EP0190239A1 - New active substance complexes - Google Patents

New active substance complexes

Info

Publication number
EP0190239A1
EP0190239A1 EP85903831A EP85903831A EP0190239A1 EP 0190239 A1 EP0190239 A1 EP 0190239A1 EP 85903831 A EP85903831 A EP 85903831A EP 85903831 A EP85903831 A EP 85903831A EP 0190239 A1 EP0190239 A1 EP 0190239A1
Authority
EP
European Patent Office
Prior art keywords
cyclodextrin
omeprazole
inclusion
inclusion complexes
cyclodextrins
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Withdrawn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
EP85903831A
Other languages
German (de)
French (fr)
Inventor
Kurt Klemm
Jörg Senn-Bilfinger
Bernhard Emschermann
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik 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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0190239A1 publication Critical patent/EP0190239A1/en
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • the invention relates to new cyclodextrin inclusion compounds, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used as pharmacologically active substances in medicaments.
  • cyclodextrins can form inclusion compounds with certain active pharmaceutical ingredients (for example EP-A-56 995, DE-A-32 26 232, DE-A-30 15 626, DE-A-33 46 123, EP-A- 91 782, DE-A-31 18 218 and EP-A-72 868).
  • EP-A-5 129 benzimidazole derivatives are known which have valuable pharmacological properties.
  • EP-A-103 553 it is further known that the benzimidazole derivatives of EP-A-5 129 ⁇ e.g.
  • omeprazole 5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl] -1H-benzimidazole] faster than desired.
  • the invention therefore relates to new inclusion complexes of omeprazole with cyclodextrins.
  • Unsubstituted cyclodextrins such as e.g. ⁇ -, ⁇ - and ⁇ -cyclodextrin, or substituted [e.g. (partially) etherified or esterified] cyclodextrins, e.g. Heptakis (3-0-methyl) 8-cyclodextrin, heptakis (2,6-di-0-methyl) -ß-cyclodextrin, hydroxyethyl-ß-cyclodextrin or hydroxypropyl-ß-cyclodextrin, where the
  • Cyclodextrins can be mixed or in pure form.
  • Preferred cyclodextrins are ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin.
  • the molar cyclodextrin: omeprazole ratio can vary within a wide range, for example from 10: 1 to 1:10, a cyclodextrin: omeprazole ratio of ol 1: 1 (for example from 1: 1 to 5: 1) being preferred since the only way to fully set the desired stabilization effect.
  • the invention further relates to a method for producing the inclusion complexes according to the invention.
  • the process is characterized in that omeprazole is reacted with the cyclodextrin in a suitable solvent.
  • solvents which are preferred on the basis of his specialist knowledge.
  • protic or aprotic solvents can be used, solvents with a certain, but not too high water content being preferred.
  • alcohols such as methanol, isopropanol or in particular 96Xiges ethanol may be mentioned.
  • the reaction temperature of the process according to the invention can fluctuate within certain limits, temperatures between 25 and 38 ° C., in particular temperatures between 30 and 34 °, being preferred. Of course, higher or lower temperatures can also be used, although losses in yield may have to be accepted. Slow cooling should be used, especially when using higher temperatures.
  • the benzimidazole derivatives mentioned at the outset can be converted into compounds which have a high storage stability both in solid and in dissolved form.
  • the inclusion complexes according to the invention thus represent storable compounds which are outstandingly suitable for use in pharmaceuticals.
  • the inclusion complexes according to the invention clearly inhibit gastric acid secretion in warm-blooded animals and, moreover, have an excellent gastric and intestinal protective action in warm-blooded animals. This gastric and intestinal protective effect is already observed when doses are administered which are below the acid secretion-inhibiting doses.
  • stomach and intestinal protection means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins, Medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
  • gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach
  • Medications e.g. certain anti-inflammatory drugs and anti-rheumatic drugs
  • chemicals e.g. ethanol
  • the inclusion complexes according to the invention are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and prophylaxis of diseases of the stomach and intestines and of diseases which are based on excessive gastric acid secretion.
  • the invention therefore furthermore relates to the inclusion complexes according to the invention for use in the treatment and prophylaxis of diseases.
  • the invention also includes the use of the inclusion pick according to the invention in the manufacture of medicaments.
  • the invention further relates to medicaments which contain one or more inclusion complexes according to the invention.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • the inclusion complexes according to the invention are used as medicaments either as such, or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, emulsions, suspensions or solutions, the active substance content advantageously being between 0.1 and 20%.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example, anti-oxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, dyes or enteric coatings are used.
  • inclusion complexes according to the invention can be administered orally or parenterally, cyclodextrins in particular being used for parenteral administration which have low toxicity.
  • the inclusion complexes according to the invention in human medicine, such as the benzimidazole derivatives themselves, in a daily dose of in particular 0.1 to 2.0 mg / kg of body weight (based on the active ingredient) in the form of several, preferably 1 to 4 individual doses to achieve the desired result. If necessary, a single application can be used every two days. With parenteral treatment, similar or (especially in the intravenous administration of the inclusion complexes) generally lower, but possibly also higher doses are used. The determination of the respectively required optimal dosage and type of application of the inclusion complexes can easily be done by any specialist on the basis of his specialist knowledge.
  • the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquillizers, such as benzodiazepines, for example diazepam; Antispasmodics, e.g. Bietamiverin, Camylofin; Anticholinergics such as Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquillizers such as benzodiazepines, for example diazepam
  • Antispasmodics e.g. Bietamiverin, Camylofin
  • Anticholinergics such as Oxyphencyclimine, phencarbamide
  • Local anesthetics e.g. Tetracaine

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Nanotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Medical Informatics (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux composés d'inclusion d'omeprazol avec des cyclodextrines se caractérisant par leur effet de protection de l'estomac. Ils présentent une stabilité élevée en stockage et sont donc particulièrement utiles dans des médicaments.New inclusion compounds of omeprazol with cyclodextrins characterized by their protective effect on the stomach. They have a high storage stability and are therefore particularly useful in medicaments.

Description

Neue WirkstoffkomplexeNew drug complexes
Die Erfindung betrifft neue Cyclodextrin-Einschlußverbindungen, Verfahren zu ihrer Herstellung, ihre Anwendung und sie enthaltende Arzneimittel. Die erfindungsgemäßen Verbindungen werden als pharmakologisch wirksame Stoffe in Arzneimitteln eingesetzt.The invention relates to new cyclodextrin inclusion compounds, processes for their preparation, their use and medicaments containing them. The compounds according to the invention are used as pharmacologically active substances in medicaments.
Stand der TechnikState of the art
Es ist bekannt, daß Cyclodextrine mit bestimmten pharmazeutischen Wirkstoffen Einschlußverbindungen bilden können (z.B. EP-A-56 995, DE-A-32 26 232, DE-A-30 15 626, DE-A-33 46 123, EP-A-91 782, DE-A-31 18 218 und EP-A-72 868). Weiterhin sind aus der europäischen Patentanmeldung EP-A-5 129 Benzimidazolderivate bekannt, die wertvolle pharmakologische Eigenschaften besitzen. Aus der europäischen Patentanmeldung EP-A-103 553 ist weiterhin bekannt, daß sich die Benzimidazolderivate der EP-A-5 129 {z.B. der Wirkstoff Omeprazol (INN) = 5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazol] schneller als erwünscht zersetzen.It is known that cyclodextrins can form inclusion compounds with certain active pharmaceutical ingredients (for example EP-A-56 995, DE-A-32 26 232, DE-A-30 15 626, DE-A-33 46 123, EP-A- 91 782, DE-A-31 18 218 and EP-A-72 868). Furthermore, from European patent application EP-A-5 129 benzimidazole derivatives are known which have valuable pharmacological properties. From European patent application EP-A-103 553 it is further known that the benzimidazole derivatives of EP-A-5 129 {e.g. decompose the active ingredient omeprazole (INN) = 5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl] -1H-benzimidazole] faster than desired.
Beschreibung der Erfindung überraschenderweise wurde nun gefunden, daß sich ausgehend von den in der EP-A-5 129 genannten Verbindungen (insbesondere ausgehend von Omeprazol) mit Cyclodextrinen Einschlußverbindungen (=Inklusionskomplexe) herstellen lassen, die sich durch eine hohe Stabilität auszeichnen.Surprisingly, it has now been found that starting from the compounds mentioned in EP-A-5 129 (in particular starting from omeprazole) with cyclodextrins, inclusion compounds (= inclusion complexes) can be prepared which are notable for high stability.
Gegenstand der Erfindung sind daher neue Inklusionskomplexe von Omeprazol mit Cyclodextrinen.The invention therefore relates to new inclusion complexes of omeprazole with cyclodextrins.
Als Cyclodextrine eignen sich unsubstituierte Cyclodextrine, wie z.B. α-, ß- und γ-Cyclodextrin, oder substituierte [z.B. (partiell) veretherte oder veresterte] Cyclodextrine, wie z.B. Heptakis-(3-0-methyl)8-cyclodextrin, Heptakis-(2,6-di-0-methyl)-ß-cyclodextrin, Hydroxyethyl-ß-cyclodextrin oder Hydroxypropyl-ß-cyclodextrin, wobei dieUnsubstituted cyclodextrins such as e.g. α-, β- and γ-cyclodextrin, or substituted [e.g. (partially) etherified or esterified] cyclodextrins, e.g. Heptakis (3-0-methyl) 8-cyclodextrin, heptakis (2,6-di-0-methyl) -ß-cyclodextrin, hydroxyethyl-ß-cyclodextrin or hydroxypropyl-ß-cyclodextrin, where the
Cyclodextrine gemischt oder in reiner Form vorliegen können. Bevorzugte Cyclodextrine sind das ß-Cyclodextrin, das Hydroxyethyl-ß-cyclodextrin und das Hydroxypropyl-ß-cyclodextrin. Das molare Verhältnis Cyclodextrin : Omeprazol kann in einem breiten Bereich, beispielsweise von 10:1 bis 1:10 variieren, wobei ein Verhältnis Cyclodextrin:Omeprazol von ≥ 1:1 (z.B. von 1:1 bis 5:1) bevorzugt ist, da sich nur so der gewünschte Stabilisierungseffekt voll einstellen kann.Cyclodextrins can be mixed or in pure form. Preferred cyclodextrins are β-cyclodextrin, hydroxyethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin. The molar cyclodextrin: omeprazole ratio can vary within a wide range, for example from 10: 1 to 1:10, a cyclodextrin: omeprazole ratio of ol 1: 1 (for example from 1: 1 to 5: 1) being preferred since the only way to fully set the desired stabilization effect.
Weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der erfindungsgemäßen Inklusionskomplexe. Das Verfahren ist dadurch gekennzeichnet, daß man Omeprazol in einem geeigneten Lösungsmittel mit dem Cyclodextrin umsetzt.The invention further relates to a method for producing the inclusion complexes according to the invention. The process is characterized in that omeprazole is reacted with the cyclodextrin in a suitable solvent.
Welche Lösungsmittel bevorzugt sind ist dem Fachmann aufgrund seines Fachwissens geläufig. So können beispielsweise protische oder aprotische Lösungsmittel eingesetzt werden, wobei Lösungsmittel mit einem gewissen, jedoch nicht allzuhohen Wasseranteil bevorzugt sind. Beispielsweise seien Alkohole, wie Methanol, Isopropanol oder insbesondere 96Xiges Ethanol genannt.The person skilled in the art is familiar with the solvents which are preferred on the basis of his specialist knowledge. For example, protic or aprotic solvents can be used, solvents with a certain, but not too high water content being preferred. For example, alcohols such as methanol, isopropanol or in particular 96Xiges ethanol may be mentioned.
Die Reaktionstemperatur des erfindungsgemäßen Verfahrens kann innerhalb gewisser Grenzen schwanken, wobei Temperaturen zwischen 25 und 38°C, insbesondere Temperaturen zwischen 30 und 34° bevorzugt sind. Es können natürlich auch höhere oder tiefere Temperaturen zur Anwendung kommen, wobei jedoch gegebenenfalls Ausbeuteverluste in Kauf genommen werden müssen. Insbesondere bei der Anwendung höherer Temperaturen sollte ein langsames Abkühlen erfolgen.The reaction temperature of the process according to the invention can fluctuate within certain limits, temperatures between 25 and 38 ° C., in particular temperatures between 30 and 34 °, being preferred. Of course, higher or lower temperatures can also be used, although losses in yield may have to be accepted. Slow cooling should be used, especially when using higher temperatures.
Das folgende Beispiel erläutert die Erfindung näher ohne sie einzuschränken. Für Stunde(n) wird die Abkürzung h verwendet. The following example explains the invention in more detail without restricting it. The abbreviation h is used for hour (s).
Be i s pi elExample
B-Cyclodextrin-EinschlußVerbindung mit 5-Hethoxy-2[(A-methoxy-3.5-dimethyl-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazol (Omeprazol)B-Cyclodextrin Inclusion Compound with 5-Hethoxy-2 [(A-methoxy-3,5-dimethyl-2-pyridylmethyl) sulfinyl] - (1H) -benzimidazole (omeprazole)
1 ,73 g 5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridylmethyl)sulfinyl](1H)-benzimidazol (5mMol) und 5,67 g 8-Cyclodextrin werden mit 20 ml 96%igem Ethanol versetzt und das Gemisch 15 h bei 30-32°C Innentemperatur kräftig gerührt. Danach kühlt man innerhalb von 3 h auf 10°C ab, gießt über ein Filter und wäscht gründlich mit 10°C kaltem Ethanol nach. Nach Trocknung im Vakuum erhält man 5,7 g der Titelverbindung. 1.73 g of 5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridylmethyl) sulfinyl] (1H) -benzimidazole (5 mmol) and 5.67 g of 8-cyclodextrin are mixed with 20 ml of 96% ethanol and the mixture was stirred vigorously for 15 h at an internal temperature of 30-32 ° C. The mixture is then cooled to 10 ° C. in the course of 3 h, poured through a filter and washed thoroughly with 10 ° C. cold ethanol. After drying in vacuo, 5.7 g of the title compound are obtained.
Gewerbliche AnwendbarkeitIndustrial applicability
Durch die Komplexierung mit Cyclodextrinen lassen sich die eingangs genannten Benzimidazolderivate in Verbindungen überführen, die sowohl in fester als auch in gelöster Form eine hohe Lagerstabilität aufweisen. Die erfindungsgemäßen Inklusionskomplexe stellen somit lagerfähige Verbindungen dar, die für den Einsatz in Arzneimitteln in hervorragender Weise geeignet sind.By complexing with cyclodextrins, the benzimidazole derivatives mentioned at the outset can be converted into compounds which have a high storage stability both in solid and in dissolved form. The inclusion complexes according to the invention thus represent storable compounds which are outstandingly suitable for use in pharmaceuticals.
Von ihrer pharmakologischen Wirkung her gesehen stellen die Cyclodextrine Hilfsstoffe dar, die die therapeutischen Eigenschaften der Benzimidazolderivate (=Wirkstoffe) in keiner Weise negativ beeinflussen oder vermindern. Wie die Benzimidazolderivate selbst hemmen die erfindungsgemäßen Inklusionskomplexe deutlich die Magensäuresekretion von Warmblütern und weisen darüberhinaus eine ausgezeichnete Magen- und Darmschutzwirkung bei Warmblütern auf. Diese Magen- und Darmschutzwirkung wird bereits bei der Verabreichung von Dosen beobachtet, die unterhalb der säuresekretionshemmenden Dosen liegen.From the point of view of their pharmacological effect, the cyclodextrins are auxiliaries which in no way negatively influence or reduce the therapeutic properties of the benzimidazole derivatives (= active ingredients). Like the benzimidazole derivatives themselves, the inclusion complexes according to the invention clearly inhibit gastric acid secretion in warm-blooded animals and, moreover, have an excellent gastric and intestinal protective action in warm-blooded animals. This gastric and intestinal protective effect is already observed when doses are administered which are below the acid secretion-inhibiting doses.
Unter "Magen- und Darmschutz" wird in diesem Zusammenhang die Verhütung und Behandlung gastrointestinaler Krankheiten, insbesondere gastrointestinaler entzündlicher Krankheiten und Läsionen (wie z.B. Ulcus ventriculi, Ulcus duodeni, Gastritis, hyperazider oder medikamentös bedingter Reizmagen) verstanden, die beispielsweise durch Mikroorganismen, Bakterientoxine, Medikamente (z.B. bestimmte Antiphlogistika und Antirheumatika), Chemikalien (z.B. Ethanol), Magensäure oder Streßsituationen verursacht werden können.In this context, "gastric and intestinal protection" means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins, Medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
Aufgrund ihrer Eigenschaften sind die erfindungsgemäßen Inklusionskomplexe für den Einsatz in der Human- und Veterinärmedizin hervorragend geeignet, wobei sie insbesondere zur Behandlung und Prophylaxe von Krankheiten des Magens und Darms und solcher Krankheiten, die auf einer überhöhten Magensäuresekretion beruhen, verwendet werden.Because of their properties, the inclusion complexes according to the invention are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and prophylaxis of diseases of the stomach and intestines and of diseases which are based on excessive gastric acid secretion.
Ein weiterer Gegenstand der Erfindung sind daher die erfindungsgemäßen Inklusionskomplexe zur Anwendung bei der Behandlung und Prophylaxe von Krankheiten. Ebenso umfaßt die Frfindung die Verwendung der erfindungsgemäßen Inklusionskomρlese bei der Herstellung von Arzneimitteln.The invention therefore furthermore relates to the inclusion complexes according to the invention for use in the treatment and prophylaxis of diseases. The invention also includes the use of the inclusion pick according to the invention in the manufacture of medicaments.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die ein oder mehrere erfindungsgemäße Inklusionskomplexe enthalten.The invention further relates to medicaments which contain one or more inclusion complexes according to the invention.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die erfindungsgemäßen Inklusionskomplexe entweder als solche, oder vorzugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Emulsionen, Suspensionen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 20% beträgt.The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The inclusion complexes according to the invention are used as medicaments either as such, or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, emulsions, suspensions or solutions, the active substance content advantageously being between 0.1 and 20%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, TablettenHilfsstoffen und anderen Trägern können beispielsweise Aiftioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder magensaftresistente Lacke verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other carriers, for example, anti-oxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, dyes or enteric coatings are used.
Die erfindungsgemäßen Inklusionskomplexe können oral oder parenteral appliziert' werden, wobei für die parenterale Applikation insbesondere solche Cyclodextrine verwendet werden, die eine geringe Toxizität aufweisen.The inclusion complexes according to the invention can be administered orally or parenterally, cyclodextrins in particular being used for parenteral administration which have low toxicity.
Da die Cyclodextrine die Benzimidazolderivate in ihrer therapeutischen Wirksamkeit nicht beeinträchtigen, ist es vorteilhaft, die erfindungsgemäßen Inklusionskomplexe in der Humanmedizin wie die Benzimidazolderivate selbst in einer Tagesdosis von insbesondere 0,1 bis 2,0 mg/kg Körpergewicht (bezogen auf den Wirkstoff), gegebenenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verabreichen. Gegebenenfalls kann auch eine einmalige Applikation alle zwei Tage zur Anwendung kommen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Inklusionskomplexe) in der Regel niedrigere, gegebenenfalls jedoch auch höhere Dosierungen zur Anwendung kommen. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Inklusionskomplexe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.Since the cyclodextrins do not impair the benzimidazole derivatives in their therapeutic activity, it is advantageous, if appropriate, to include the inclusion complexes according to the invention in human medicine, such as the benzimidazole derivatives themselves, in a daily dose of in particular 0.1 to 2.0 mg / kg of body weight (based on the active ingredient) in the form of several, preferably 1 to 4 individual doses to achieve the desired result. If necessary, a single application can be used every two days. With parenteral treatment, similar or (especially in the intravenous administration of the inclusion complexes) generally lower, but possibly also higher doses are used. The determination of the respectively required optimal dosage and type of application of the inclusion complexes can easily be done by any specialist on the basis of his specialist knowledge.
Sollen die erfindungsgemäßen Inklusionskomplexe zur Behandlung der oben genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere pharmakologisch aktive Bestandteile anderer Arzneimittelgruppen, wie Antacida, beispielsweise Aluminiumhydroxid, Magnesiumaluminat; Tranquillizer, wie Benzodiazepine, beispielsweise Diazepam; Spasmolytika, wie z.B. Bietamiverin, Camylofin; Anticholinergica, wie z.B. Oxyphencyclimin, Phencarbamid; Lokalanaesthetika, wie z.B. Tetracain, Procain; gegebenenfalls auch Fermente, Vitamine oder Aminosäuren enthalten. If the inclusion complexes according to the invention are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquillizers, such as benzodiazepines, for example diazepam; Antispasmodics, e.g. Bietamiverin, Camylofin; Anticholinergics such as Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.

Claims

Patentansprüche Claims
1. Inklusionskomplexe von Omeprazol mit Cyclodextrinen.1. Inclusion complexes of omeprazole with cyclodextrins.
2. Inklusionskomplex von Omeprazol mit ß-Cyclodextrin.2. Inclusion complex of omeprazole with β-cyclodextrin.
3. Inklusionskomplex von Omeprazol mit Hydroxyethyl-ß-Cyclodextrin.3. Inclusion complex of omeprazole with hydroxyethyl-β-cyclodextrin.
4. Inklusionskomplex von Omeprazol mit Hydroxypropyl-ß-Cyclodextrin.4. Inclusion complex of omeprazole with hydroxypropyl-β-cyclodextrin.
5. Verfahren zur Herstellung von Inklusionskomplexen nach Anspruch 1, dadurch gekennzeichnet, daß man Omeprazol in einem geeigneten Lösungsmittel mit einem Cyclodextrin umsetzt.5. A process for the preparation of inclusion complexes according to claim 1, characterized in that omeprazole is reacted with a cyclodextrin in a suitable solvent.
6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß das Lösungsmittel hauptsächlich aus Ethanol besteht.6. The method according to claim 5, characterized in that the solvent consists mainly of ethanol.
7. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß die Umsetzung bei Temperaturen zwischen 25 und 38°C durchgeführt wird.7. The method according to claim 5, characterized in that the reaction is carried out at temperatures between 25 and 38 ° C.
8. Arzneimittel enthaltend einen oder mehrere Inklusionskomplexe nach einem oder mehreren der Ansprüche 1 oder 2 oder 3 oder 4.8. Medicament containing one or more inclusion complexes according to one or more of claims 1 or 2 or 3 or 4.
9. Inklusionskomplexe nach einem oder mehreren der Ansprüche 1 oder 2 oder 3 oder 4 zur Anwendung bei der Behandlung beziehungsweise Prophylaxe von Krankheiten des Magens und/oder Darms und solcher Krankheiten, die auf einer erhöhten Magensäuresekretion beruhen. 9. Inclusion complexes according to one or more of claims 1 or 2 or 3 or 4 for use in the treatment or prophylaxis of diseases of the stomach and / or intestine and those diseases which are based on increased gastric acid secretion.
EP85903831A 1984-07-27 1985-07-24 New active substance complexes Withdrawn EP0190239A1 (en)

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DE3427787 1984-07-27
DE19843427787 DE3427787A1 (en) 1984-07-27 1984-07-27 ACTIVE SUBSTANCE COMPLEXES OF 5-METHOXY-2 ((4-METHOXY-3,5-DIMETHYL-2-PYRIDYL) METHYLSULFINYL) -1H-BENZIMIDAZOLE WITH CYCLODEXTRINES, THEIR PRODUCTION AND MEDICINAL PRODUCTS

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EP0190239A1 true EP0190239A1 (en) 1986-08-13

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CA1327010C (en) * 1986-02-13 1994-02-15 Tadashi Makino Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production
US6749864B2 (en) 1986-02-13 2004-06-15 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition
US5433959A (en) 1986-02-13 1995-07-18 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition
DE3809808A1 (en) * 1988-03-23 1989-10-05 Hexal Pharma Gmbh & Co Kg SOLIDS, ESPECIALLY FESTORAL AND RECTAL, ETOFENAMATE-CONTAINING MEDICINAL PRODUCTS
ES2026761A6 (en) * 1990-10-31 1992-05-01 Genesis Para La Investigacion A process for the preparation of omeprazol.
TW224049B (en) * 1991-12-31 1994-05-21 Sunkyong Ind Ltd
WO1996038175A1 (en) * 1995-06-02 1996-12-05 Takeda Chemical Industries, Ltd. Stabilized composition comprising an antiulcerative benzimidazole
CZ291842B6 (en) * 1997-03-13 2003-06-18 Hexal Ag Pharmaceutical formulation
CN1087739C (en) * 1998-12-28 2002-07-17 中国科学院成都有机化学研究所 Inclusion and resolution preparation process of optical purity benzimidazoles medicines resisting peptic ulcer
GB2376231A (en) * 2001-06-06 2002-12-11 Cipla Ltd Benzimidazole-cyclodextrin inclusion complex
BR0309622A (en) * 2002-04-29 2005-02-09 Ciba Sc Holding Ag Liquid aqueous compositions of reactive cyclodextrin derivatives and a finishing process using said composition

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