EP0523086A1 - Pharmazeutische wässrige lösung von 4- 2-(benzolsulfonylamino)-ethyl]-phenoxyessigsäure - Google Patents

Pharmazeutische wässrige lösung von 4- 2-(benzolsulfonylamino)-ethyl]-phenoxyessigsäure

Info

Publication number
EP0523086A1
EP0523086A1 EP91906603A EP91906603A EP0523086A1 EP 0523086 A1 EP0523086 A1 EP 0523086A1 EP 91906603 A EP91906603 A EP 91906603A EP 91906603 A EP91906603 A EP 91906603A EP 0523086 A1 EP0523086 A1 EP 0523086A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
basic salt
solutions
benzenesulfonylamino
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91906603A
Other languages
German (de)
English (en)
French (fr)
Inventor
Heinrich Woog
Werner Gruber
Werner Heller
Fritz Demmer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim 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 Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0523086A1 publication Critical patent/EP0523086A1/de
Withdrawn legal-status Critical Current

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
    • A61K9/0012—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a stable pharmaceutical aqueous solution of 4- [2-benzenesulfonyl-a ino) -ethyl] -phenoxyacetic acid.
  • This solution is used as an injection or infusion solution or in concentrated form as an additive to infusion solutions.
  • the active ingredient 4- [2- (benzenesulfonylamino) ethyl] phenoxyacetic acid and its preparation is described in EP-A-004, Oll as example 1.
  • This compound is particularly suitable for the production of medicaments for the treatment of diseases which are associated with increased platelet aggregation.
  • the active substance has a significant lipid-lowering effect and has a pronounced inhibitory effect on platelet aggregation.
  • Atherosclerotic diseases of the vascular system diseases of the kidney, and the treatment of the shock lung.
  • the following indications also come into consideration in this connection: prevention of damage to the microcirculation by radiation therapy (eg in the kidney); Treatment of sudden hearing loss; Preventing the 're- occlusion in bypass operations, (e.g., urokinase, streptokinase kinase, tPA and their derivatives.)
  • bypass operations e.g., urokinase, streptokinase kinase, tPA and their derivatives.
  • fibrinolytic agents Prevention or reduction of platelet drop in dialysis or extracorporeal circulation and keeping open arterial and venous cannulas and catheters, also together with prostacyclin and prostacyclin mimetics
  • Prevention of at Neutralization of heparin with side effects of protamine sulfate Prevention of attacks with unstable angina and TIA (transient ischaemic attacks
  • the active ingredient can take the form of solid pharmaceutical forms, such as, for example, B. tablets, pellets or dragees, or liquid pharmaceutical formulations can be administered as a solution for injection or infusion.
  • the active ingredient should be administered parenterally in the highest possible concentration of up to 50 mg / ml in order to achieve a therapeutically sufficient dosage.
  • the free acid of the active ingredient as such is relatively slightly soluble in aqueous solution, so that the corresponding sodium salt was first used to prepare the solutions.
  • the sodium salt has a solubility of about 55 mg / ml (164 mmol / 1). In itself, this should be sufficient to prepare the concentrated solutions suitable for injections.
  • particle-free injection or infusion solutions are required which are practically free of suspended particles.
  • limits are set for particle size, which must not exceed certain values.
  • the maximum permissible particle size per container is 10-25 ⁇ .
  • a basic salt former is added to the aqueous solution or suspension of the active ingredient.
  • Suitable salt formers also come from basic amino acids, such as arginine, histidine or lysine; Meglumine (N-methylglucosamine) or tri (hydroxymethyl) aminomethane (TRIS®, Tro etamol®) in question.
  • These pharmaceutical solutions contain the active ingredient in a concentration of 25-100 mg / ml (about 75-300 mmol / 1, molar mass of the Na salt: 335.5 g / mol).
  • the proportion of the basic salt former can vary widely depending on the type of salt former used.
  • the molar ratio between active substance and basic salt former is usually in the range from 1: 0.1 to 1: 2, preferably 1: 0.5 to 1: 1.5. However, an approximately equimolar amount is particularly preferably used.
  • basic amino acids are used, their concentrations are generally between 10 and 60 mg / ml (approximately 60 to 350 mmol / l), preferably 13 to 50 mg / ml (approximately 70 to 320 mmol / l).
  • Meglumine is used in an amount of 14 to -70 mg / ml (about 70 to 360 mmol / 1), preferably 16 to 64 mg / ml (about 80 to 330 mmol / 1).
  • the finished pharmaceutical dosage form of an injection solution in ampoule form contains the active ingredient in an amount of 0.25 to 3 g, the volume being between 5 ml and 10 ml depending on requirements.
  • concentrated solutions which are used as an additive to conventional infusion solutions and are added to these solutions shortly before application, are commercially available.
  • concentrated solutions contain the active substance in a concentration of 25 to 100 mg / ml (about 70 to 300 mmol / 1), with a total volume of 10 ml and an amount of active ingredient from 0.25 to 1 g.
  • amino acids which can be used as basic salt formers can be used in the form of their racemates or their optically active forms, but preferably in the L form.
  • solutions according to the invention are also physiologically well tolerated in higher concentrations of the active ingredient and, when used, show very good vein tolerance. In addition, they survive heat treatment at 100 to 130 ° C to reduce germs without significant decomposition. Furthermore, these solutions have the advantage that, surprisingly, they can be stored even at room temperature over a longer period of time without cloudiness occurring or the active substance changing chemically. Based on previous experience, such solutions are stable in storage over a period of at least three years.
  • the solutions according to the invention have increased solubility compared to the sodium salt of the active ingredients. While the sodium salt of 4- [benzenesulfonylamino) ethyl] phenoxyacetic acid has a solubility of 55 mg / ml (164 mmol / 1), a significantly higher solubility was found in the solutions prepared with basic salt formers.
  • the solubility is 78 mg / ml (233 mmol / 1)
  • the arginine salt has a solubility of 320 mg / ml (954 mmol / 1) and the corresponding meglumine salt even has a solubility of 430 mg / ml (1282 mmol / 1). Due to this shift in the solubility limit to significantly higher values, it can be assumed that the tendency to form visible or invisible floating particles in the solution is relatively low.
  • there is the possibility of producing a concentrate of the active substances can be used as an additive to conventional infusion solutions. Such highly concentrated solutions can be added to other infusion solutions, which are used, for example, to feed the patient, without further addition, which means that the required volume of infusion can be significantly reduced compared to separate administration.
  • the solutions according to the invention have a pH of 8.0 to 8.4, the basic salt formers being present in a buffer capacity of up to 0.1 val / l.
  • the equivalence point is at pH 6.2, in the case of the meglumine salt at pH 7.4, while the sodium salt has an equivalence point at pH 8.5.
  • the injection solution has the best compatibility with the arginine salt, since it surprisingly has the lowest pH value and the lowest equivalence point.
  • the solutions according to the invention do not lead to significant changes in pH at the injection site, so that an almost painless intravenous or intra-arterial application of these solutions is possible.
  • like solutions can be applied undiluted.
  • the buffer capacities of the basic salt formers used are of the order of 0.1 val / 1, preferably 0.05 to 0.1 val / 1.
  • the solutions according to the invention can be brought to the pH of the blood of 7.4 by adding an approximately equivalent amount of acid, for example hydrochloric acid. With a normal ampoule content of 10 ml injection solution with a content of about 0.1 eq / 1 of the basic salt former, the addition of 10 ml of a 0.1 normal hydrochloric acid solution is sufficient to set the desired physiological pH.
  • the solutions according to the invention are used as an additive to infusion solutions in the form of concentrated solutions, the solution is applied unchanged via infusion pumps or diluted with corresponding infusion solutions, such as a 5% glucose solution or one 0.9% sodium chloride solution.
  • the solutions according to the invention can furthermore contain customary pharmacological auxiliaries, such as, for. B. mannitol, also organic solubilizers such. B. polyethylene glycols, propylene glycol or other alkaloids such as ethanol.
  • customary pharmacological auxiliaries such as, for. B. mannitol, also organic solubilizers such. B. polyethylene glycols, propylene glycol or other alkaloids such as ethanol.
  • further pharmaceutical active ingredients can be present in the solution, provided the active ingredients are mutually compatible and simultaneous administration is therapeutically expedient.
  • Example 1 The following embodiments explain the invention by way of example, without any intention that the inventive concept should be restricted thereby:
  • Example 1
  • the solution suitable for filling in approx. 1000 ampoules is produced as follows:
  • the solution suitable for filling in approx. 1000 ampoules is produced as follows:
  • 4- [2- (benzenesulfonylamino) ethyl] phenoxy acetic acid is introduced into 7 l of water for injections with nitrogen gas and suspended by vigorous stirring.
  • the 4- [2- (benzenesulfonylamino) ethyl] phenoxyacetic acid is dissolved by slowly adding the arginine.
  • a pH of 8.0 to 8.2 is established.
  • the mannitol is dissolved and the solution made up to a final volume of 10 l and stirred well.
  • the solution is sterile filtered through the usual filters, filled into ampoules and sterilized with nitrogen before and after gassing.
  • the pH of the solution thus obtained is 8.1.
  • 4- [2- (Benzol ⁇ sulfonylamino) -ethyl] -phenoxyacetic acid is initially introduced into 15 l of water for injections with nitrogen gassing and suspended by vigorous stirring. By slowly adding the meglumine, 4- [benzenesulfonylamino) ethyl] phenoxyacetic acid is dissolved. The solution is made up to the final volume and stirred well, sterile-filtered through the usual filters, filled with nitrogen in ampoules with pre- and post-gassing, and sterilized. The pH value of the infusion solution concentrate thus obtained is 8.3.
  • the solution suitable for filling in approx. 1000 ampoules is produced as follows:
  • 4- [benzenesulfonylamino) ethyl] phenoxy acetic acid is initially introduced into 15 l of water for injection purposes while gassing with nitrogen and suspended by vigorous stirring. By slowly adding the arginine, the 4- [benzenesulfonylamino) ethyl] phenoxyacetic acid is dissolved. The solution is filled up to the final volume and stirred well, sterile filtered through the usual filters, filled into ampoules with nitrogen before and after gassing and sterilized. The pH of the infusion solution concentrate thus obtained is 8.2.
  • the titration basicity corresponds to 0.68 ml of 0.1 normal hydrochloric acid, which are required per ampoule to lower the pH from 8.2 to 7.4.
  • the solution suitable for filling in approx. 1000 ampoules is produced as follows:
  • 4- [2- (benzenesulfonylamino) ethyl] phenoxy acetic acid is introduced into 15 l of water for injections with nitrogen gassing and suspended by vigorous stirring. By slowly adding the arginine, the 4- [benzene-sulfonylamino) ethyl] phenoxyacetic acid is dissolved. The solution is made up to the final volume and stirred well, filtered through the usual filters, filled into ampoules with nitrogen before and after gassing, and sterilized. The pH of the infusion solution concentrate thus obtained is 8.2. The titration basicity corresponds to 0.34 ml 0.1. normal hydrochloric acid, which are required per ampoule to lower the pH from 8.2 to 7.4.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP91906603A 1990-04-02 1991-03-26 Pharmazeutische wässrige lösung von 4- 2-(benzolsulfonylamino)-ethyl]-phenoxyessigsäure Withdrawn EP0523086A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4010536 1990-04-02
DE4010536A DE4010536A1 (de) 1990-04-02 1990-04-02 Pharmazeutische waessrige loesung von 4-(2-(benzolsulfonylamino)-ethyl)-phenoxyessigsaeure

Publications (1)

Publication Number Publication Date
EP0523086A1 true EP0523086A1 (de) 1993-01-20

Family

ID=6403562

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91906603A Withdrawn EP0523086A1 (de) 1990-04-02 1991-03-26 Pharmazeutische wässrige lösung von 4- 2-(benzolsulfonylamino)-ethyl]-phenoxyessigsäure

Country Status (6)

Country Link
US (1) US5324749A (enrdf_load_stackoverflow)
EP (1) EP0523086A1 (enrdf_load_stackoverflow)
JP (1) JPH05505813A (enrdf_load_stackoverflow)
AU (1) AU7550391A (enrdf_load_stackoverflow)
DE (1) DE4010536A1 (enrdf_load_stackoverflow)
WO (1) WO1991015202A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE202014105015U1 (de) 2014-10-21 2014-10-29 Ebm-Papst Mulfingen Gmbh & Co. Kg Erdungsvorrichtung

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499142A3 (en) * 1991-02-09 1993-05-05 Hoechst Aktiengesellschaft Potentiation of the antireactive-antiasthmatic effect of inhaled loop diuretics by inhaled non steroidal anti-flammatory drugs
CA2136007C (en) * 1993-03-17 1999-12-14 Kiyoaki Katano Novel compound with platelet aggregation inhibitor activity
US6727286B2 (en) 2001-11-02 2004-04-27 Cumberland Pharmaceuticals Inc. Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
WO2003039532A1 (en) * 2001-11-02 2003-05-15 Cumberland Pharmaceuticals Inc. Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
US6806291B1 (en) * 2003-10-09 2004-10-19 The Foundation For The Lsu Health Sciences Center Analgesic compounds, their synthesis and pharmaceutical compositions containing them
CA2606598C (en) 2005-05-13 2014-12-23 Topotarget Uk Limited Pharmaceutical formulations of hdac inhibitors
CA2872012C (en) 2012-05-08 2017-06-20 Aeromics, Llc New methods
WO2015069956A2 (en) 2013-11-06 2015-05-14 Aeromics, Llc Novel formulations

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DE2809377A1 (de) * 1978-03-04 1979-09-13 Boehringer Mannheim Gmbh Phenoxyalkylcarbonsaeure-derivate, verfahren zu deren herstellung sowie diese verbindungen enthaltende arzneimittel
GB2054370B (en) * 1979-07-24 1983-09-21 Rosco As Injectable potentiated sulphonamide compositions
DE3000377A1 (de) * 1980-01-07 1981-07-09 Boehringer Mannheim Gmbh, 6800 Mannheim Neue sulfonamide, verfahren zu deren herstellung sowie diese verbindungen enthaltende arzneimittel
DE3151196A1 (de) * 1981-12-23 1983-06-30 Kurt Heinz Prof. Dr. 7800 Freiburg Bauer Verfahren zur herstellung von gut loeslichen 5-aminosalicylsaeure-arzneimittelzubereitungen
NZ221977A (en) * 1986-10-09 1991-03-26 Smithkline Beckman Corp Thrombolytic composition comprising a plasminogen activator (tpa, uk or sk) and a thromboxane synthase inhibitor; kits thereof and process for preparation thereof
US4931460A (en) * 1987-09-17 1990-06-05 E. R. Squibb & Sons, Inc. Post-ischemic myocardial dysfunction using thromboxane A2 antagonists
US4808627A (en) * 1987-12-16 1989-02-28 E. R. Squibb & Sons, Inc. Method of preventing or treating toxemia in pregnancy using a thromboxane A2 receptor antagonist
DE68909958D1 (de) * 1988-01-19 1993-11-25 Tanabe Seiyaku Co Phenoxyessigsäure-Derivate, ihre Herstellung, pharmazeutische Zusammensetzungen, die sie enthalten, und deren Verwendung.
US4820733A (en) * 1988-03-07 1989-04-11 E.R. Squibb & Sons, Inc. Method of preventing or reducing platelet loss during extracorporeal circulation using a thromboxane A2 receptor antagonist

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE202014105015U1 (de) 2014-10-21 2014-10-29 Ebm-Papst Mulfingen Gmbh & Co. Kg Erdungsvorrichtung

Also Published As

Publication number Publication date
AU7550391A (en) 1991-10-30
US5324749A (en) 1994-06-28
DE4010536A1 (de) 1991-10-10
WO1991015202A1 (de) 1991-10-17
DE4010536C2 (enrdf_load_stackoverflow) 1992-05-07
JPH05505813A (ja) 1993-08-26

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