EP0804184A1 - USE OF $g(v)-GUANIDINOCARBOXYLIC ACID ESTERS - Google Patents

USE OF $g(v)-GUANIDINOCARBOXYLIC ACID ESTERS

Info

Publication number
EP0804184A1
EP0804184A1 EP94909036A EP94909036A EP0804184A1 EP 0804184 A1 EP0804184 A1 EP 0804184A1 EP 94909036 A EP94909036 A EP 94909036A EP 94909036 A EP94909036 A EP 94909036A EP 0804184 A1 EP0804184 A1 EP 0804184A1
Authority
EP
European Patent Office
Prior art keywords
enzyme inhibitors
acid esters
inhibitors according
helicobacter pylori
treatment
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Withdrawn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
EP94909036A
Other languages
German (de)
French (fr)
Inventor
Rudolf W. Wabnitz
Jutta Riedl
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.)
ASCHE AG
Original Assignee
ASCHE AG
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 ASCHE AG filed Critical ASCHE AG
Publication of EP0804184A1 publication Critical patent/EP0804184A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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

Definitions

  • the invention relates to the use of enzyme inhibitors for the manufacture of a medicament for the treatment of Helicobacter pylori-associated diseases II of the gastrointestinal tract.
  • Helicobacter pylori is a spiral gram-negative bacterium with flagella, whose natural habitat is the gastric mucosa. There it secretes a large number of enzymes that attack the gastric mucosa and are the cause of gastrititis, lesions and ulcers in the stomach and duodenum.
  • enzyme inhibitors are surprisingly very suitable for the treatment of Helicobacter pylori infections and the diseases of the gastrointestinal tract induced by them.
  • Protease inhibitors have proven to be particularly suitable (see also “Römpp Chemie Lexikon” Georg Thieme Verlag, Stuttgart, New York, 9th edition of the Literature collection under the keyword “proteases”; Page 3647 and 3648). Combinations of protease inhibitors and lipase inhibitors are also suitable.
  • Enzyme inhibitors which inhibit a broad spectrum of enzymes are particularly suitable.
  • Such inhibitors are, for example, the known ⁇ -guanidino carboxylic acid esters, such as the ⁇ -guanidino alkane carboxylic acid esters (Biochem. Biophys. Acta 242, 1971, 203-208, 268. 1972221-224 and 285, 1972, 224-234 and DE-B 2050484) and in particular the p-guanidinobenzoic acid esters (Biochem. Biophys. Acta 484, 1977, 417-422 and DE-B 25 48 886, proteinase inhibition, University Printing and Publishing House, Dr. C. Wolf & Sohn, Kunststoff, 1982).
  • the known ⁇ -guanidino carboxylic acid esters such as the ⁇ -guanidino alkane carboxylic acid esters (Biochem. Biophys. Acta 242, 1971, 203-208, 268. 1972221-224 and 285, 1972, 224-234 and DE-B 2050484) and in particular the p-guanidinobenzoic acid esters (Biochem.
  • nafamostat 4 - [(aminoiminomethyl) amino] benzoic acid 6- (aminoiminomethyl) -2-naphthyl esters and their salts, such as, for example, their mesylates or tosylates.
  • the enzyme inhibitors are mixed with the usual fillers and auxiliaries and processed into tablets, dragées, capsules, suspensions, foams or sprays.
  • Suitable fillers for the production of coated tablets, capsules or tablets are, for example, sugar alcohols such as mannitol, monosaccharides such as glucose, galactose or fructose, disaccharides such as sucrose or lactose, polysaccharides such as amylose, starch or cellulose, chemically modified polysaccharides such as methyl cellulose or Hydroxypropylmethyl cellulose or inorganic fillers such as magnesium oxide, talc or disperse silica.
  • Suitable auxiliaries are, for example, the usual mold release agents, such as magnesium stearate, stearic acid or calcium behenate and, if appropriate, also flavoring agents.
  • the medicaments can be formulated, for example, as described in DE-A 3404595, EP-B 0142561 or EP-B 0274498.
  • Such additional active ingredients are, for example, preparations which protect the mucous membrane, such as antacids, sucralfate or bismuth, substances which inhibit gastric secretion, such as anticholinergics, antimuscarinics, prostaglandin analogs, histamine H2-receptor antagonists or benzimidazole derivatives or others
  • Medications such as gastro-prokinetics, carbenoxolone sodium, succus liquiritiae, special psychotropic drugs, somatostatin analogues or simethicone, but also antifungals (tioconazole, miconazole, bifonazole, ketoconazole, clotrimazole, econazole, isoconazolitone and antiponazole trolazazolitone, fluconazolitazolitone, and fluconazolazole tritazolazolitone).
  • antifungals tioconazole, miconazole, bifonazole, ketoconazole, clotrimazole, econazole, isoconazolitone and antiponazole trolazazolitone, fluconazolitazolitone, and fluconazolazole tritazolazolitone.
  • Suspensions, foams and sprays are also produced in a conventional manner.
  • the concentration of enzyme inhibitor in medicinal products is usually 5 to 200 mg per unit dose.
  • the patient is usually administered 1 to 3 dose units per day.
  • the active ingredient is mixed with lactose and corn starch in the manner familiar to the person skilled in the art and granulated with a 1-5% strength aqueous hydroxypropylmethyl cellulose solution. After drying at 30-70 ° C under vacuum, the batch is mixed with magnesium stearate, mixed for 1 to 5 minutes and pressed in the usual way.
  • the core obtained in this way is then coated with an aqueous suspension of hydroxypropylmethyl cellulose, color pigment, talc and polyethylene glycol.
  • an aqueous suspension of hydroxypropylmethyl cellulose, color pigment, talc and polyethylene glycol are suitable for this.
  • 1 tablet contains:
  • the active ingredient is mixed with the excipients in one batch and filled into bags. If necessary, it is then flavored.
  • the composition is as follows: Camostate 100.00 mg
  • the capsule content is dosed between the capsule shell to be welded in the usual way (e.g. Scherer method).
  • This is prepared separately from the capsule content by swelling the gelatin in preserved water and glycerol, stirring the pigments and drying them in a targeted manner.
  • the final composition is:
  • the capsule content consists predominantly of peanut oil in which the active ingredient is suspended. Soy lecithin is added to the viscous mixture for better wetting. To protect against oxidation, 2,6-di-tert-butyl-4-methylphenol is used, which is previously dissolved in peanut oil.
  • the capsule contents contain finally
  • a commercially available hard gelatin capsule of a suitable size is filled with a mass which has the following composition:
  • the mass is made by triturating the active ingredient with lactose and mixing with the hydrogenated castor oil and hydrocollide. Then talc and magnesium stearate are added and mixed in over 5-15 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Enzyme inhibitors are used to prepare a medicament for treating gastro-intestinal diseases associated with helicobacter pylori.

Description

VERWENDUNG VON w-GUANIDINOCARBONSAEUREESTER ZUR HERSTELLUNG EINES ARZNEI¬ MITTELSUSE OF w-GUANIDINOCARBONIC ACID ESTER FOR THE PRODUCTION OF A MEDICINAL PRODUCT
Die Erfindung betrifft die Verwendung von Enzym-Inhibitoren zur Herstellung eines Arzneimittels zur Behandlung von Helicobacter pylori assoziierten Erkrankunge-ii des Magen-Darm-Traktes.The invention relates to the use of enzyme inhibitors for the manufacture of a medicament for the treatment of Helicobacter pylori-associated diseases II of the gastrointestinal tract.
Helicobacter pylori ist ein spiraliges mit Flagellen bestücktes gramnegatives Bakterium, dessen natürlicher Lebensraum die Magenschleimhaut ist. Dorthin sondert es eine Vielzahl von Enzymen ab, die die Magenschleimhat angreifen und die Ursache für Gastrititiden, Läsionen und Ulcera im Magen und Duodenum sind.Helicobacter pylori is a spiral gram-negative bacterium with flagella, whose natural habitat is the gastric mucosa. There it secretes a large number of enzymes that attack the gastric mucosa and are the cause of gastrititis, lesions and ulcers in the stomach and duodenum.
So haben beispielsweise über 80 % der Menschen, die an chronischer Gastritis leiden eine Helicobacter pylori Infektion.For example, over 80% of people who suffer from chronic gastritis have Helicobacter pylori infection.
Da die durch Helicobacter pylori induzierte Gastritis als Risikofaktor für Zwölffinger¬ darmgeschwüre (Ulcus duodeni) gilt, ist nicht überaschend, daß , man bei 95 % aller Patienten, die an diesen Geschwüren leiden, auch eine Helicobacter pylori Infektion nachweisen kann. Ähnlich verhält es sich bei Magengeschwüren (Ulcus ventriculi); hier konnte bei 65 % aller Patienten eine Helicobacter pylori Infektion nachgewiesen werden. Nach den vorliegenden Untersuchungen ist das Risiko der mit Helicobacter pylori infizierten Menschen, an Magenkrebs zu erkranken, zwei- bis sechsmal so hoch, wie das der mcht infizierten.Since the gastritis induced by Helicobacter pylori is considered a risk factor for duodenal ulcers (duodenal ulcer), it is not surprising that, in 95% of all patients suffering from these ulcers, a Helicobacter pylori infection can also be detected. The situation is similar with gastric ulcers (ulcer ventriculi); a Helicobacter pylori infection was found in 65% of all patients. According to the available studies, the risk of people infected with Helicobacter pylori to develop stomach cancer is two to six times higher than that of those who are not infected.
Die Behandlung der Helicobacter pylori Infektionen mit Antibiotika als Monotherapie hat sich als relativ ineffektiv erwiesen, so daß man meist zu einer Kombinationstherapie aus Antibiotika (zum Beispiel Tetracyclin, Amoxycillin) Metronidazol und Wismut oder mit dem Protoneninhibitor Omeprazol übergeht, Behandlungsmethoden die nicht unproblematisch sind.Treatment of Helicobacter pylori infections with antibiotics as monotherapy has proven to be relatively ineffective, so that a combination therapy of antibiotics (for example tetracycline, amoxycillin), metronidazole and bismuth or with the proton inhibitor omeprazole is usually used, treatment methods that are not without problems.
Es wurde nun gefunden, daß sich Enzym-Inhibitoren überraschenderweise recht gut zur Behandlung von Helicobacter pylori Infektionen und den von diesen induzierten Erkrankungen des Magen-Darm-Traktes eignen.It has now been found that enzyme inhibitors are surprisingly very suitable for the treatment of Helicobacter pylori infections and the diseases of the gastrointestinal tract induced by them.
Eine Liste betreffend Publikationen zum Thema Enzym-Inhibitoren findet man beispielsweise in "Römpp Chemie Lexikon" Georg Thieme Verlag, Stuttgart, New York, 9. Auflage unter dem Stichwort "Inhibitoren" (Seite 1983 und 1984).A list of publications on the subject of enzyme inhibitors can be found, for example, in "Römpp Chemie Lexikon" Georg Thieme Verlag, Stuttgart, New York, 9th edition under the keyword "Inhibitors" (pages 1983 and 1984).
Als besonders geeignet haben sich Protease-Inhibitoren erwiesen (siehe hierzu "Römpp Chemie Lexikon" Georg Thieme Verlag, Stuttgart, New York, 9. Auflage die Literatursammlung unter dem Stichwort "Proteasen"; Seite 3647 und 3648). Geeignet sind auch Kombinationen von Protease-Inhibitoren und Lipase-Inhibitoren.Protease inhibitors have proven to be particularly suitable (see also "Römpp Chemie Lexikon" Georg Thieme Verlag, Stuttgart, New York, 9th edition of the Literature collection under the keyword "proteases"; Page 3647 and 3648). Combinations of protease inhibitors and lipase inhibitors are also suitable.
Besonders geeignet sind solche Enzym-Inhibitoren die ein breites Spektrum von Enzymen hemmen.Enzyme inhibitors which inhibit a broad spectrum of enzymes are particularly suitable.
Derartige Inhibitoren sind beispielsweise die bekannten ω-Guanidinocarbonsäureester, wie die ω-Guanidinoalkancarbonsäureester (Biochem. Biophys. Acta 242, 1971, 203-208, 268. 1972221-224 und 285, 1972, 224-234 sowie DE-B 2050484) und insbesondere die p- Guanidinobenzoesäureester (Biochem. Biophys. Acta 484, 1977, 417-422 sowie DE-B 25 48 886, Proteinase-Inhibition, Universitätsdruckerei und Verlag, Dr. C. Wolf & Sohn, München, 1982).Such inhibitors are, for example, the known ω-guanidino carboxylic acid esters, such as the ω-guanidino alkane carboxylic acid esters (Biochem. Biophys. Acta 242, 1971, 203-208, 268. 1972221-224 and 285, 1972, 224-234 and DE-B 2050484) and in particular the p-guanidinobenzoic acid esters (Biochem. Biophys. Acta 484, 1977, 417-422 and DE-B 25 48 886, proteinase inhibition, University Printing and Publishing House, Dr. C. Wolf & Sohn, Munich, 1982).
Ein bekannter ω-Guanidinoalkancarbonsäureester ist beispielsweise das Gabexate = 4-[6- [[(Aminoiminomethyl)-amino]-l-oxo-benzoesäureethylester. Bekannte p-Guanidino- benzoesäureester sind das Camostate = 4-[[4-[(Aminoiminomethyl)-amino]-benzoyl]- oxy]-2-(dimethylamino)-2-oxoethyl-phenylessigsäureester, dessen aktiver Metabolit das FOY-251 = 4-((4-[(Aminoiminomethyl)-amino]-benzoyl]-oxy-phenylessigsäureester (CA. 102, 1984, 106774v) und das Nafamostat = 4-[(Aminoiminomethyl)-amino]-benzoesäure- 6-(aminoiminomethyl)-2-naphthylester sowie deren Salze, wie zum Beispiel deren Mesylate oder Tosylate.A well-known ω-guanidinoalkane carboxylic acid ester is, for example, the gabexate = 4- [6- [[(aminoiminomethyl) amino] -l-oxo-benzoic acid ethyl ester. Known p-guanidino-benzoic acid esters are camostate = 4 - [[4 - [(aminoiminomethyl) amino] benzoyl] - oxy] -2- (dimethylamino) -2-oxoethyl-phenylacetic acid ester, the active metabolite of which is FOY-251 = 4 - ((4 - [(aminoiminomethyl) amino] benzoyl] oxyphenylacetic acid ester (CA. 102, 1984, 106774v) and the nafamostat = 4 - [(aminoiminomethyl) amino] benzoic acid 6- (aminoiminomethyl) -2-naphthyl esters and their salts, such as, for example, their mesylates or tosylates.
Zur Herstellung der Arzneimittel werden die Enzym-Inhibitoren mit den üblichen Füllstoffen und Hilfsstoffen vermischt und zu Tabletten, Dragees, Kapseln, Suspensionen, Schäume oder Sprays verarbeitet.To produce the pharmaceuticals, the enzyme inhibitors are mixed with the usual fillers and auxiliaries and processed into tablets, dragées, capsules, suspensions, foams or sprays.
Zur Herstellung von Dragees, Kapseln oder Tabletten eignen sich als Füllstoffe beispielsweise Zuckeralkohole, wie Mannit, Monosaccharide, wie Glucose, Galactose oder Fruktose, Disaccharide, wie Saccharose oder Lactose, Polysaccharide, wie Amylose, Stärke oder Zellulose, chemisch modifizierte Polysaccharide, wie Methylzellulose oder Hydroxypropylmethylzellulose oder anorganische Füllstoffe, wie Magnesiumoxid, Talkum oder disperse Kieselsäure. Geeignete Hilfsstoffe sind beispielsweise die üblichen Formtrennmittel, wie Magnesiumstearat, Stearinsäure oder Calziumbehenat und gegebenenfalls auch Geschmackskorregentien. Um eine gesteuerte Wirkstofffreisetzung zu erzielen, kann man die Arzneimittel beispielsweise so formulieren, wie dies der DE-A 3404595, der EP-B 0142561 oder der EP-B 0274498 beschrieben ist.Suitable fillers for the production of coated tablets, capsules or tablets are, for example, sugar alcohols such as mannitol, monosaccharides such as glucose, galactose or fructose, disaccharides such as sucrose or lactose, polysaccharides such as amylose, starch or cellulose, chemically modified polysaccharides such as methyl cellulose or Hydroxypropylmethyl cellulose or inorganic fillers such as magnesium oxide, talc or disperse silica. Suitable auxiliaries are, for example, the usual mold release agents, such as magnesium stearate, stearic acid or calcium behenate and, if appropriate, also flavoring agents. In order to achieve controlled release of the active ingredient, the medicaments can be formulated, for example, as described in DE-A 3404595, EP-B 0142561 or EP-B 0274498.
Es ist selbstverständlich auch möglich freie Kombinationen einzusetzen oderIt is of course also possible to use free combinations or
Kombinationspräparate zu bereiten, die neben den Enzym-Inhibitoren zusätzlich nochCombination preparations to prepare in addition to the enzyme inhibitors
Wirkstoffe enthalten, die üblicherweise zur Behandlung von Magen-Darm-Erkrankungen verwendet werden. Solche zusätzlichen Wirkstoffe sind beispielsweise die Schleimhaut schützenden Präparate, wie Antazida, Sucralfat oder Wismut, die gastrale Sekretion hemmende Substanzen, wie Anticholin ergika, Antimuskarinika, Prostaglandin-Analoga, Histamin-H2-Rezeptor-Antagonisten oder Benzimidazol-Derivate oder sonstigeContain active ingredients that are commonly used to treat gastrointestinal disorders. Such additional active ingredients are, for example, preparations which protect the mucous membrane, such as antacids, sucralfate or bismuth, substances which inhibit gastric secretion, such as anticholinergics, antimuscarinics, prostaglandin analogs, histamine H2-receptor antagonists or benzimidazole derivatives or others
Medikamente, wie Gastro-Prokinetika, Carbenoxolon-Natrium, Succus liquiritiae, spezielle Psychopharmaka, Somatostatin-Analoga oder Simethicon aber auch Antimykotica (Tioconazol, Miconazol, Bifonazol, Ketoconazol, Clotrimazol, Econazol, Isoconazol, Fluconazol, Itraconazol) und antiparasitäre Mittel.Medications, such as gastro-prokinetics, carbenoxolone sodium, succus liquiritiae, special psychotropic drugs, somatostatin analogues or simethicone, but also antifungals (tioconazole, miconazole, bifonazole, ketoconazole, clotrimazole, econazole, isoconazolitone and antiponazole trolazazolitone, fluconazolitazolitone, and fluconazolazole tritazolazolitone).
Die Herstellung von Suspensionen, Schäume und Sprays erfolgt ebenfalls in konventioneller Weise.Suspensions, foams and sprays are also produced in a conventional manner.
In den Arzneimitteln beträgt die Konzentration an Enzym-Inhibitor normalerweise 5 bis 200 mg pro Dosiseinheit. Üblicherweise werden dem Patienten 1 bis 3 Dosiseinheiten pro Tag verabfolgt.The concentration of enzyme inhibitor in medicinal products is usually 5 to 200 mg per unit dose. The patient is usually administered 1 to 3 dose units per day.
Die nachfolgenden Beispiele dienen zur näheren Erläuterung der Erfindung. The following examples serve to explain the invention in more detail.
Beispiel 1example 1
FilmtablettenFilm-coated tablets
In der dem Fachmann geläufigen Weise werden der Wirkstoff mit Lactose und Maisstärke gemischt und mit einer 1 - 5%igen wäßrigen Hydroxypropylmethylcellulose-Lösung granuliert. Nach der Trocknung bei 30 - 70° C unter Vakuum wird der Ansatz mit Magnesiumstearat versetzt, 1 bis 5 Minuten gemischt und in üblicher Weise verpreßt.The active ingredient is mixed with lactose and corn starch in the manner familiar to the person skilled in the art and granulated with a 1-5% strength aqueous hydroxypropylmethyl cellulose solution. After drying at 30-70 ° C under vacuum, the batch is mixed with magnesium stearate, mixed for 1 to 5 minutes and pressed in the usual way.
Der so erhaltene Kern wird anschließend mit einer wäßrigen Suspension aus Hydroxypropylmethylcellulose, Farbpigment, Talcum und Polyethylenglykol überzogen. Geeignet hierfür sind beispielsweise Wirbelschichtcoater mit einem kontinuierlichen Lackauftrag über Sprühpistolen.The core obtained in this way is then coated with an aqueous suspension of hydroxypropylmethyl cellulose, color pigment, talc and polyethylene glycol. For example, fluidized bed coaters with a continuous coating of spray guns are suitable for this.
1 Tablette enthält:1 tablet contains:
Kern:Core:
Camostate 100,00 mgCamostate 100.00 mg
Lactose 80,00 mgLactose 80.00 mg
Maisstärke 100,00 mgCorn starch 100.00 mg
Hydroxypropylmethylcellulose 15,00 mgHydroxypropylmethyl cellulose 15.00 mg
Viskosität 5Viscosity 5
Magnesiumstearat 1,5 mgMagnesium stearate 1.5 mg
Hülle:Shell:
Hydroxypropylmethylcellulose 4,00 mgHydroxypropyl methyl cellulose 4.00 mg
Viskosität 5Viscosity 5
Polyethylenglykol 3000-6000 1,00 mgPolyethylene glycol 3000-6000 1.00 mg
Eisenoxid-Farbpigment 2,00 mgIron oxide color pigment 2.00 mg
Talcum 1,00 mgTalcum 1.00 mg
Beispiel 2Example 2
(Maeenlösliches Pulver in Beuteln")(Maize-soluble powder in bags ")
Der Wirkstoff wird mit den Hilfsstoffen in einem Ansatz gemischt und in Beutel abgefüllt. Gegebenenfalls wird anschließend aromatisiert. Die Zusammensetzung lautet wie folgt: Camostate 100,00 mgThe active ingredient is mixed with the excipients in one batch and filled into bags. If necessary, it is then flavored. The composition is as follows: Camostate 100.00 mg
Saccharose 200,00 mgSucrose 200.00 mg
Natriumcarboxymethylcellulose 2,00 mg Polysorbat oderSodium carboxymethyl cellulose 2.00 mg polysorbate or
Polyoxyethylenstearat 1,00 mgPolyoxyethylene stearate 1.00 mg
Anisöl 0,3 mgAnise oil 0.3 mg
Beispiel 3Example 3
(WeichgelatinekapseH(Soft gelatin capsule H.
In der üblichen Weise (z.B. Scherer- Verfahren) wird der Kapselinhalt zwischen die zu verschweißende Kapselhülle dosiert. Diese wird separat vom -Kapselinhalt durch Quellen der Gelatine in konserviertem Wasser und Glycerol, verrühren der Pigmente und gezieltem Trocknen hergestellt.The capsule content is dosed between the capsule shell to be welded in the usual way (e.g. Scherer method). This is prepared separately from the capsule content by swelling the gelatin in preserved water and glycerol, stirring the pigments and drying them in a targeted manner.
Die endgültige Zusammensetzung ist:The final composition is:
Glycerol 50,00 mgGlycerol 50.00 mg
H2O 30,00 mgH 2 O 30.00 mg
Eisenoxid-Farbpigment 2,00 mgIron oxide color pigment 2.00 mg
P-Hydroxybenzoesäuremethylester- 0,5 mg propylesterP-hydroxybenzoic acid methyl ester - 0.5 mg propyl ester
Gelatine 300,00 mgGelatin 300.00 mg
Der -Kapselinhalt besteht überwiegend aus Erdnußöl, in dem der Wirkstoff suspendiert wird. Zur besseren Benetzung wird dem zähflüssigen Ansatz Soja-Lecithin zugegeben. Zum Schutz vor Oxidation dient 2,6-Di-tert.-butyl-4-methylphenol, welches zuvor in Erdnußöl gelöst wird.The capsule content consists predominantly of peanut oil in which the active ingredient is suspended. Soy lecithin is added to the viscous mixture for better wetting. To protect against oxidation, 2,6-di-tert-butyl-4-methylphenol is used, which is previously dissolved in peanut oil.
Der Kapselinhalt enthält schließlichThe capsule contents contain finally
Camostate 100,00 mgCamostate 100.00 mg
Soja-Lecithin 5,00 mgSoy Lecithin 5.00 mg
2,6-Di-tert.-butyl-4-methylphenol 0,1 mg2,6-di-tert-butyl-4-methylphenol 0.1 mg
Erdnußöl ad 800,00 mg Beispiel 4Peanut oil ad 800.00 mg Example 4
( Retard-Hartgel ati nekapseln(Retard hard gel capsules
Eine handelsübliche Hartgelatinekapsel geeigneter Größe wird mit einer Masse befüllt, die folgende Zusammensetzung besitzt:A commercially available hard gelatin capsule of a suitable size is filled with a mass which has the following composition:
Camostate 100,00 mgCamostate 100.00 mg
Lactose 100,00 mg hydriertes Rizinusöl 50,00 mgLactose 100.00 mg hydrogenated castor oil 50.00 mg
Hydroxypropylmethylcellulose 4000 cps 100,00 mgHydroxypropylmethylcellulose 4000 cps 100.00 mg
Talkum 40,00 mgTalc 40.00 mg
Magnesiumstearat 10,00 mgMagnesium stearate 10.00 mg
Die Masse wird durch Verreiben des Wirkstoffes mit Lactose und Vermischen mit dem hydrierten Rizinusöl und Hydrokollid hergestellt. Anschließend werden Talkum und Magnesiumstearat zugegeben und über 5-15 Minuten untergemischt. The mass is made by triturating the active ingredient with lactose and mixing with the hydrogenated castor oil and hydrocollide. Then talc and magnesium stearate are added and mixed in over 5-15 minutes.

Claims

Patentansprüche Claims
1. Verwendung von Enzym-Inhibitoren zur Herstellung eines Arzneimittels zur Behandlung von Helicobacter pylori assoziierten Erkrankungen des Magen-Darm- Traktes.1. Use of enzyme inhibitors for the manufacture of a medicament for the treatment of Helicobacter pylori-associated diseases of the gastrointestinal tract.
2. Verwendung von Enzym-Inhibitoren gemäß Patentanspruch 1, dadurch gekennzeichnet, daß diese Protease-Inhibitoren sind.2. Use of enzyme inhibitors according to claim 1, characterized in that these are protease inhibitors.
3. Verwendung von Enzym-Inhibitoren gemäß Patentanspruch 2, dadurch gekennzeichnet, daß diese ω-Guanidinocarbonsäureester sind.3. Use of enzyme inhibitors according to claim 2, characterized in that these are ω-guanidinocarboxylic acid esters.
4. Verwendung von Enzym-Inhibitoren gemäß Patentanspruch 3, dadurch gekennzeichnet, daß diese p-Guanidinobenzoesäureester oder ε -Guanidinocapronsäureester sind.4. Use of enzyme inhibitors according to claim 3, characterized in that these are p-guanidinobenzoic acid esters or ε-guanidinocaproic acid esters.
5. Verwendung von Enzym-Inhibitoren gemäß Patentanspruch 4, dadurch gekennzeichnet, daß diese Camostate, Naphamostate, FOY-251 und/oder Gabexate und deren Salze sind.5. Use of enzyme inhibitors according to claim 4, characterized in that these are Camostate, Naphamostate, FOY-251 and / or Gabexate and their salts.
6. Verwendung von Enzym-Inhibitoren gemäß Patentanspruch 1 bis 5, dadurch gekenn¬ zeichnet, daß das hergestellte Arzneimittel zusätzlich noch Wirkstoffe enthält, die üblicherweise zur Behandlung von Magen-D arm-Erkrankungen verwendet werden. 6. Use of enzyme inhibitors according to claim 1 to 5, characterized gekenn¬ characterized in that the medicinal product additionally contains active ingredients which are usually used for the treatment of gastrointestinal diseases.
EP94909036A 1993-02-19 1994-02-18 USE OF $g(v)-GUANIDINOCARBOXYLIC ACID ESTERS Withdrawn EP0804184A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4305536 1993-02-19
DE4305536A DE4305536A1 (en) 1993-02-19 1993-02-19 Use of enzyme inhibitors for the manufacture of a medicament
PCT/EP1994/000523 WO1994018964A1 (en) 1993-02-19 1994-02-18 USE OF φ-GUANIDINOCARBOXYLIC ACID ESTERS

Publications (1)

Publication Number Publication Date
EP0804184A1 true EP0804184A1 (en) 1997-11-05

Family

ID=6481132

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94909036A Withdrawn EP0804184A1 (en) 1993-02-19 1994-02-18 USE OF $g(v)-GUANIDINOCARBOXYLIC ACID ESTERS

Country Status (5)

Country Link
EP (1) EP0804184A1 (en)
JP (1) JP2002515002A (en)
AU (1) AU6205394A (en)
DE (1) DE4305536A1 (en)
WO (1) WO1994018964A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2004678A1 (en) * 2006-03-15 2008-12-24 Csir Modulation of glutamine synthetase activity
GB0808690D0 (en) * 2007-05-17 2008-06-18 Serentis Ltd Therapeutic use

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5775922A (en) * 1980-10-29 1982-05-12 Nippon Chemiphar Co Ltd Novel remedy for peptic ulcer
JPS6229566A (en) * 1985-07-30 1987-02-07 Taiyo Yakuhin Kogyo Kk Novel guanidinomthylbenzoic acid derivative
JPS63126860A (en) * 1986-11-17 1988-05-30 Nippon Haipotsukusu:Kk Guanidinomethylbenzoic acid derivative
JPS63218652A (en) * 1987-03-09 1988-09-12 Taiyo Yakuhin Kogyo Kk Novel guanidinomethylbenzoic acid derivative and remedy for peptic ulcer containing said derivative
JPH04217950A (en) * 1990-03-28 1992-08-07 Asahi Chem Ind Co Ltd Hydroxamic acid derivative, enzyme inhibitor and antiulcer agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9418964A1 *

Also Published As

Publication number Publication date
WO1994018964A1 (en) 1994-09-01
AU6205394A (en) 1994-09-14
DE4305536A1 (en) 1994-08-25
JP2002515002A (en) 2002-05-21

Similar Documents

Publication Publication Date Title
DE3309516C2 (en)
DE69331948T2 (en) PLEASANT TASTING PHARMACEUTICAL COMPOSITIONS
DE69217191T2 (en) MULTIPARTICLE TABLET WITH QUICK RESOLUTION
DE69820287T2 (en) Pharmaceutical preparation comprising chlodronate as the active ingredient and silicified microcrystalline cellulose as the excipient
DE69213800T2 (en) Oral gastric juice-stable drugs with controlled release of active ingredients containing bile acids and their salts
DE2332484C2 (en) Drugs with delayed release of active substances
CA1333998C (en) Cholesterol-lowering combination compositions of niacin and magnesium salt
EP1086701B1 (en) Simethicone containing laxative composition
DE2551280A1 (en) L-DOPA PREPARATION
KR100479968B1 (en) Use of gastrointestinal lipase inhibitors
DE69530759T2 (en) FILM COATED TABLET CONTAINING PARACETAMOL AND DOMPERIDONE
CN109893516A (en) For treating the pharmaceutical composition of helicobacter pylori
US5310560A (en) Medicine for the treatment of illnesses of the respiratory organs
EP1315481B1 (en) Medicament for treating intestinal diseases
KR100238565B1 (en) Ingestible pharmaceutical compositions for treating upper gastrointestinal tract distress
US20080038336A1 (en) Solid pharmaceutical composition containing a combination of an intestinal motility regulating agent and an antiflatulent
CA2132427A1 (en) Method and composition for suppresion of side effects of anti-inflammatory drugs
DE602004009079T2 (en) CARBOSTYRIL DERIVATIVES FOR ACCELERATED SPOKEN SPECIALTY
WO1995020383A1 (en) Modified-release metronidazole compositions and methods for making and using same
EP1480626A1 (en) Ambroxol for treating painful conditions in the mouth and pharyngeal cavity
JPH07242560A (en) Antimicrobial
EP0804184A1 (en) USE OF $g(v)-GUANIDINOCARBOXYLIC ACID ESTERS
JPH0656677A (en) Antacid composition
EP0301373B1 (en) Products containing gallopamil and prazosine
US5294440A (en) Composition for treatment of cold sores

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19951123

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE

RTI1 Title (correction)

Free format text: USE OF OMEGA-GUANIDINOCARBOXYLIC ACID ESTERS

17Q First examination report despatched

Effective date: 19991229

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20000509