WO2003099280A1 - Novel formulation for the parenteral application of crobenetine - Google Patents

Novel formulation for the parenteral application of crobenetine Download PDF

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Publication number
WO2003099280A1
WO2003099280A1 PCT/EP2003/005400 EP0305400W WO03099280A1 WO 2003099280 A1 WO2003099280 A1 WO 2003099280A1 EP 0305400 W EP0305400 W EP 0305400W WO 03099280 A1 WO03099280 A1 WO 03099280A1
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pharmaceutical composition
acetic acid
bill
composition according
acetate buffer
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PCT/EP2003/005400
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German (de)
French (fr)
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Bernd Kruss
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Boehringer Ingelheim
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Priority to AU2003240699A priority Critical patent/AU2003240699A1/en
Priority to JP2004506804A priority patent/JP2005531573A/en
Priority to EP03730101A priority patent/EP1511487A1/en
Priority to CA002487153A priority patent/CA2487153A1/en
Publication of WO2003099280A1 publication Critical patent/WO2003099280A1/en

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    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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 a novel formulation of (-) - (1R, 2 "S) -2- (2" -benzyloxy) propyl 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan (Bill 890) or one of its pharmacologically acceptable salts, especially its hydrochloride, for parenteral, in particular for intravenous administration, their preparation and use.
  • BMI 890 and "active ingredient” is always the compound known from WO 99/14199 (-) - (1 R, 2 "S) -2- (2" -benzyloxy) propyl-4'-hydroxy 5,9,9-trimethyl-6,7-benzomorphan of the formula
  • Bill 890 in the form of the free base or the corresponding acid addition salts with pharmacologically acceptable acids, in particular in the form of their hydrochloride.
  • Other designations for Bill 890 include crobenetins and [2R- [2,3 (S *), 6]] - 1, 2,3,4,5,6-hexahydro-6,11,11-trimethyl-3- [2 - (phenylmethoxy) propyl] -2,6-methano-3-benzazocin-10-ol.
  • Bill 890 is a sodium channel blocker with neuroprotective properties; the main indications are thromboembolic stroke, brain injury and pain.
  • the object of the invention is to provide a new formulation for the active ingredient BIM 890, in particular for the hydrochloride thereof.
  • the invention relates to pharmaceutical compositions for parenteral administration comprising the active ingredient Bill 890 or one of its physiologically tolerated salts, in particular its hydrochloride, and mannitol as an auxiliary agent. material.
  • the amount of mannitol is preferably chosen so that an isotonic solution is obtained.
  • the pharmaceutical compositions of the invention also contain other conventional excipients and carriers such as 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.
  • acetic acid / acetate buffer consisting of acetic acid and sodium acetate or sodium acetate trihydrate
  • 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 chosen so that a certain pH and a certain buffer capacity is achieved.
  • the solvent is usually water for injections.
  • the pharmaceutical composition contains an acetic acid / acetate buffer in addition to the isotonicity of mannitol.
  • an acetic acid / acetate buffer in addition to the isotonicity of mannitol.
  • Particularly preferred is a 0.005 to 0.05 molar, preferably a 0.005 to 0.02 molar acetic acid / acetate buffer having a pH of 3.8 to 5, most preferably is a 0.01 molar acetic acid / acetate Buffers with a pH of 4.
  • Concentration here refers to the total concentration of acetic acid and acetate together; the ratio of acetic acid to acetate results from the desired pH. The indicated pH value is measured both in the pure buffer solution and in the finished injection or infusion solution.
  • An embodiment according to the invention of a parenteral preparation of Bill 890 or one of its physiologically acceptable salts, such as e.g. the hydrochloride, contains the active ingredient in dosages of 1 mg / kg body weight to 30 mg / kg body weight daily, preferably in the range 3-15 mg / kg body weight.
  • the application is preferably via continuous infusion over 24 hours, or optionally over several days, to maintain a steady state plasma level.
  • Preferred is a concentration of 0.03% (w / v) to 0.2% (w / v); particularly preferred is a concentration of 0.03% (w / v) to 0.07% (w / v).
  • the administered amount of the drug can be controlled.
  • the application of 250 ml of a solution according to Example 3 corresponds to a dose of 175 mg Bill 890 daily.
  • Example 4 Infusion solution 700 mq / 250 mL ("0.01 molar" acetate buffer pH 4)
  • Example 6 Infusion solution 200 mg / 100 ml ("0.01 molar" acetate buffer pH 4)

Abstract

The invention relates to a novel formulation containing crobenetine, or one of its pharmaceutically acceptable salts, for parenteral application.

Description

Neue Formulierung zur parenteralen Applikation von Crobenetine New formulation for parenteral administration of crobenetine
Die Erfindung betrifft eine neue Formulierung von (-)-(1R,2"S)-2-(2"-Benzyloxy)- propyl-4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan (Bill 890) oder eines seiner pharmakologisch verträglichen Salze, insbesondere seines Hydrochlorids, zur parenteralen, insbesondere zur intravenösen Anwendung, deren Herstellung und Verwendung.The invention relates to a novel formulation of (-) - (1R, 2 "S) -2- (2" -benzyloxy) propyl 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan (Bill 890) or one of its pharmacologically acceptable salts, especially its hydrochloride, for parenteral, in particular for intravenous administration, their preparation and use.
Mit den Bezeichnungen „BMI 890" und „Wirkstoff" ist stets die aus der WO 99/14199 bekannte Verbindung (-)-(1 R,2"S)-2-(2"-Benzyloxy)propyl-4'-hydroxy-5,9,9-trimethyl- 6,7-benzomorphan der FormelThe term "BMI 890" and "active ingredient" is always the compound known from WO 99/14199 (-) - (1 R, 2 "S) -2- (2" -benzyloxy) propyl-4'-hydroxy 5,9,9-trimethyl-6,7-benzomorphan of the formula
Figure imgf000002_0001
in Form der freien Base oder der entsprechenden Säureadditionssalze mit pharmakologisch unbedenklichen Säuren, insbesondere in Form ihres Hydrochlorids, gemeint. Andere Bezeichnungen für Bill 890 sind Crobenetine und [2R-[2,3(S*),6]]- 1 ,2,3,4,5,6-Hexahydro-6,11 ,11-trimethyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3- benzazocin-10-ol. Bill 890 ist ein Natrium-Kanal-Blocker mit neuroprotektiven Eigenschaften; die Hauptindikationsgebiete sind thromboembolischer Schlaganfall, Hirnverletzungen und Schmerz.
Figure imgf000002_0001
in the form of the free base or the corresponding acid addition salts with pharmacologically acceptable acids, in particular in the form of their hydrochloride. Other designations for Bill 890 include crobenetins and [2R- [2,3 (S *), 6]] - 1, 2,3,4,5,6-hexahydro-6,11,11-trimethyl-3- [2 - (phenylmethoxy) propyl] -2,6-methano-3-benzazocin-10-ol. Bill 890 is a sodium channel blocker with neuroprotective properties; the main indications are thromboembolic stroke, brain injury and pain.
Aufgabe der Erfindung ist es, eine neue Formulierung für den Wirkstoff BIM 890, insbesondere für dessen Hydrochlorid, bereitzustellen.The object of the invention is to provide a new formulation for the active ingredient BIM 890, in particular for the hydrochloride thereof.
Gegenstand der Erfindung sind pharmazeutische Zusammensetzungen zur parenteralen Applikation umfassend den Wirkstoff Bill 890 oder eines seiner physiologisch verträglichen Salze, insbesondere sein Hydrochlorid, und Mannitol als einen Hilfs- stoff. Die Menge an Mannitol wird bevorzugterweise so gewählt, das eine isotonische Lösung erhalten wird.The invention relates to pharmaceutical compositions for parenteral administration comprising the active ingredient Bill 890 or one of its physiologically tolerated salts, in particular its hydrochloride, and mannitol as an auxiliary agent. material. The amount of mannitol is preferably chosen so that an isotonic solution is obtained.
Gegebenenfalls enthalten die erfindungsgemäßen pharmazeutische Zusammensetzungen außerdem weitere übliche Hilfs- und Trägerstoffe wie beispielsweise einen Essigsäure/Acetat-Puffer bestehend aus Essigsäure und Natriumacetat bzw. Natriumacetat-Trihydrat oder einen Zitronensäure/Phosphat-Puffer bestehend z.B. aus Zitronensäure und Dinatriumhydrogenphosphat bzw. Dinatriumhydrogen- phosphat-Dihydrat. Üblicherweise wird die Menge der Pufferkomponenten so gewählt, daß ein bestimmter pH-Wert und eine bestimmte Pufferkapazität erreicht wird. Als Lösungsmittel dient üblicherweise Wasser für Injektionszwecke.Optionally, the pharmaceutical compositions of the invention also contain other conventional excipients and carriers such as 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. Usually, the amount of the buffer components is chosen so that a certain pH and a certain buffer capacity is achieved. The solvent is usually water for injections.
Bevorzugterweise enthält die pharmazeutische Zusammensetzung neben dem Isotonanz Mannitol einen Essigsäure/Acetat-Puffer. Besonders bevorzugt ist dabei ein 0,005 bis 0,05 molarer, vorzugsweise ein 0,005 bis 0,02 molarer Essigsäure/ Acetat-Puffer mit einem pH-Wert von 3,8 bis 5, ganz besonders bevorzugt ist ein 0,01 molarer Essigsäure/Acetat-Puffer mit einem pH-Wert von 4. Die Konzentrationsangabe bezieht sich hierbei auf die Gesamtkonzentration von Essigsäure und Acetat zusammen; das Verhältnis von Essigsäure zu Acetat ergibt sich aus dem gewünsch- ten pH-Wert. Der angegebene pH-Wert wird sowohl in der reinen Puffer- als auch in der fertigen Injektions- bzw. Infusionslösung gemessen.Preferably, the pharmaceutical composition contains an acetic acid / acetate buffer in addition to the isotonicity of mannitol. Particularly preferred is a 0.005 to 0.05 molar, preferably a 0.005 to 0.02 molar acetic acid / acetate buffer having a pH of 3.8 to 5, most preferably is a 0.01 molar acetic acid / acetate Buffers with a pH of 4. Concentration here refers to the total concentration of acetic acid and acetate together; the ratio of acetic acid to acetate results from the desired pH. The indicated pH value is measured both in the pure buffer solution and in the finished injection or infusion solution.
Die folgende Tabelle gibt als Beispiele die genaue Zusammensetzung eines 0,005, 0,01 bzw. 0.05 molaren Essigsäure/Acetat-Puffers für bestimmte pH-Werte wieder. Die Konzentrationen sind jeweils in mg/ml angegeben und beziehen sich auf 99 %- ige Essigsäure („HOAc") bzw. Natriumacetat-Trihydrat („NaOAc").The following table gives as an example the exact composition of a 0.005, 0.01 or 0.05 molar acetic acid / acetate buffer for certain pH values. The concentrations are given in mg / ml and refer to 99% acetic acid ("HOAc") or sodium acetate trihydrate ("NaOAc").
Figure imgf000003_0001
Für die oben genannten Indikationen ist eine leichte Steuerbarkeit der Dosierung erforderlich, um die Aufrechterhaltung von steady-state Plasmaspiegeln sicher gewährleisten zu können. Die erfindungsgemäße parenterale Formulierung von Bill 890 erfüllt diese Voraussetzungen.
Figure imgf000003_0001
For the above indications, easy controllability of the dosage is required to ensure the maintenance of steady-state plasma levels safely. The parenteral formulation of Bill 890 of the present invention meets these requirements.
Eine erfindungsgemäße Ausführung einer parenteralen Zubereitung von Bill 890 oder eines seiner physiologisch verträglichen Salze, wie z.B. das Hydrochlorid, enthält den Wirkstoff in Dosierungen von 1 mg/kg Körpergewicht bis 30 mg/kg Körpergewicht täglich, vorzugsweise im Bereich 3-15 mg/kg Körpergewicht. Die Mengen-, Konzentrations- bzw. Dosierungsangaben beziehen sich stets auf die Wirkstoffbase, unabhängig davon, ob Bill 890 in Form der „Base" (= Verbindung der auf Seite 1 angegebenen Formel) oder in Form eines der pharmakologisch verträglichen Salze eingesetzt wird'An embodiment according to the invention of a parenteral preparation of Bill 890 or one of its physiologically acceptable salts, such as e.g. the hydrochloride, contains the active ingredient in dosages of 1 mg / kg body weight to 30 mg / kg body weight daily, preferably in the range 3-15 mg / kg body weight. The quantitative, concentration or dosage information always refers to the active substance base, regardless of whether Bill 890 is used in the form of the "base" (= compound of the formula given on page 1) or in the form of one of the pharmacologically acceptable salts.
Die Anwendung erfolgt vorzugsweise über eine kontinuierliche Infusion über 24 Stunden oder gegebenenfalls über mehrere Tage, um einen Steady-State Plasmaspiegel aufrechtzuerhalten. Die Applikationsvolumina liegen im Bereich von 100 bis 500 ml, d.h. die Anwendungskonzentrationen des Wirkstoffs liegen im Bereich 50 mg/500 ml = 0,1 mg/ml (0,01 %) bis 1500 mg/500 ml = 3 mg/ml (0,3%). Bevorzugt ist eine Konzentration von 0,03 % (g/v) bis 0,2 % (g/v); besonders bevorzugt ist eine Konzentration von 0,03 % (g/v) bis 0,07 % (g/v).The application is preferably via continuous infusion over 24 hours, or optionally over several days, to maintain a steady state plasma level. The application volumes are in the range of 100 to 500 ml, i. the application concentrations of the active ingredient are in the range of 50 mg / 500 ml = 0.1 mg / ml (0.01%) to 1500 mg / 500 ml = 3 mg / ml (0.3%). Preferred is a concentration of 0.03% (w / v) to 0.2% (w / v); particularly preferred is a concentration of 0.03% (w / v) to 0.07% (w / v).
Durch Gabe eines bestimmten Volumens einer der erfindungsgemäßen Injektionsbzw. Infusions-Lösungen kann die verabreichte Menge des Wirkstoffs gesteuert werden. Beispielsweise entspricht die Applikation von 250 ml einer Lösung gemäß Beispiel 3 einer Gabe von 175 mg Bill 890 täglich.By administering a certain volume of the Injektionsbzw invention. Infusion solutions, the administered amount of the drug can be controlled. For example, the application of 250 ml of a solution according to Example 3 corresponds to a dose of 175 mg Bill 890 daily.
Die folgenden Beispiele sollen die Erfindung näher erläutern: BEISPIELEThe following examples are intended to explain the invention in more detail: EXAMPLES
Beispiel 1example 1
Infusionslösung 250 mg/500 mL („0,01 molarer" Acetatpuffer pH 4)Solution for infusion 250 mg / 500 mL ("0.01 molar" acetate buffer pH 4)
Bill 890 Hydrochlorid 274 mg*Bill 890 hydrochloride 274 mg *
Mannitol 25000 mgMannitol 25000 mg
Essigsäure 99% 250,5 mgAcetic acid 99% 250.5 mg
Natriumacetat-Trihydrat 113,0 mg Wasser für Injektionszwecke ad 500 mlSodium acetate trihydrate 113.0 mg water for injections ad 500 ml
*) entspricht 250 mg Bill 890 in Form der Base*) equals 250 mg Bill 890 in the form of the base
Beispiel 2Example 2
Infusionslösung 250 mg/500 mL („0,01 molarer" Acetatpuffer pH 4,5)Solution for infusion 250 mg / 500 mL ("0.01 molar" acetate buffer pH 4.5)
Bill 890 Hydrochlorid 274 mg*Bill 890 hydrochloride 274 mg *
Mannitol 25000 mg Essigsäure 99% 180,0 mgMannitol 25000 mg acetic acid 99% 180.0 mg
Natriumacetat-Trihydrat 265,0 mgSodium acetate trihydrate 265.0 mg
Wasser für Injektionszwecke ad 500 mlWater for injections ad 500 ml
*) entspricht 250 mg Bill 890 in Form der Base *) equals 250 mg Bill 890 in the form of the base
Beispiel 3Example 3
Infusionslösung 350 mg/500 mL („0.02 molarer" Acetatpuffer pH 4)Solution for infusion 350 mg / 500 mL ("0.02 molar" acetate buffer pH 4)
Bill 890 Hydrochlorid 383,6 mg**Bill 890 hydrochloride 383.6 mg **
Mannitol 25000 mgMannitol 25000 mg
Essigsäure 99% 501 ,0 mgAcetic acid 99% 501, 0 mg
Natriumacetat-Trihydrat 226,0 mgSodium acetate trihydrate 226.0 mg
Wasser für Injektionszwecke ad 500 mlWater for injections ad 500 ml
*) entspricht 350 mg Bill 890 in Form der Base*) equals 350 mg Bill 890 in the form of the base
Beispiel 4 Infusionslösung 700 mq/250 mL („0.01 molarer" Acetatpuffer pH 4)Example 4 Infusion solution 700 mq / 250 mL ("0.01 molar" acetate buffer pH 4)
BMI 890 Hydrochlorid 767 mg***BMI 890 hydrochloride 767 mg ***
Mannitol 11000 mgMannitol 11000 mg
Essigsäure 99% 125,25 mg Natriumacetat-Trihydrat 56,5 mgAcetic acid 99% 125.25 mg Sodium acetate trihydrate 56.5 mg
Wasser für Injektionszwecke ad 250 mlWater for injections ad 250 ml
***) entspricht 700 mg BIN 890 in Form der Base ***) corresponds to 700 mg BIN 890 in the form of the base
Beispiel 5Example 5
Infusionslösung 700 mg/500 mL („0,005 molarer" Acetatpuffer pH 4,5)Infusion solution 700 mg / 500 mL ("0.005 molar" acetate buffer pH 4.5)
Bill 890 Hydrochlorid 767 mg***Bill 890 hydrochloride 767 mg ***
Mannitol 25000 mgMannitol 25000 mg
Essigsäure 99% 90,0 mgAcetic acid 99% 90.0 mg
Natriumacetat-Trihydrat 132,5 mgSodium acetate trihydrate 132.5 mg
Wasser für Injektionszwecke ad 500 mlWater for injections ad 500 ml
*) entspricht 700 mg BIM 890 in Form der Base*) corresponds to 700 mg BIM 890 in the form of the base
Beispiel 6 Infusionslösung 200 mg/100 mL („0,01 molarer" Acetatpuffer pH 4)Example 6 Infusion solution 200 mg / 100 ml ("0.01 molar" acetate buffer pH 4)
BIN 890 Hydrochlorid 219,1 mg****BIN 890 hydrochloride 219.1 mg ****
Mannitol 5000 mgMannitol 5000 mg
Essigsäure 99% 50,1 mg Natriumacetat-Trihydrat 22,6 mgAcetic acid 99% 50.1 mg Sodium acetate trihydrate 22.6 mg
Wasser für Injektionszwecke ad 100 mlWater for injections ad 100 ml
****) entspricht 200 mg Bill 890 in Form der Base ****) corresponds to 200 mg Bill 890 in the form of the base

Claims

Patentansprüche claims
1. Pharmazeutische Zusammensetzung enthaltend Mannitol und Bill 890 oder eines seiner pharmakologisch verträglichen Salze.1. Pharmaceutical composition containing mannitol and Bill 890 or one of its pharmacologically acceptable salts.
2. Pharmazeutische Zusammensetzung nach Anspruch 1 , bei der das Hydrochlorid von Bill 890 als Wirkstoff verwendet wird.2. A pharmaceutical composition according to claim 1, wherein the hydrochloride of Bill 890 is used as the active ingredient.
3. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Zusammensetzung zusätzlich einen Puffer enthält.3. Pharmaceutical composition according to claim 1 or 2, characterized in that the composition additionally contains a buffer.
4. Pharmazeutische Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, daß es sich um einen Essigsäure/Acetat-Puffer handelt.4. Pharmaceutical composition according to claim 3, characterized in that it is an acetic acid / acetate buffer.
5. Pharmazeutische Zusammensetzung nach Anspruch 4, dadurch gekennzeichnet, daß der Essigsäure/Acetat-Puffer eine molare Konzentration zwischen 0,05 und 0,5 und einen pH-Wert von 3,8 bis 5 hat.5. Pharmaceutical composition according to claim 4, characterized in that the acetic acid / acetate buffer has a molar concentration between 0.05 and 0.5 and a pH of 3.8 to 5.
6. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 5 zur parenteralen Gabe.6. Pharmaceutical composition according to one of claims 1 to 5 for parenteral administration.
7. Pharmazeutische Zusammensetzung gemäß einem der voranstehenden An- sprüche, dadurch gekennzeichnet, daß sie zur intravenösen Anwendung bestimmt ist.7. Pharmaceutical composition according to one of the preceding claims, characterized in that it is intended for intravenous use.
8. Pharmazeutische Zusammensetzung gemäß einem der voranstehenden Ansprüche, dadurch gekennzeichnet, daß die Wirkstoff-Konzentration zwischen 0,1 mg/ml und 3 mg/ml liegt.8. Pharmaceutical composition according to one of the preceding claims, characterized in that the active ingredient concentration is between 0.1 mg / ml and 3 mg / ml.
9. Verwendung von Mannitol zur Herstellung eines Arzneimittels enthaltend Bill 890 oder eines seiner pharmakologisch verträglichen Salze, insbesondere sein Hydrochlorid, zur Behandlung von Schlaganfall. 9. Use of mannitol for the manufacture of a medicament containing Bill 890 or one of its pharmacologically acceptable salts, in particular its hydrochloride, for the treatment of stroke.
10. Verwendung nach Anspruch 9, dadurch gekennzeichnet, daß das Arzneimittel zusätzlich einen Puffer enthält.10. Use according to claim 9, characterized in that the medicament additionally contains a buffer.
11. Verwendung nach Anspruch 10, dadurch gekennzeichnet, daß es sich um einen Essigsäure/Acetat-Puffer handelt.11. Use according to claim 10, characterized in that it is an acetic acid / acetate buffer.
12. Verwendung nach Anspruch 11 , dadurch gekennzeichnet, daß der Essigsäure/ Acetat-Puffer eine molare Konzentration zwischen 0,05 und 0,5 und einen pH-Wert von 3,8 bis 5 hat.12. Use according to claim 11, characterized in that the acetic acid / acetate buffer has a molar concentration between 0.05 and 0.5 and a pH of 3.8 to 5.
13. Verwendung gemäß einem der Ansprüche 9 bis 12, dadurch gekennzeichnet, daß die pharmazeutische Zusammensetzung zur intravenösen Anwendung bestimmt ist.13. Use according to any one of claims 9 to 12, characterized in that the pharmaceutical composition is intended for intravenous use.
14. Verwendung gemäß einem der Ansprüche 9 bis 13, dadurch gekennzeichnet, daß die Wirkstoff-Konzentration zwischen 0,1 mg/ml und 3 mg/ml liegt.14. Use according to any one of claims 9 to 13, characterized in that the active ingredient concentration is between 0.1 mg / ml and 3 mg / ml.
15. Verfahren zur Behandlung von akutem Schlaganfall, dadurch gekennzeichnet, daß eine pharmazeutische Zusammensetzung gemäß einem der Ansprüche 1 bis 10 verwendet wird.15. A method for the treatment of acute stroke, characterized in that a pharmaceutical composition according to any one of claims 1 to 10 is used.
16. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung zur parenteralen Applikation zur Behandlung von Schlaganfall enthaltend Bill 890 oder eines seiner pharmakologisch verträglichen Salze, dadurch gekennzeichnet, daß Mannitol als Isotonanz verwendet wird.16. A process for preparing a pharmaceutical composition for parenteral administration for the treatment of stroke containing Bill 890 or one of its pharmacologically acceptable salts, characterized in that mannitol is used as isotonicity.
17. Verfahren nach Anspruch 16, dadurch gekennzeichnet, daß die Zusammensetzung zusätzlich einen Puffer enthält.17. The method according to claim 16, characterized in that the composition additionally contains a buffer.
18. Pharmazeutische Zusammensetzung nach Anspruch 17, dadurch gekennzeichnet, daß es sich um einen Essigsäure/Acetat-Puffer handelt. 18. Pharmaceutical composition according to claim 17, characterized in that it is an acetic acid / acetate buffer.
19. Pharmazeutische Zusammensetzung nach Anspruch 18, dadurch gekennzeichnet, daß der Essigsäure/Acetat-Puffer eine molare Konzentration zwischen 0,05 und 0,5 und einen pH-Wert von 3,8 bis 5 hat. 19. Pharmaceutical composition according to claim 18, characterized in that the acetic acid / acetate buffer has a molar concentration between 0.05 and 0.5 and a pH of 3.8 to 5.
PCT/EP2003/005400 2002-05-29 2003-05-23 Novel formulation for the parenteral application of crobenetine WO2003099280A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2003240699A AU2003240699A1 (en) 2002-05-29 2003-05-23 Novel formulation for the parenteral application of crobenetine
JP2004506804A JP2005531573A (en) 2002-05-29 2003-05-23 New formulation for parenteral use of clobenetine
EP03730101A EP1511487A1 (en) 2002-05-29 2003-05-23 Novel formulation for the parenteral application of crobenetine
CA002487153A CA2487153A1 (en) 2002-05-29 2003-05-23 New formulation for the parenteral application of crobenetine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10223784A DE10223784A1 (en) 2002-05-29 2002-05-29 New formulation for parenteral administration of crobenetine
DE10223784.0 2002-05-29

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JP (1) JP2005531573A (en)
AR (1) AR040135A1 (en)
AU (1) AU2003240699A1 (en)
CA (1) CA2487153A1 (en)
DE (1) DE10223784A1 (en)
PE (1) PE20040067A1 (en)
TW (1) TW200406205A (en)
UY (1) UY27824A1 (en)
WO (1) WO2003099280A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10223783A1 (en) * 2002-05-29 2003-12-11 Boehringer Ingelheim Pharma New formulation for parenteral administration of a Na-channel blocker

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BONHOMME-FAIVRE L ET AL: "Formulation of a charcoal suspension for intratumoral injection. Study of galenical excipients.", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY. UNITED STATES FEB 1999, vol. 25, no. 2, February 1999 (1999-02-01), pages 175 - 186, XP009014807, ISSN: 0363-9045 *
DEWAR D ET AL: "Intrastriatal malonate induces axonal damage which is attenuated by sodium channel blockade with crobenetine (BIII 890).", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 27, no. 2, 2001, 31st Annual Meeting of the Society for Neuroscience;San Diego, California, USA; November 10-15, 2001, pages 2313, XP009014806, ISSN: 0190-5295 *
MEYTHALER, JAY: "BIII - 890 -CL Boehringer Ingelheim", CURRENT OPINION IN INVESTIGATIONAL DRUGS (PHARMAPRESS LTD.) (2002), 3(12), 1733-1735, XP001153994 *
PSCHORN U ET AL: "Intravenous infusion of BIII 890 CL reduces lesion size in models of permanent and transient focal cerebral ischaemia in the rat.", SOCIETY FOR NEUROSCIENCE ABSTRACTS., vol. 25, no. 1-2, 1999, 29th Annual Meeting of the Society for Neuroscience.;Miami Beach, Florida, USA; October 23-28, 1999, pages 585, XP009014811, ISSN: 0190-5295 *

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EP1511487A1 (en) 2005-03-09
DE10223784A1 (en) 2003-12-11
JP2005531573A (en) 2005-10-20
CA2487153A1 (en) 2003-12-04
UY27824A1 (en) 2003-12-31
AR040135A1 (en) 2005-03-16
AU2003240699A1 (en) 2003-12-12
PE20040067A1 (en) 2004-03-30
TW200406205A (en) 2004-05-01

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