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WO2001078732A1 - Solution pour perfusion stable au stockage a base de ciprofloxacine - Google Patents

Solution pour perfusion stable au stockage a base de ciprofloxacine Download PDF

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Publication number
WO2001078732A1
WO2001078732A1 PCT/EP2001/004163 EP0104163W WO0178732A1 WO 2001078732 A1 WO2001078732 A1 WO 2001078732A1 EP 0104163 W EP0104163 W EP 0104163W WO 0178732 A1 WO0178732 A1 WO 0178732A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
acid
infusion solutions
infusion
mol
Prior art date
Application number
PCT/EP2001/004163
Other languages
German (de)
English (en)
Inventor
Klaus Sommermeyer
Hans-Jörg Müller
Tilo Hniopek
Bernd Eschenbach
Original Assignee
Fresenius Kabi Deutschland Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fresenius Kabi Deutschland Gmbh filed Critical Fresenius Kabi Deutschland Gmbh
Priority to AU2001273941A priority Critical patent/AU2001273941A1/en
Publication of WO2001078732A1 publication Critical patent/WO2001078732A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to storage-stable infusion solutions of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid, containing 0.015 to 0.5 g of the active ingredient mentioned 100 ml of aqueous solution and a sufficient amount of a physiologically acceptable acid to dissolve the active ingredient and to stabilize the solution.
  • the invention further relates to the method for producing and using such infusion solutions.
  • the invention describes ready-to-use infusion solutions as well as other dosage forms which are introduced into such infusion solutions before application, the active ingredient being 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid is known as ciprofloxacin.
  • EP-A-0049 355 protects i.a. Medicines containing 7-amino-l-cyclopropyl-4-oxo-l, 4-dihydronaphtyridine-3-carboxylic acid.
  • EP-A-0 078 362 protects 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids.
  • the active ingredients known from the two EPs have high antibacterial effects and are suitable as medicaments for combating bacterial infections in humans and animals.
  • the known compounds are not or only very little suitable for producing infusion and / or injection solutions because, for example, the pH and / or the solubility and / or the shelf life, in particular with regard to excretions, of the ready-to-use infusion and / or injection solutions do not meet the pharmaceutical requirements for such solutions.
  • DE 33 33 719 AI discloses solutions of the lactic acid salts of piperazinyl-quinolonic and / or -azaquinolonecarboxylic acids which, in addition to the lactic acid salts mentioned and optionally conventional auxiliaries, additionally contain at least one acid which does not lead to precipitation.
  • acids which do not lead to precipitation include lactic acid, methanesulfonic acid, propionic acid or succinic acid, although lactic acid is by far preferred.
  • the lactic acid content of the infusion solutions according to DE 33 33 719 AI can carry 0.1 to 90%.
  • the lactic acid content of the solution to be applied can be 0.1 to 10%.
  • EP-A-0 219 784 The problems occurring according to DE 33 33 719 AI (corresponds to EP-A 0 138 018) are tried to be avoided by EP-A-0 219 784 by providing infusion solutions of ciprofloxacin which contain 0.015 to 0.5 g of the active ingredient per 100 ml of aqueous solution and, depending on the active substance concentration, 0.9 to 5.0 mol, based on 1 mol of active substance, of one or more physiologically tolerated acids.
  • the infusion solutions according to EP-A 0 219 784 contain, in addition to the active ingredient, water and other customary formulation auxiliaries, an amount of one or more acids from the group consisting of hydrochloric acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid, sufficient to dissolve the active ingredient and stabilize the solution.
  • hydrochloric acid methanesulfonic acid, propionic acid, succinic acid, glutaric acid
  • Citric acid fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid, phosphoric acid, adipic acid, hydroxyacetic acid, sulfuric acid, nitric acid, Acetic acid, malic acid, L-aspartic acid and lactic acid.
  • the reduction of the amount of acid to be used for stabilization is of fundamental interest, especially when the stability of infusion solutions is comparable.
  • EP-A-0 287 926 relates to parenterally administrable solutions of quinolonecarboxylic acids, i.a. Ciprofloxacin, where it is proposed to use particularly pure main active ingredient components to improve storage stability.
  • EP-A-0 287 926 relates to such parenterally administrable solutions in which no more than 1 to 10 ppm, based on the main active component (ciprofloxacin) of the solution, are present on secondary components (“impurities” of the active ingredient)
  • secondary components carried in by the main active ingredient in the infusion solution succeed in reducing the excretions from the infusion solutions (cloudiness during storage) in accordance with EP-A-0 287 926.
  • reducing the secondary components is a relatively complex operation.
  • the publication DE 197 03 023 A discloses that the number of detectable particles is reduced by using glass bottles which have a silicone coating on the inner surface. This can further improve the shelf life of high-purity infusion solutions. It can therefore be assumed that the formation of precipitates is due to the number of particles that are inherently present. The more particles there are, the more particles are formed. This accelerates the formation of particles over time.
  • EP-A-0 219 784 lists, inter alia, lactic acid, phosphoric acid, adipic acid, hydroxyacetic acid and sulfuric acid as possible auxiliaries in an amount of 0.9 to 5 mol per 1 mol of active ingredient, these alternatives are completely missing in EP 0 219 784 B1 , wherein the amount of acid (s) according to EP 0 219 784 B should be between 1.04 and 2.2 moles per 1 mole. Hydroxyacetic acid and phosphoric acid in substoichiometric amounts do not give usable results. In this respect, the successful use of sulfuric acid was not obvious, at least not in the amount according to the invention of less than 0.9 mol per 1 mol of active ingredient.
  • those infusion solutions are of particular interest which are distinguished by the fact that the total sulfuric acid content is less than 0.8 mol based on 1 mol of ciprofloxacin (active ingredient). Also very particularly preferred are infusion solutions in which the total sulfuric acid content is less than 0.6 mol per 1 mol of active ingredient. Quite unexpectedly, it has also been found that the use of sulfuric acid together with certain additional acids enables infusion solutions of ciprofloxacin in which the stabilization is superadditive, quasi synergistic.
  • Special infusion solutions are characterized in that they have an additional acid, in addition to sulfuric acid, a mono- or diester of orthophosphoric acid with glycerol or a higher-value physiologically compatible sugar such as glucose, sucrose, fructose or sugar alcohol such as sorbitol, mannitol or xylitol, the total content of sulfuric acid and additional acid is less than 1.04 mol per 1 mol of active ingredient.
  • the acid to be used for additional stabilization of the infusion solutions of ciprofloxacin is particularly preferably glycerol esters of orthophosphoric acid.
  • Monoglycerin orthophosphoric acid esters are particularly preferred.
  • infusion solutions in which, in addition to sulfuric acid, the acid (s) glycerol-1-phosphate, glycerol-2-phosphate or a mixture of the glycerol-phosphoric acid monoesters is or are.
  • Diphosphates are also particularly suitable acids. These include in particular glucose diphosphate and fructose 1,6-diphosphate. The acids mentioned are about as strong as phosphoric acid.
  • additions of glycerol 1-phosphate, glycerol 2-phosphate, glucose diphosphate and / or fructose 1,6-diphosphate significantly exceed phosphoric acid in terms of improving the storage stability.
  • the minimum amount of acid required per mole of active ingredient to dissolve naturally also depends on the active ingredient concentration and the acid (s) used and is therefore not constant. It should also be noted that the information in the amounts of acid relates only to the amounts which, according to generally known basic chemical rules, are not converted into the corresponding salt (s) by adding bases. Dissociation of the acids was not taken into account in the quantities, so that they relate to the dissociated and undissociated quantity of acids.
  • the infusion solutions according to the invention can also contain further formulation agents such as complexing agents, antioxidants, isotonizing agents and / or agents for adjusting the pH.
  • the osmolality of the infusion solutions is 0.20 to 0.70 Osm / kg, preferably 0.26 to 0.39 Osm / kg and is adjusted by isotonic agents such as NaCl, mannitol, glucose, sucrose and glycerol or mixtures of such substances. If necessary, substances can also be used that are contained in common, commercially available infusion carrier solutions.
  • the usual infusion carrier solutions include infusion solutions with an electrolyte supply without carbohydrates such as saline, Ringer's lactate solution, etc. and those with carbohydrates and solutions for the supply of amino acids, each with and without carbohydrate content.
  • infusion carrier solutions are in Rote Liste 1998, list of finished medicinal products of the members of the Federal Association of the Pharmaceutical Industry, Editio Cantor, Aulendorf / Württ. listed.
  • infusion solutions which, in addition to water, active ingredient and other formulation auxiliaries, contain such an amount of sodium chloride or other auxiliaries customary for isotonization that a solution which is isotonic or slightly hypotonic or hypertonic with the tissue fluid of the human or animal body is present.
  • the infusion solutions according to the invention have a pH of 3.0 to 5.2. pH values of 3.6 to 4.7 and 3.9 to 4.5 are preferred. PH values in the range from 4.1 to 4.3 are very particularly preferred.
  • the infusion solutions according to the invention can be present in dosage units suitable for infusion with removable contents of 40 to 600 ml, preferably 50 to 120 ml.
  • the present invention also relates to a process for the preparation of infusion solutions according to the independent claim relating to the infusion solutions, which is characterized in that a suitable amount of the active ingredient, optionally in the form of a salt such as alkali or alkaline earth metal salt or addition salt, a hydrate or a hydrate of the salt or in the form of mixtures of these salts or hydrates, with a quantity of sulfuric acid and optionally a physiologically compatible monoester or diester of orthophosphoric acid or a mixture of several physiologically compatible monoester or diester derivatives of orthophosphoric acid, the total amount of acid being less than 0.9 Mole per 1 mole of active ingredient, optionally adding formulation auxiliaries and filling up with water or a conventional infusion carrier solution in such a way that a concentration range of 0.015 to 0.5 g is established for the active ingredient, be when using an alkali or alkaline earth metal salt of the active ingredient, the amounts required for dissolution are also contained in the amounts necessary for neutralizing the active ingredient ani
  • the solutions correspond to the properties already listed with regard to pH, amounts of acid and osmolality.
  • an acid whose anion corresponds to the anion of the active ingredient salt or of the salt hydrate.
  • the pH of the infusion solutions according to the invention can be adjusted to the above-mentioned values with (physiologically) compatible acids and / or bases, i.e. Set 3.0 to 5.2, especially 3.6 to 4.7.
  • the solutions or only a part thereof can be slightly warmed, preferably to temperatures between 20 ° C and 80 ° C
  • the solutions according to the invention can be produced particularly economically using concentrated solutions.
  • the amounts of active ingredient required for a batch with the main amount of acid required for the batch e.g. 95% based on molar basis
  • This concentrate is then diluted.
  • any other auxiliary substances - such as Table salt for isotonization - added, as well as the possibly missing amount of acid.
  • the solution After the solution has been prepared, it is generally filtered in order to remove most of the particles. Suitable filtering methods are known per se, so that reference can be made to the prior art. The number of particles is limited to what is medically necessary and economically sensible. These data and suitable methods are known from specialist books.
  • the solutions according to the invention show a high storage stability, which is not limited by the number of particles.
  • the effort as described in documents EP 0 287 926 and DE-A-197 30 23 to make the solutions durable can be dispensed with.
  • Example 1 was essentially repeated. However, the solution obtained was not filled into a glass bottle but into a polyolefin-based bag, which is also suitable for medical purposes.
  • the solution thus obtained was filtered like Example 1, filled into a glass bottle for medical purposes and then sterilized at 121 ° C.
  • the sterile solution thus obtained was stored at room temperature for 2 months and regularly checked visually. After two months there was a visually detectable crystal formation. The attempt was then stopped.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des solutions pour perfusion stables au stockage, à base de 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipérazinyl)-quinoline-3-acide carboxylique (ciprofloxacine), contenant entre 0,015 et 0,5 g de principe actif par 100 ml de solution aqueuse et de l'acide sulfurique dans une quantité inférieure à 0,9 mole pour 1 mole de principe actif, suffisante pour dissoudre le principe actif et pour stabiliser la solution. L'invention concerne en outre des procédés permettant de préparer les solutions pour perfusion, ainsi que leur utilisation. Les solutions pour perfusion selon l'invention permettent de réduire la teneur en acide, sont plus stables au stockage que d'autres solutions connues, tout en ayant la même teneur en acide et permettent de tolérer une plus grande proportion de constituants auxiliaires dans le principe actif.
PCT/EP2001/004163 2000-04-15 2001-04-11 Solution pour perfusion stable au stockage a base de ciprofloxacine WO2001078732A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001273941A AU2001273941A1 (en) 2000-04-15 2001-04-11 Ciprofloxacin infusion solutions having a good storage stability

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10018783.8 2000-04-15
DE10018783A DE10018783A1 (de) 2000-04-15 2000-04-15 Lagerstabile Infusionslösung des Ciprofloxacins mit verringertem Säuregehalt

Publications (1)

Publication Number Publication Date
WO2001078732A1 true WO2001078732A1 (fr) 2001-10-25

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DE (1) DE10018783A1 (fr)
WO (1) WO2001078732A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026233A1 (fr) * 2000-09-29 2002-04-04 Fresenius Kabi Deutschland Gmbh Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide
DE102004005186B3 (de) * 2004-02-02 2005-10-13 Krka Tovarna Zdravil, D.D. Verfahren zur Herstellung von gereinigtem Ciprofloxacin
US7629460B2 (en) 2004-08-25 2009-12-08 Boehringer Ingelheim International Gmbh Dihydropteridione derivatives, process for their manufacture and their use as medicament
US7728134B2 (en) 2004-08-14 2010-06-01 Boehringer Ingelheim International Gmbh Hydrates and polymorphs of 4[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament
US7750152B2 (en) 2003-02-26 2010-07-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Intermediate compounds for making dihydropteridinones useful as pharmaceutical compositions and processes of making the same
US7759485B2 (en) 2004-08-14 2010-07-20 Boehringer Ingelheim International Gmbh Process for the manufacture of dihydropteridinones
US7759347B2 (en) 2004-06-21 2010-07-20 Boehringer Ingelheim International Gmbh 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments
EP1778238B1 (fr) * 2004-08-14 2011-10-12 Boehringer Ingelheim International GmbH Solutions de perfusion de dihydropteridinones stables au stockage
US8058270B2 (en) 2004-08-14 2011-11-15 Boehringer Ingelheim International Gmbh Dihydropteridinones for the treatment of cancer diseases
USRE43115E1 (en) 2004-12-02 2012-01-17 Boehringer Ingelheim International Gmbh Process for the manufacture of fused piperazin-2-one derivatives
US8143247B2 (en) 2004-08-14 2012-03-27 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
US8188086B2 (en) 2006-02-08 2012-05-29 Boehringer Ingelheim International Gmbh Specific salt, anhydrous and crystalline form of a dihydropteridione derivative
US8193188B2 (en) 2004-07-09 2012-06-05 Boehringer Ingelheim International Gmbh Methods of using pyridodihydropyrazinones
US8329695B2 (en) 2007-08-03 2012-12-11 Boehringer Ingelheim International Gmbh Crystalline form of the free base N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7r)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide
US8546566B2 (en) 2010-10-12 2013-10-01 Boehringer Ingelheim International Gmbh Process for manufacturing dihydropteridinones and intermediates thereof
US9358233B2 (en) 2010-11-29 2016-06-07 Boehringer Ingelheim International Gmbh Method for treating acute myeloid leukemia
US9370535B2 (en) 2011-05-17 2016-06-21 Boehringer Ingelheim International Gmbh Method for treatment of advanced solid tumors
US9867831B2 (en) 2014-10-01 2018-01-16 Boehringer Ingelheim International Gmbh Combination treatment of acute myeloid leukemia and myelodysplastic syndrome
US9956225B2 (en) 2013-07-26 2018-05-01 Boehringer Ingelheim International Gmbh Treatment of myelodysplastic syndrome

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219784A2 (fr) * 1985-10-24 1987-04-29 Bayer Ag Solutions d'infusion de l'acide 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipérazinyl)-chinolone-3-carboxylique
WO1990001933A1 (fr) * 1988-08-26 1990-03-08 Alcon Laboratories, Inc. Combinaison d'un antibiotique de quinolone et de steroides pour utilisation ophtalmique locale

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219784A2 (fr) * 1985-10-24 1987-04-29 Bayer Ag Solutions d'infusion de l'acide 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipérazinyl)-chinolone-3-carboxylique
WO1990001933A1 (fr) * 1988-08-26 1990-03-08 Alcon Laboratories, Inc. Combinaison d'un antibiotique de quinolone et de steroides pour utilisation ophtalmique locale

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026233A1 (fr) * 2000-09-29 2002-04-04 Fresenius Kabi Deutschland Gmbh Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide
US8003786B2 (en) 2003-02-26 2011-08-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Dihydropteridinone compounds
US7816530B2 (en) 2003-02-26 2010-10-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Piperazinyl compounds
US7750152B2 (en) 2003-02-26 2010-07-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Intermediate compounds for making dihydropteridinones useful as pharmaceutical compositions and processes of making the same
US7786299B2 (en) 2003-02-26 2010-08-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Methods for treating diseases or conditions using dihydropteridinone compounds
DE102004005186B3 (de) * 2004-02-02 2005-10-13 Krka Tovarna Zdravil, D.D. Verfahren zur Herstellung von gereinigtem Ciprofloxacin
US7759347B2 (en) 2004-06-21 2010-07-20 Boehringer Ingelheim International Gmbh 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments
US8193188B2 (en) 2004-07-09 2012-06-05 Boehringer Ingelheim International Gmbh Methods of using pyridodihydropyrazinones
US8445675B2 (en) 2004-08-14 2013-05-21 Boehringer Ingelheim International Gmbh Storage stable perfusion solution for dihydropteridinones
US8143247B2 (en) 2004-08-14 2012-03-27 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
US8591895B2 (en) 2004-08-14 2013-11-26 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
US7728134B2 (en) 2004-08-14 2010-06-01 Boehringer Ingelheim International Gmbh Hydrates and polymorphs of 4[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament
US8202867B2 (en) 2004-08-14 2012-06-19 Boehringer Ingelheim International Gmbh Methods of using hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide
US8034816B2 (en) 2004-08-14 2011-10-11 Boehringer Ingelheim International Gmbh Hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament
EP1778238B1 (fr) * 2004-08-14 2011-10-12 Boehringer Ingelheim International GmbH Solutions de perfusion de dihydropteridinones stables au stockage
US8058270B2 (en) 2004-08-14 2011-11-15 Boehringer Ingelheim International Gmbh Dihydropteridinones for the treatment of cancer diseases
US7759485B2 (en) 2004-08-14 2010-07-20 Boehringer Ingelheim International Gmbh Process for the manufacture of dihydropteridinones
US8138373B2 (en) 2004-08-14 2012-03-20 Boehringer Ingelheim International Gmbh Process for the manufacture of dihydropteridinones
US8138341B2 (en) 2004-08-14 2012-03-20 Boehringer Ingelheim International Gmbh Intermediate compounds useful for the manufacture of dihydropteridinones
US7700769B2 (en) 2004-08-25 2010-04-20 Boehringer Ingelheim International Gmbh Dihydropteridione derivatives, process for their manufacture and their use as medicament
US7723517B2 (en) 2004-08-25 2010-05-25 Boehringer Ingelheim International Gmbh Dihydropteridione derivatives, process for their manufacture and their use as medicament
US7629460B2 (en) 2004-08-25 2009-12-08 Boehringer Ingelheim International Gmbh Dihydropteridione derivatives, process for their manufacture and their use as medicament
US7807831B2 (en) 2004-08-25 2010-10-05 Boehringer Ingelheim International Gmbh Dihydropteridione derivatives, process for their manufacture and their use as medicament
USRE43115E1 (en) 2004-12-02 2012-01-17 Boehringer Ingelheim International Gmbh Process for the manufacture of fused piperazin-2-one derivatives
US8664222B2 (en) 2006-02-08 2014-03-04 Boehringer Ingelheim International Gmbh Specific salt, anhydrous and crystalline form of a dihydropteridione derivative
US8188086B2 (en) 2006-02-08 2012-05-29 Boehringer Ingelheim International Gmbh Specific salt, anhydrous and crystalline form of a dihydropteridione derivative
US8329695B2 (en) 2007-08-03 2012-12-11 Boehringer Ingelheim International Gmbh Crystalline form of the free base N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7r)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide
US8546566B2 (en) 2010-10-12 2013-10-01 Boehringer Ingelheim International Gmbh Process for manufacturing dihydropteridinones and intermediates thereof
US9358233B2 (en) 2010-11-29 2016-06-07 Boehringer Ingelheim International Gmbh Method for treating acute myeloid leukemia
US9370535B2 (en) 2011-05-17 2016-06-21 Boehringer Ingelheim International Gmbh Method for treatment of advanced solid tumors
US9956225B2 (en) 2013-07-26 2018-05-01 Boehringer Ingelheim International Gmbh Treatment of myelodysplastic syndrome
US9867831B2 (en) 2014-10-01 2018-01-16 Boehringer Ingelheim International Gmbh Combination treatment of acute myeloid leukemia and myelodysplastic syndrome

Also Published As

Publication number Publication date
AU2001273941A1 (en) 2001-10-30
DE10018783A1 (de) 2001-10-25

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