimental part. Specific polymorphs and a hemihydrate of acid addition salt of dabigatran etexilate with methanesulfonic acid is described in WO 2005/028468. Examples for pharmaceutical composition containing dabigatran etexilate are disclosed in WO 03/074056, WO 2005/018615 and WO 2005/023249.
• Prodrugs of the drugs mentioned above are such derivatives containing one or more groups capable of being cleaved in vivo, particularly a group which can be converted in-vivo into a carboxy group or/and a group capable of being cleaved in vivo from an imino or amino group.
• Compounds containing two groups capable of being cleaved in vivo are so-called double prodrugs.
• Groups which can be converted in-vivo into a carboxy group and groups capable of being cleaved in vivo from an imino or amino group are disclosed e.g. in WO 98/37075, being herewith incorporated by reference, as well as in other WO publications cited hereinbefore in connection with specific antithrombotics.
• the direct thrombin inhibitor according to the invention may be used in a form selected from tautomers, optical isomers, enantiomers, race- mates, diastereomers, pharmacologically acceptable acid addition salts, solvates or hydrates, as far as such forms exist, depending on the individual compound. If multiple enantiomers exist, the use in form of a substantially pure enantiomer is preferred.
• Pharmacological acceptable acid addition salts of the direct thrombin inhibitors listed above comprise salts selected from the group consisting of the hydro- chloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydro- methanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrolactate, hydrooxalate, hydro- succinate, hydrobenzoate and hydro-p-toluolsulphonate, preferably hydro- chloride, hydrobromide, hydrosulphate, hydrophosphate, hydromaleate, hydrofumarate and hydromethansulphonate.
• Some of the direct thrombin inhibitors may add more than one equivalent acid, e.g. two equivalents.
• the salts of hydrochloric acid, methanesulfonic acid, maleic acid, benzoic acid and acetic acid are especially preferred.
• a preferred embodiment are the salts of dabigatran etexilate with hydrochloric acid, maleic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid and malonic acid, the enantiomers, mixtures and hydrates thereof.
• Particularly preferred are tartaric acid, salicylic acid, methanesulfonic acid and citric acid as well as the enantiomers, mixtures and hydrates thereof.
• the most preferred salt of is the methanesulfonic acid addition salt of dabigatran etexilate.
• any reference to a direct thrombin inhibitor within the scope of the present invention should be understood as a reference to any specific direct thrombin inhibitor selected from compounds (1 ) to (8) mentioned hereinbefore.
• a preferred embodiment of the invention relates to new indications of the active substance ethyl 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -1 -methyl-1 /-/-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate, the salts, the enantiomers, the mixtures and the hydrates thereof.
• This active substance with the chemical formula
• the compound of formula I is first converted into the actual effective compound, namely the compound of formula II, in the body.
• the main type of indication for the compound of chemical formula I is the post-operative prophylaxis of deep vein thrombosis and the prevention of strokes.
• the direct thrombin inhibitors like e.g. dabigatran etexilate cannot only be used effectively for the post-operative prophylaxis of deep vein throm- bosis and the prevention of strokes, but are also suitable for the prevention and/or treatment of children.
• the invention relates to the use of a compound, optionally in the form of tautomers, racemates, enantiomers, diastereomers, pharmacologically acceptable acid addition salts, solvates, hydrates or prodrugs thereof, selected from the group consisting of dabigatran, dabigatran etexilate, 1 -methyl -2-[4-(/V- hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic acid-( ⁇ /-2- pyhdyl- ⁇ /-2-ethoxycarbonylethyl)-amide, melagatran (inogatran), ximelagatran, hirudin, hirolog and argatroban for preparing a medicament for the treatment and/or prophylaxis of a disease selected from among thrombosis and/or venous thromboembolic events (VTE) in children, preferably VTE selected from among primary VTE prevention, secondary VTE
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of stroke in children,
• non haemorhagic stroke in children or for stroke prevention in children selected from among primary and secondary stroke prevention in children with atrial fibrillation and primary and secondary stroke prevention in children at elevated risk for stroke (children after transitoric ischemic attack (TIA) or stroke and post myocard infarction or acute coronary syndrome in children, children with very low ejection fraction of the heart).
• TIA transitoric ischemic attack
• stroke and post myocard infarction or acute coronary syndrome in children with very low ejection fraction of the heart.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of myocardial infarction (sometimes also named acute coronary syndrome [ACS]) in children, preferably ACS resp. myocardial infarction in children with/after stent implantation, with percutaneous coronary intervention (PCI) without stent implantation and without PCI in children.
• myocardial infarction sometimes also named acute coronary syndrome [ACS]
• ACS acute coronary syndrome
• PCI percutaneous coronary intervention
• the treatment and/or prophylaxis of myocardial infarction resp. ACS may either begin immediately after the event (acute treatment) or a certain time after the event (e.g. after myocardial infarction, post-MI) (chronic therapy, secondary prevention).
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of myocardial infarction in children, in particular myocardial infarction in children with arterio coronary venous bypass (ACVB) and also in children after thrombolysis.
• ACVB arterio coronary venous bypass
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of thrombosis or thromboembolic events in children with an off pump coronary artery by pass grafting surgery.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of graft thrombosis in children, in particular graft thrombosis in ACVB children and also in children after thrombolysis.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of stroke in children, particularly for the prevention of stroke in children with atrial fibrillation.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of post-operative prophylaxis of deep vein thrombosis (DVT) in children.
• DVD deep vein thrombosis
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of thrombosis or thromboembolic events in children, in particular in off pump coronary artery bypass and/or grafting surgery.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of stent thrombosis in children, in particular stent thrombosis in PCI patients and also in patients after thrombolysis
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of elevated cardiovascular risk in children, preferably elevated cardiovascular risk in children under treatment with antihypertensive and/or lipid lowering drugs, in children with elevated inflammatory status, in children with elevated coagulant parameters (e.g. PAI 1 ) or in children with diabetes mellitus.
• elevated cardiovascular risk in children under treatment with antihypertensive and/or lipid lowering drugs
• PAI 1 coagulant parameters
• diabetes mellitus e.g. PAI 1
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of congenital heart disease in children, in particular open foramen ovale, congenital heart failure, congenital disposition of the vessels and vessel anormalities (e.g. aortic isthmus stenosis) in children.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of diseases selected from among disorders in children, e.g. due to artificial heart valves, arrhythmia, heart failure, hypertrophic obstuctive cardiomyopathy (HOCM) and diabetes mellitus.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of peripheral arterial disease (PAD) in children, in particular of peripheral arterial disease in children suffering from diabetes mellitus, in children with or without implanted stent(-s) in the peripheral vessel(-s) and in children who underwent peripheral bypass surgery.
• PID peripheral arterial disease
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of a disease selected from among brain micro vessel disease and pulmonary infarction in children.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the prevention and/or treatment of shunt thrombosis, catheter thrombosis (including central venous line [CVL]) and thromboembolic events in children, in particular in children on dialysis with shunt or without shunt and in the dialysis machine.
• shunt thrombosis catheter thrombosis (including central venous line [CVL])
• CVL central venous line
• the invention relates to the use of the compounds mentioned hereinbefore for the treatment and/or prophylaxis of pulmonary embolism (PE) in children, in particular of PE in children with higher risk for PE (e.g. congenital coagulopathy, children after multiple pulmonary embolisms) and in children with deep venous thromboembolism (DVT) and/or any other kind of VTE.
• PE pulmonary embolism
• VDT deep venous thromboembolism
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of thrombosis, venous thromboembolic events (VTE), pulmonary embolism (PE) and deep venous thromboembolism (DVT) (anticoagulant therapy) in medical care children (immobilized children), in particular in children immobilized after any kind of surgery, in children immobilized after any kind of accident or trauma, in immobilized children with additional risk factors for VTE, in children with cancer, particularly in children with acute lymphoblastic leukaemia (ALL), in children with heart failure, in children with multiple sclerosis (MS) or in children with another diagnosis which results in immobilization of the child.
• VTE venous thromboembolic events
• PE pulmonary embolism
• DVD deep venous thromboembolism
• VTE venous thromboembolic events
• PE pulmonary embolism
• DVT deep venous thromboembolism
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of of the diseases mentioned in this application occurring in pregnant girls, in particular stroke, heart failure (high risk gravidas), congenital hyper- coagulation disease and haemolysis in pregnant girls, as well as for the treatment and/or prophylaxis of elevated liver enzymes and low platelets (HELLP) syndrome (in pregnant girls).
• HELLP elevated liver enzymes and low platelets
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of acute or chronic arterial thromboembolism (for example due to cardiac catheterisation, central venous line (CVL) etc.) in children.
• a medicament for the treatment and/or prophylaxis of acute or chronic arterial thromboembolism for example due to cardiac catheterisation, central venous line (CVL) etc.
• prophylaxis includes application prior to surgery resp. catherisation as well as during the surgery resp. catherisation.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of congenital heart disease in children, in particular postoperative congentital heart disease in children and VTE in children.
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of venous thromboembolism and/or VTE in children with cancer (e.g. acute lymphoblastic leukaemia (ALL)), particularly in children under chemotherapy involving Asparaginase.
• cancer e.g. acute lymphoblastic leukaemia (ALL)
• ALL acute lymphoblastic leukaemia
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of a disease selected from the group consisting of: neurodegenerative disease, brain micro vessel disease, diseases which are mediated via PAR 1 to PAR 4 receptors and oxidative stress induced by thrombin in children.
• a disease selected from the group consisting of: neurodegenerative disease, brain micro vessel disease, diseases which are mediated via PAR 1 to PAR 4 receptors and oxidative stress induced by thrombin in children.
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of Haematological diseases, heparin induced thrombocythompenia (HIT), disseminated intravascular coagulation (DIC) in children.
• Haematological diseases heparin induced thrombocythompenia (HIT)
• DIC disseminated intravascular coagulation
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of a disease selected from among thrombosis in children, thrombosis and/or venous thromboemobilc events in polychemo- therapy (particularly in polychemotherapy involving Asparaginase) in children suffering from cancer, particularly in children suffering form leukaemia such as acute lymphoblastic leukaemia (ALL).
• ALL acute lymphoblastic leukaemia
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of central vein thrombosis (CVT) in children.
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of HIV encephalitis in children suffering from human immunodefience virus (HIV).
• HIV human immunodefience virus
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of rheumatoid disorders in children, in particular rheumatoid arthritis and systemic lupus erythematodes (SLE) in children.
• SLE systemic lupus erythematodes
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of Tinnitus Aurium in children.
• the invention is related to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis of kidney disease in children, in particular proteinuria (urinary albumin excretion) in patients with chronic kidney disease and proteinuria (urinary albumin excretion) in patients with Diabetes and albuminuria.
• proteinuria urinary albumin excretion
• urinary albumin excretion urinary albumin excretion
• the thrombin inhibitors listed above are useful for the prevention and/or treat- ment of events provoked by the above-mentioned diseases (like VTE, PE), optimize the blood flow to organs or regions, and/or are suitable for direct treatment of the diseases.
• a preferred embodiment is the use of the direct thrombin inhibitors according to the invention for the preparation of a medicament for treating or preventing VTE associated with any one of the diseases mentioned above resp. below.
• patient as used in this application is to be understood as referring to children. Within the meaning of the instant invention children are patients with an age below 18 years, preferably, below 16 years, more preferably below 14 years, yet more preferably below 12 years. In particular children may be patients with an age in the range of 1 to 10 years.
• a preferred group of patients are children up to 5 years old; another preferred group of patients are children between 6 and 10 years; yet another preferred group of patients are children between 11 and 16 years.
• Preferred indications are: treatment of non-haemorhagic stroke in children, primary and secondary stroke prevention in children with very low ejection fraction of the heart; acute stroke in children, treatment and/or prophylaxis of myocardial infarction resp. acute coronary syndrome (ACS) in children, preferably ACS resp.
• ACS acute coronary syndrome
• PAI 1 or in children with diabetes mellitus; treatment and/or prophylaxis of congenital heart disease in children, in particular open foramen ovale, congenital heart failure, congenital disposition of the vessels and vessel anormalities in children; treatment and/or prophylaxis of cardiovascular disorders in children due to artificial heart valves in children, arrhythmia in children, heart failure in children, hypertrophic obstuctive cardiomyopathy (HOCM) in children or diabetes mellitus in children; treatment and/or prophylaxis of peripheral arterial disease (PAD) in children, in particular PAD in children with diabetes mellitus, in children with or without implanted stent(-s) in the peripheral vessel(-s) and in children who underwent peripheral bypass surgery; treatment and/or prophylaxis of brain micro vessel disease in children; treatment and/or prophylaxis of pulmonary infarction in children; treatment and/or prophylaxis of shunt thrombosis in children, particularly in children on dialysis,
• congenital coagulopathy children after multiple pulmonary embolisms
• treatment and/or prophylaxis of stroke in pregnant girls ofheart failure in pregnant girls (high risk gravidas), of congenital hypercoagulation disease in pregnant girls, of haemolysis in pregnant girls and of elevated liver enzymes and low platelets (HELLP) syndrome in pregnant girls
• HELLP liver enzymes and low platelets
• CNS-field a. neurodegenerative disease (e.g. Alzheimer disease) in children b. brain micro vessel disease in children c. diseases which are mediated via PAR 1 to PAR 4 receptors in children d. oxidative stress induced by thrombin in children
• Cancer a Primary and secondary prevention and/or treatment of cancer in children b. Prevention of thrombosis in polychemotherapy in children, particularly in polychemotherapy including Asparaginase, c. Prevention of thrombosis in children d. Treatment of thrombosis in children e. Mortality reduction as mono-therapy and in combination with anticancer agents in children
• the invention relates to the use of the compounds mentioned hereinbefore for preparing a medicament for the treatment and/or prophylaxis in children of one or several of the diseases mentioned hereinbefore, wherein the disease is associated with VTE.
• the direct thrombin inhibitor may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form.
• the composition may, for example, be presented in a form suitable for oral, topical, lingual, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
• the active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvinyl pyrrolidone, semisynthetic glicerides of fatty acids, benz- alconium chloride, sodium phosphate, EDTA, polysorbate 80.
• the compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient.
• the dosis range applicable per day is between 0.1 mg to 600 mg, preferably between 50 mg to 300 mg/day.
• Each dosage unit may conveniently contain from 0.1 mg to 200 mg, preferably from 50 mg to 150 mg.
• Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example inert dilu
• Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core may also consist of a number of layers.
• the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
• Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• a sweetener such as saccharine, cyclamate, glycerol or sugar
• a flavour enhancer e.g of. a flavouring such as vanilline or orange extract.
• suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
• preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid
• Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
• Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
• the starting material dabigatran etexilate (ethyl 3-[(2- ⁇ [4-(amino-hexyloxy- carbonylimino-methyl)-phenylamino]-methyl ⁇ -1 -methyl-'/ H-benzimidazole-5- carbonyl)-pyridin-2-yl-amino]-propionate) may for example be prepared as described in International Application WO 98/37075, Example 113.
• composition active substance 75.0 mg mannitol 50.0 mg water for injections ad 10.0 ml
• Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.
• This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
• This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
• 1 suppository contains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg

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• 2007
  • 2007-07-13 CL CL2007002067A patent/CL2007002067A1/es unknown
  • 2007-07-13 WO PCT/EP2007/057258 patent/WO2008009640A1/en not_active Ceased
  • 2007-07-13 AR ARP070103125A patent/AR062058A1/es not_active Application Discontinuation
  • 2007-07-13 CA CA002657270A patent/CA2657270A1/en not_active Abandoned
  • 2007-07-13 JP JP2009519957A patent/JP2009543844A/ja active Pending
  • 2007-07-13 EP EP07787526A patent/EP2043691A1/en not_active Withdrawn
  • 2007-07-16 TW TW096125874A patent/TW200817000A/zh unknown
  • 2007-07-17 US US11/779,032 patent/US20080015176A1/en not_active Abandoned
• 2010
  • 2010-09-27 US US12/891,184 patent/US20110015129A1/en not_active Abandoned

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