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WO2003105844A1 - Association medicamenteuse composee de bloquants du canal sodium et d'une substance fibrinolytique destinee au traitement d'etats ischemiques - Google Patents

Association medicamenteuse composee de bloquants du canal sodium et d'une substance fibrinolytique destinee au traitement d'etats ischemiques Download PDF

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Publication number
WO2003105844A1
WO2003105844A1 PCT/EP2003/005813 EP0305813W WO03105844A1 WO 2003105844 A1 WO2003105844 A1 WO 2003105844A1 EP 0305813 W EP0305813 W EP 0305813W WO 03105844 A1 WO03105844 A1 WO 03105844A1
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Prior art keywords
hydrogen
methyl
ethyl
optionally
different
Prior art date
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German (de)
English (en)
Inventor
Sophie Banzet
Hermann Duettmann
Annerose Mauz
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Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Priority to CA002485751A priority Critical patent/CA2485751A1/fr
Priority to JP2004512748A priority patent/JP2005536478A/ja
Priority to EP03759907A priority patent/EP1515720A1/fr
Priority to AU2003250338A priority patent/AU2003250338A1/en
Publication of WO2003105844A1 publication Critical patent/WO2003105844A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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 invention relates to new drug combinations based on sodium channel blockers 1 and fibrinolytics 2, processes for their preparation and their use for the production of medicaments for the treatment of ischemic conditions.
  • the invention relates to drug combinations containing one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic 2, optionally in the presence of customary auxiliaries or carriers.
  • sodium channel blockers 1 which can be used according to the invention:
  • the sodium channel blocker (s) are preferably selected from the group consisting of Pirmencol, Sipatrigine, Irampanel, Pilsicainide, Oxcarbazepine, Topiramate, Fosphenytoin, Flunarizine, Ropivacaine, Levobupivacail, Zonisipride, Mexon , Bisaramil, Milacainide, Safinamide, Bupivacaine, Tetrodotoxin, NS 7, the compounds of the general formula 1a
  • X is a single bond, -O-, C-
  • R 1 is hydrogen, methyl, ethyl, phenyl
  • R 2 is hydrogen, methyl
  • R 3 is hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, methoxy
  • R 4 is hydrogen, methyl, ethyl
  • R 5 is hydrogen, methyl, ethyl
  • R 7 is tert-butyl, cyclohexyl or phenyl, where phenyl may optionally be substituted by R 9 and R 1 0, which may be the same or different;
  • R8 is hydrogen, C-
  • R 9 is hydrogen, methyl, fluorine, chlorine, bromine, methoxy
  • R10 is hydrogen, methyl, fluorine, chlorine, bromine, methoxy; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids;
  • R "1 ', R 2 ' and R 3 ' are the same or different, hydrogen, methyl or ethyl
  • R 4 ' is hydrogen, methyl or ethyl
  • R 5 ', R 6 ' and R 7 ' are the same or different, hydrogen, methyl or ethyl
  • R 8 'and R 9 ' are hydrogen, fluorine, chlorine, bromine, methyl,
  • sodium channel blocker (s) 1 selected from the group consisting of Pirmencol,
  • Ci -C 3 alkylene -0-CH 2 -CH 2 -0- or -0-CH 2 -CH 2 -NH-;
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or chlorine
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen or methyl
  • R 6 is methyl or ethyl
  • R 7 is tert-butyl, cyclohexyl or phenyl, where phenyl may optionally be substituted by R 9 and R 10 , which may be the same or different
  • R 8 is hydrogen
  • R 9 is hydrogen, methyl, fluorine or chlorine
  • R 1 ° is hydrogen, methyl, fluorine or chlorine
  • R " ! ', R 2 ' and R 3 ' the same or different, hydrogen or methyl
  • R 4 ' is hydrogen or methyl
  • R 5 ', R 6 ' and R 7 ' are the same or different, hydrogen or methyl, preferably
  • R 8 ' is hydrogen, methyl, hydroxy or methoxy, preferred
  • R 9 ' can be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable
  • the sodium channel blocker (s) 1 are selected from the group consisting of
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen or methyl
  • R 7 is phenyl, which phenyl may optionally be substituted by R 9 and R 1 0, which may be the same or different;
  • R 8 is hydrogen
  • R 9 is hydrogen, methyl, fluorine or chlorine
  • R 10 is hydrogen, methyl, fluorine or chlorine; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids;
  • R 1 ', R 2 ' and R 3 ' are identical or different, hydrogen or methyl;
  • R 4 ' is hydrogen or methyl;
  • R5 ', R6' and R 7 'methyl; R 8 ' is hydrogen or methyl, preferably hydrogen;
  • R 9 ' can be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
  • Ci-Cs-alkyl generally represents a branched or unbranched hydrocarbon radical having 1 to 4 or 1 to 8 carbon atoms, which is optionally substituted by one or more halogen atoms, preferably fluorine can be, which can be the same or different from each other.
  • halogen atoms preferably fluorine can be
  • Hydrocarbon residues called: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2, -dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1 -Ethy
  • lower alkyl radicals having 1 to 4 carbon atoms such as methyl, ethyl, propyl, / so-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl.
  • alkylene means a branched or unbranched double-bonded hydrocarbon bridge having 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different from one another.
  • Alkoxy generally represents a straight-chain or branched hydrocarbon radical bonded via an oxygen atom - one is preferred Lower alkoxy group with 1 to 4 carbon atoms. - The methoxy group is particularly preferred.
  • the compound of the formula 1a is (-) - (1 R, 2 "S) -2- (2" - benzyloxy) propyl-4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
  • This compound is also known as the Crobenetine.
  • the component ⁇ is particularly preferably selected from the group consisting of fosphenytoin, zonisamide, sipatrigine, irampanel, mexiletine, NS 7, crobenetine, (2R) -N-allyloxyethyl-1, 2,3,4,5 , 6-hexahydro-6, 11, 11 -trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride and (2R, 2 "S) -N- (2-allyloxypropyl) -1, 2nd , 3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride, particularly preferably crobenetine, (2R) -N-allyloxyethyl-1,2 , 3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride and (2R,
  • the compounds 1 can be used in the form of their salts, in particular for pharmaceutical use, in the form of their pharmacologically acceptable acid addition salts with an inorganic or organic acid.
  • succinic acid for example, succinic acid,
  • Hydrobromic acid acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. Mixtures of the aforementioned acids can also be used.
  • the compounds of formula 1a are known from WO 99/14199.
  • the compounds of formula 1b are not yet known in the prior art.
  • the compounds of the formula 1b which are not yet known in the prior art and can be used according to the invention can be analogous to known compounds Create synthesis methods. Possible synthetic routes to the compounds of the formula V_ are explained below by way of example.
  • allyloxyacetic acid 1.8 g are placed in 15 ml of dichloromethane, mixed with 4.8 g of TBTU and 7.5 ml of ethyldiisopropylamine and stirred at RT for 15 min. It is then cooled to -5 ° G and 3.1 g of 1, 2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methano-3-benzazocin-10-ol are added. The mixture is stirred for 30 minutes at 0 ° C. and for 1 h at RT. Then one time each with 100ml 2nHCL and 100ml 10%
  • Washed potassium carbonate solution dried and i.Vac. concentrated.
  • the residue is taken up in 50 ml of THF and added dropwise under nitrogen to a suspension of 1.0 g of lithium aluminum hydride in 50 ml of THF. (Temp. Rises to 35 ° C.)
  • the mixture is then heated to 50 ° C., stirred for 1 h, cooled and 1 ml at 0-10 ° C.
  • Example 4 .2R, 2 "S.-N-r2-.2-methyl-propenoxy) -propy ⁇ -1, 2,3,4,5,6-hexahvdro-6,11.11-trimethyl-2,6-methano-3 -benzazocin-10-ol-hydrochloride
  • the residue is dissolved in 20 ml dichloromethane and added dropwise at RT 1.5 g SOCI 2 . After 30 min. becomes i.Vak. concentrated, the residue taken up in 20 ml of THF and added dropwise under nitrogen to a suspension of 0.5 g of lithium aluminum hydride in 20 ml of terahydrofuran. The mixture is then heated to 50 ° C. for 2 h, cooled, 1.5 ml of 4N NaOH are added dropwise and the mixture is stirred for 30 min. The precipitate is filtered off with suction and the mother liquor is vacuum. concentrated. The residue is filtered through a short silica gel column (approx. 30 mL silica gel, approx.
  • Firbrinolytics 2 which can be used according to the invention:
  • fibrinolytics 2 are preferably selected from the group of plasminogen activators.
  • plasminogen activators human tissue plasminogen activator, t-PA
  • tenecteplase reteplase
  • streptokinase urokinase
  • urokinase anistreplase
  • monteplase nateplase
  • duteplase lanoteplase
  • silteplase amediplase and desmoteplase. All of these fibrinolytics are known in the art.
  • Alteplase (amino acid sequence: GenBank Accession No. AAB59510) is a fibrinolytic approved as a medicament, the production of which by recombinant expression, preferably in cell lines of the Chinese hamster Cricetulus griseus (CHO cells), as well as its pharmaceutical formulation and medical use are described in detail in the prior art (Pennica et al., Nature 301, 214-221 (1983); EP 0 093 619; Andersen et al., Biotechnol Bioeng 70 (1), 25-31 (2000); Dowd et al., Biotechnol Prog 16 ( 5), 786-794 (2000); Fann et al., Biotechnol Bioeng 69 (2), 204-212 (2000); Werner et al., Drug research 48 (8), 870-880 (1998); Wemicke et Will , Anal Biochem 203 (1), 146-150 (1992); Bos et al., Biochim Biophys Acta 11
  • Tenectepiase (TNK-tPA; T103N, N117Q, KHRR (296-299) AAAA-tPA) is also a drug approved fibrinolytic. Its preparation and use is described in references WO 93/24635; Keyt et al., Proc Natl Acad Sei US S. 1994 Apr 26; 91 (9): 3670-4; Turcasso et Nappi, Ann Pharmacother. 2001 Oct; 35 (10): 1233-40; MacGahan, Issues Emerg Health Technol. 2001 Jan; (t3): 1-6; Davydov et Cheng, Clin Ther. 2001 Jul; 23 (7): 982-97; The Assent II investigators, Lancet. 1999 Aug 28; 354 (9180): 716-22 described in detail.
  • the literature describes a large number of further plasminogen activators which can be used as component 2 for the combination according to the invention.
  • fibrinolytics 2 are particularly preferably selected from the group consisting of old plase (t-PA), tenectepiase, reteplase, streptokinase, urokinase, anistreplase, monoplase and nateplase.
  • Fibrinolytics 2 which are particularly preferred according to the invention are selected from the group of old plase (t-PA), tenectepiase, reteplase, urokinase and anistreplase, where Alteplase, Tenectepiase and Reteplase, particularly preferably Alteplase, are of outstanding importance according to the invention.
  • the present invention further relates to the use of the combinations according to the invention of one or more, preferably a sodium channel blocker 1 , and one or more, preferably a fibrinolytic 2 for the preparation of a medicament for the treatment of ischemic conditions of different Genesis.
  • the present invention preferably relates to the use of the combinations according to the invention of one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic, 2 for the manufacture of a medicament for the treatment of cardiac or cerebral ischemia, particularly preferably for the treatment of stroke.
  • ischemic stroke particularly preferably of acute, ischemic stroke.
  • the present invention further relates to a method for the treatment of ischemic conditions of different origins, which is characterized in that a combination according to the invention of one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic, 2 is applied.
  • the present invention preferably relates to a method for the treatment of cardiac or cerebral ischemia, particularly preferably stroke, according to the invention preferably furthermore ischemic stroke, particularly preferably acute, ischemic stroke, which is characterized in that a combination according to the invention of one or more, preferably one Sodium channel blocker _ and one or more, preferably a fibrinolytic 2 is applied.
  • the present invention further relates to the use of one or more, preferably a sodium channel blocker, for the production of a medicament for the combined treatment of ischemic conditions of different origins with one or more, preferably a fibrinolytic, 2.
  • the present invention preferably relates to the use mentioned above for the production of a Medicament for the combined treatment of cardiac or brain ischemia, particularly preferably for the treatment of stroke with one or more, preferably a fibrinolytic 2.
  • a Medicament for the combined treatment of cardiac or brain ischemia, particularly preferably for the treatment of stroke with one or more, preferably a fibrinolytic 2.
  • a fibrinolytic 2 Of particular importance in the context of The present invention is the above use for the combined treatment of ischemic stroke, particularly preferably of acute, ischemic stroke with one or more, preferably one fibrinolytic 2.
  • the present invention further relates to a method for the treatment of ischemic conditions of different origins, which is characterized in that one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic, 2 simultaneously or sequentially in a single or two separate, preferably in two separate dosage forms can be applied.
  • the present invention preferably relates to a method for the treatment of cardiac or brain ischemia, particularly preferably of stroke, according to the invention preferably further of ischemic stroke, particularly preferably of acute, ischemic stroke, which is characterized in that one or more, preferably a sodium channel blocker, and a or more, preferably one fibrinolytic 2, can be administered simultaneously or sequentially in a single or two separate, preferably in two separate, dosage forms.
  • the pharmaceutical combinations according to the invention can contain the active constituents 1 and 2 in a single or in two separate administration forms.
  • the two components are preferably in two separate dosage forms
  • the two components are preferably in two separate dosage forms
  • the application of the combination of 1 and 2 according to the invention in the context of the abovementioned use and in the context of the abovementioned method can be carried out by simultaneous administration of the combination of 1 and 2 or, if 1 and 2 are present, in different administration forms by simultaneous or sequential administration of the components 1 and 2 take place.
  • Sequential in the context of the present invention is to be understood as any application of components _ or 2 that does not take place simultaneously.
  • simultaneous application in particular also understood the type of application in which at least one of components 1 and 2 is administered for example by means of an infusion over a longer period of time and the other component is also used during this application interval. If both components _ and 2 are administered by infusion over a longer period of time, it also means in the sense of the present invention that the infusion intervals overlap at least briefly.
  • components 1 and 2 are preferably administered simultaneously or at least at a short time interval, i.e. for example within an hour.
  • Treatment with the pharmaceutical combinations according to the invention is particularly effective here if it takes place within a very short time after the onset of the stroke.
  • the therapy is particularly preferably started at the latest within about 5 hours, particularly preferably within 4 hours, further preferably within 3 hours after the onset of the stroke.
  • the compounds 1. can be administered orally, transdermally, by inhalation or parenterally.
  • the compounds are present as active constituents in customary dosage forms, for example in compositions which essentially consist of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc.
  • An effective dose of the compounds _ is between 1 and 1000, preferably between 1 and 500, particularly preferably between 5-300 mg / dose in the case of oral administration , with intravenous, subcutaneous or intramuscular use between 0.001 and 100, preferably between 0.1 and 70 mg per dose.
  • component 1 according to the invention is in particular possible to use component 1 according to the invention as an infusion solution, preferably in a physiological saline solution or
  • crobenetine can be applied as component _ initially in a dose of 20-70 mg, preferably 30 to 60 mg, particularly preferably 50 mg over a period of about 30 minutes to 2 hours, preferably over 45 to 90 minutes, particularly preferably over an hour become.
  • Crobenetine can then be followed by further applications in doses of, for example, 5 to 50 mg, preferably 10 to 40 mg, particularly preferably 20 to 30 mg over a period of 2 to 8 hours, preferably 3 to 7 hours preferably connect for 4 to 6 hours. If necessary, this second application of component 1 crobenetine can be followed by others.
  • formulations comprise at least one compound of the formula 1a or 1b or one of its pharmaceutically acceptable salts and a cyclodextrin derivative, in particular gamma-cyclodextrin ( ⁇ -CD), hydroxypropyl-gamma-cyclodextrin (HP- ⁇ -CD), hydroxypropyl-beta -cyclodextrin (HP-ß-CD) or sulfobutyl ether-beta-cyclodextrin (SBE-ß-CD).
  • a cyclodextrin derivative is hydroxypropyl- ⁇ -cyclodextrin.
  • Hydroxypropyl- ⁇ -cyclodextrin with a molar degree of substitution from 0.5 to 0.7 is commercially available, for example, from Wacker-Chemie GmbH, D-Burghausen, under the name “CAVASOL® W8 HP Pharma”. “CAVASOL® W8 HP Pharma "is particularly preferred for these pharmaceutical compositions.
  • the pharmaceutical compositions according to the invention intended for parenteral use can contain hydroxy acids such as malic acid, lactic acid, tartaric acid or citric acid.
  • auxiliaries and carriers such as the isotonic agents glucose, mannitol or sodium chloride or sodium acetate or sodium acetate trihydrate as a buffer in combination with acetic acid or a citric acid / phosphate buffer consisting, for example, of citric acid and disodium hydrogen phosphate or Disodium hydrogen phosphate dihydrate. Water is usually used as the solvent for injections.
  • the molar ratio of the compound of formula 1a or 1b to cyclodextrin in these formulations is, for example, between 1: 1 and 1: 5.
  • a molar ratio of 1: 2.5 to 1: 3.5 is preferred.
  • this molar ratio according to the invention is preferably between 1: 0.5 and 1: 3; a molar ratio of 1: 0.5 to 1: 1.5 is particularly preferred.
  • These formulations are particularly preferably used when crobenetine is applied as component 1.
  • formulations for parenteral administration which are in addition to a compound of the formula 1a or 1b or a their pharmaceutically acceptable salts containing mannitol as an adjuvant.
  • the amount of mannitol is preferably chosen so that an isotonic solution is obtained.
  • these pharmaceutical compositions also contain other customary auxiliaries and excipients such as, for example, an acetic acid / acetate buffer consisting of acetic acid and sodium acetate or sodium acetate trihydrate or a citric acid / phosphate buffer consisting e.g. from citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dihydrate.
  • the amount of the buffer components is usually chosen so that a certain pH value and a certain buffer capacity is achieved. Water is usually used as the solvent for injections.
  • the pharmaceutical composition preferably contains an acetic acid / acetate buffer.
  • a 0.005 to 0.05 molar, preferably a 0.005 to 0.02 molar acetic acid / acetate buffer with a pH of 3.8 to 5 is particularly preferred, a 0.01 molar acetic acid / acetate is very particularly preferred.
  • Buffer with a pH of around 4. The concentration given here refers to the total concentration of acetic acid and acetate; the ratio of acetic acid to acetate results from the desired pH. The specified pH value is measured both in the pure bufferais and in the finished solution for injection or infusion.
  • These formulations are particularly preferably used when crobenetine is used as component ⁇ . D.2.1)
  • Formulation example 7 solution for infusion (acetate buffer pH 4)
  • Formulation example 8 infusion solution (acetate buffer pH 4.5)
  • Formulation example 9 solution for infusion (acetate buffer pH 4)
  • Formulation example 11 (solution for infusion (acetate buffer pH 4.5)) Crobenetine hydrochloride 767 mg mannitol 25000 mg
  • Formulation example 12 solution for infusion (acetate buffer pH 4)
  • the amount of the active ingredient administered can be controlled by administration of a certain volume of one of the solutions described above.
  • the daily application of 100 ml of a solution according to Example 1 corresponds to a dose of 280 mg crobenetine daily.
  • Fibrinolytic 2 is usually a polypeptide that must be administered parenterally.
  • the application can take place in particular by intravenous, intraarterial, intramuscular, intra- or subcutaneous injection, but administration by inhalation of a powder or aerosol is also possible.
  • Typical formulations are freeze-dried preparations (lyophilisates) of the polypeptide, which are reconstituted with a solution for injection or infusion immediately before administration.
  • the reconstitution solution can be water or a buffered aqueous solution.
  • the formulation can also consist of an aqueous solution, which is preferably buffered with a physiologically compatible buffer and can additionally contain conventional stabilizers, solubilizers, and preservatives.
  • auxiliaries for such Solid or liquid formulations are alkali hydrogen phosphate / alkali dihydrogen phosphate, sodium chloride, serum albumin, polyoxyethylene sorbitan monolaurate (Tween ® 20), polyoxyethylene sorbitan monooleate (Tween ® 80), ethylenediamine tetraacetate (EDTA), sucrose, mannitol, dextran alkanol, and amino acid
  • the application is usually parenteral, preferably by intravenous injection or infusion.
  • the mode of application and dosage depend on the fibrinolytic chosen, in particular on its specific biological activity and half-life in the blood plasma.
  • Alteplase which has a relatively short half-life, is typically administered in a total dose of 100 mg as follows: 10-15 mg as an intravenous bolus, followed by an intravenous infusion of 50 mg over a period of 30 to 60 minutes, followed by another infusion of 60-180 minutes up to the maximum dose.
  • Tenectepiase has a longer half-life and can therefore be used as a single bolus based on body weight up to a maximum dose of
  • Reteplase which has a medium half-life and a lower specific activity, is administered as an intravenous double bolus every 30 minutes at a dose of 10 units (560 mg) per bolus.
  • the person skilled in the art knows how to find suitable dosages for a new medicament.
  • the person skilled in the art can use formulation and
  • composition Alteplase 10 mg / 20 mg / 50 mg / 100 mg.
  • further components arginine, phosphoric acid, polysorbate 80.
  • Tenectepiase (powder and solvent for solution for injection) Composition: Tenectepiase 8,000 U / 10,000 U (40 mg / 50 mg), other components: arginine, phosphoric acid, polysorbate 20.
  • Reteplase (powder and solvent for solution for injection) Composition: Reteplase 0.56 g (equivalent to 10 units). further components: tranexamic acid, potassium monohydrogen phosphate,
  • Phosphoric acid sucrose, polysorbate 80. Water for injections 10 ml.
  • Streptokinase (dry substance for infusion solution)
  • Composition highly purified streptokinase 250,000 IU / 750,000 IU /
  • Streptokinase (oral tablets)
  • Composition streptokinase 10,000 IU, streptodomase 2500- 10,000 IU.
  • other ingredients magnesium stearate, calcium hydrogen phosphate,
  • Urokinase (dry matter) Composition: Urokinase 500 000 I.U. further components: sodium monohydrogen phosphate,
  • Urokinase (dry matter) Composition: Urokinase (human) 500,000 IU other ingredients: sodium dihydrogen phosphate, sodium monohydrogen phosphate, sodium chloride, dextran 40.
  • Anistreplase (dry substance and solvent for intravenous injection) Composition .: 209-230 mg dry substance with anistreplase 29.55-

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  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouvelles associations médicamenteuses à base de bloquants du canal sodium (1) et d'une substance fibrinolytique (2). L'invention concerne également leur procédé de production ainsi que leur utilisation pour produire des médicaments destinés au traitement d'états ischémiques.
PCT/EP2003/005813 2002-06-15 2003-06-04 Association medicamenteuse composee de bloquants du canal sodium et d'une substance fibrinolytique destinee au traitement d'etats ischemiques Ceased WO2003105844A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002485751A CA2485751A1 (fr) 2002-06-15 2003-06-04 Association medicamenteuse composee de bloquants du canal sodium et d'une substance fibrinolytique destinee au traitement d'etats ischemiques
JP2004512748A JP2005536478A (ja) 2002-06-15 2003-06-04 虚血症状を治療するためのナトリウムチャンネルブロッカー及び血栓溶解薬の薬物組み合わせ
EP03759907A EP1515720A1 (fr) 2002-06-15 2003-06-04 Association medicamenteuse composee de bloquants du canal sodium et d'une substance fibrinolytique destinee au traitement d'etats ischemiques
AU2003250338A AU2003250338A1 (en) 2002-06-15 2003-06-04 Medicament combinations of sodium channel blockers and fibrinolytics for treating ischaemic conditions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10226814.2 2002-06-15
DE10226814A DE10226814A1 (de) 2002-06-15 2002-06-15 Neue Arzneimittelkombinationen zur Behandlung ischämischer Zustände

Publications (1)

Publication Number Publication Date
WO2003105844A1 true WO2003105844A1 (fr) 2003-12-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/005813 Ceased WO2003105844A1 (fr) 2002-06-15 2003-06-04 Association medicamenteuse composee de bloquants du canal sodium et d'une substance fibrinolytique destinee au traitement d'etats ischemiques

Country Status (6)

Country Link
EP (1) EP1515720A1 (fr)
JP (1) JP2005536478A (fr)
AU (1) AU2003250338A1 (fr)
CA (1) CA2485751A1 (fr)
DE (1) DE10226814A1 (fr)
WO (1) WO2003105844A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1941879A1 (fr) * 2007-01-05 2008-07-09 PAION Deutschland GmbH Agent neuroprotecteur pour le traitement des lésions neuronales.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999014199A1 (fr) * 1997-09-12 1999-03-25 Boehringer Ingelheim Pharma Kg 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-1o-oles substitues, procedes permettant de les preparer et leur utilisation comme medicaments
WO2002064085A2 (fr) * 2001-02-02 2002-08-22 Ortho-Mcneil Pharmaceutical, Inc. Traitement de dysfonctionnements neurologiques au moyen de sulfamates de fructopyranose et d'erythropoietine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999014199A1 (fr) * 1997-09-12 1999-03-25 Boehringer Ingelheim Pharma Kg 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-1o-oles substitues, procedes permettant de les preparer et leur utilisation comme medicaments
WO2002064085A2 (fr) * 2001-02-02 2002-08-22 Ortho-Mcneil Pharmaceutical, Inc. Traitement de dysfonctionnements neurologiques au moyen de sulfamates de fructopyranose et d'erythropoietine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BITTNER CH; ZUBER M; EISNER L: "Akute Ischaemie der Hand bei einem Drogenabhängigen nach akzidenteller intraarterieller Injektion", SWISS SURGERY, vol. 8, no. 6, 2002, pages 281 - 284, XP009016623 *
DE LEY, G; WEYNE, J; DEMEESTER, G; STRYCKMANS K; GOETHALS, P; LEUSEN, I: "Streptokinase treatment versus calcium overload blockade in experimental thromboembolic stroke", STROKE, vol. 20, no. 3, 1989, pages 357 - 361, XP009016621 *
YANG, Y; LI Q; MIYASHITA H; HOWLETT W; SIDDIQUI M; SHUAIB A: "Usefulness of post-ischaemic thrombolysis with or without neuroprotection in a focal embolic model of cerebral ischaemia", J. NEUROSURGERY, vol. 92, no. 5, 2000, pages 841 - 847, XP009016622 *
YANG, Y; LI Q; SHUAIB A: "Enhanced neuroprotection and reduced haemmorrhagic incidence in focal cerebral ischaemia of rat by low dose combination therapy of urokinase and topiramate", NEUROPHARMACOLOGY, vol. 39, no. 5, 2000, pages 881 - 888, XP002253109 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1941879A1 (fr) * 2007-01-05 2008-07-09 PAION Deutschland GmbH Agent neuroprotecteur pour le traitement des lésions neuronales.

Also Published As

Publication number Publication date
DE10226814A1 (de) 2004-01-08
CA2485751A1 (fr) 2003-12-24
JP2005536478A (ja) 2005-12-02
AU2003250338A1 (en) 2003-12-31
EP1515720A1 (fr) 2005-03-23

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