WO1986000913A1 - Nouveaux complexes de substances actives - Google Patents

Nouveaux complexes de substances actives Download PDF

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Publication number
WO1986000913A1
WO1986000913A1 PCT/EP1985/000371 EP8500371W WO8600913A1 WO 1986000913 A1 WO1986000913 A1 WO 1986000913A1 EP 8500371 W EP8500371 W EP 8500371W WO 8600913 A1 WO8600913 A1 WO 8600913A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclodextrin
omeprazole
inclusion complexes
inclusion
cyclodextrins
Prior art date
Application number
PCT/EP1985/000371
Other languages
German (de)
English (en)
Inventor
Kurt Klemm
Jörg Senn-Bilfinger
Bernhard Emschermann
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gesellschaft M
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 Gesellschaft M filed Critical Byk Gulden Lomberg Chemische Fabrik Gesellschaft M
Publication of WO1986000913A1 publication Critical patent/WO1986000913A1/fr

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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.
PCT/EP1985/000371 1984-07-27 1985-07-24 Nouveaux complexes de substances actives WO1986000913A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19843427787 DE3427787A1 (de) 1984-07-27 1984-07-27 Wirkstoffkomplexe von 5-methoxy-2((4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl)-1h-benzimidazol mit cyclodextrinen, deren herstellung und arzneimittel
DEP3427787.0 1984-07-27

Publications (1)

Publication Number Publication Date
WO1986000913A1 true WO1986000913A1 (fr) 1986-02-13

Family

ID=6241764

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1985/000371 WO1986000913A1 (fr) 1984-07-27 1985-07-24 Nouveaux complexes de substances actives

Country Status (4)

Country Link
EP (1) EP0190239A1 (fr)
AU (1) AU4636885A (fr)
DE (1) DE3427787A1 (fr)
WO (1) WO1986000913A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0484265A1 (fr) * 1990-10-31 1992-05-06 Centro Genesis Para La Investigacion, S.L. Procédé de préparation d'oméprazol
WO1993013138A1 (fr) * 1991-12-31 1993-07-08 Sunkyong Industries Co., Ltd. Medicaments enterosolubles administrables par voie orale contenant des composes instables en milieu acide
WO1996038175A1 (fr) * 1995-06-02 1996-12-05 Takeda Chemical Industries, Ltd. Composition stabilisee comprenant un benzimidazole anti-ulcereux
CN1087739C (zh) * 1998-12-28 2002-07-17 中国科学院成都有机化学研究所 光学纯的苯并咪唑类抗消化性溃疡药物的包结拆分制备法
WO2002098423A1 (fr) * 2001-06-06 2002-12-12 Cipla Limited Compose d'inclusion de s-omeprazole (esomeprazole) avec des cyclodextrines
KR100563764B1 (ko) * 1997-03-13 2006-03-24 헥살 아게 아미노산과 시클로덱스트린과의 병용에 의한 산(酸) 민감성 벤즈이미다졸류의 안정화 방법

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1327010C (fr) * 1986-02-13 1994-02-15 Tadashi Makino Compositions pharmaceutiques contenant un compose anti-ulcereux de type benzimidazole et sa 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 (de) * 1988-03-23 1989-10-05 Hexal Pharma Gmbh & Co Kg Feste, insbesondere festorale und rektale, etofenamat enthaltende arzneimittel
BR0309622A (pt) * 2002-04-29 2005-02-09 Ciba Sc Holding Ag Composições aquosas lìquidas de derivados de ciclodextrina reativos e um processo de acabamento que usa a referida composição

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2415631A1 (fr) * 1978-01-27 1979-08-24 Chinoin Gyogyszer Es Vegyeszet Complexe d'inclusion de cyclodextrine et d'indomethacine et procede pour sa preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2415631A1 (fr) * 1978-01-27 1979-08-24 Chinoin Gyogyszer Es Vegyeszet Complexe d'inclusion de cyclodextrine et d'indomethacine et procede pour sa preparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 101, No. 17, 22 October 1984, Columbus, Ohio (US) OKABE FUSUMU et al.: "Effects of Betacyclodextrin Chlatrate Compound on Gastric Secretion and Gastric Ulcers in Rats", see page 53, Abstract 143881c, & Oyo Yakuri 1984, 27 (5) 289-36 *
CHEMICAL ABSTRACTS, Vol. 90, No. 2, 8 January 1979, Columbus, Ohio (US) MIZUKAMI YUZO et al.: "Study on the Stability of Drugs", see page 364, Abstract 12228b & Yakuzaigaku, 1978, 38 (1) 45-50 *
Proceedings of the First International Symposium on Cyclodextrins, 30 September - 2 October 1981, 1982 J. Szejtli, D. Reidel Publishing Cy. Dordrecht, (NL) A. STADLER-SZOKE: "A Forecast for Application of Cyclodextrins in the Pharma-Industry", pages 377 to 388 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0484265A1 (fr) * 1990-10-31 1992-05-06 Centro Genesis Para La Investigacion, S.L. Procédé de préparation d'oméprazol
WO1993013138A1 (fr) * 1991-12-31 1993-07-08 Sunkyong Industries Co., Ltd. Medicaments enterosolubles administrables par voie orale contenant des composes instables en milieu acide
WO1996038175A1 (fr) * 1995-06-02 1996-12-05 Takeda Chemical Industries, Ltd. Composition stabilisee comprenant un benzimidazole anti-ulcereux
KR100563764B1 (ko) * 1997-03-13 2006-03-24 헥살 아게 아미노산과 시클로덱스트린과의 병용에 의한 산(酸) 민감성 벤즈이미다졸류의 안정화 방법
CN1087739C (zh) * 1998-12-28 2002-07-17 中国科学院成都有机化学研究所 光学纯的苯并咪唑类抗消化性溃疡药物的包结拆分制备法
WO2002098423A1 (fr) * 2001-06-06 2002-12-12 Cipla Limited Compose d'inclusion de s-omeprazole (esomeprazole) avec des cyclodextrines

Also Published As

Publication number Publication date
DE3427787A1 (de) 1986-01-30
AU4636885A (en) 1986-02-25
EP0190239A1 (fr) 1986-08-13

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