EP0666759A1 - Preparation permettant d'assurer la therapie et notamment la prophylaxie de maladies du tractus digestif - Google Patents

Preparation permettant d'assurer la therapie et notamment la prophylaxie de maladies du tractus digestif

Info

Publication number
EP0666759A1
EP0666759A1 EP93922890A EP93922890A EP0666759A1 EP 0666759 A1 EP0666759 A1 EP 0666759A1 EP 93922890 A EP93922890 A EP 93922890A EP 93922890 A EP93922890 A EP 93922890A EP 0666759 A1 EP0666759 A1 EP 0666759A1
Authority
EP
European Patent Office
Prior art keywords
preparation according
designed
dose
substance
bacteria
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Withdrawn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
EP93922890A
Other languages
German (de)
English (en)
Inventor
Rainer Denecke
Irmingard Gebert
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.)
Individual
Original Assignee
Individual
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
Priority claimed from DE4307352A external-priority patent/DE4307352A1/de
Application filed by Individual filed Critical Individual
Publication of EP0666759A1 publication Critical patent/EP0666759A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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 a preparation for the therapy and in particular prophylaxis of diseases of the digestive tract which occur in the presence of pathogenic and / or facultative-pathogenic bacteria.
  • Replacement blaff can trigger pylori.
  • Proteus vulgaris should also be mentioned, which, like Helicobacter pylori, is urease-positive. Mixed infections are very common.
  • Helicobacter pylori and gastric carcinoma A reference to a connection between Helicobacter pylori and gastric carcinoma can be found in the article "Helicobacter pylori and gastric carcinoma", R.J.L.F. Loffeld, I. Willems, J.A. Flendrig & Arends, J.W. Histopathology 1990, 17, pages 537-541.
  • REPLACEMENT LEAF essential for the repression of pathogenic germs.
  • acid suppression favors certain aetiopathogenetic factors for various gastrointestinal lesions (eg gastric carcinoma and carcinoids).
  • acid suppression is obsolete and should be replaced by lantibiotic prophylaxis and therapy for ethical and economic reasons.
  • the object of the present invention is therefore to provide a preparation of the type mentioned in the introduction in such a way that it ensures high effectiveness without side effects.
  • a defined dose of a polypeptide antibiotic is contained as the active substance, the application of which achieves an active substance concentration of at least 5 ⁇ g / ml at the site of action.
  • nisin The antibacterial activity of lantibiotics, in particular nisin, is already known.
  • a use as a food additive is described for example in EP-A-0 453 972.
  • the antibacterial activity of nisin is also specified in US Pat. No. 5,043,176.
  • the use of nisin in the cosmetic field is described in DE-OS 39 38 140.
  • the bacteria mentioned at the beginning are the etiopathogenetic factor for chronic gastritis. This leads to mucosal atrophy and intestinal metaplasia over time. The end stage of these processes is usually a stomach tumor.
  • REPLACEMENT LEAF reduce. Colonization of the stomach with pathogenic bacteria (e.g. Gastrospirillum hominis or Helicobacter pylori) can lead to a weakening of the mucous membrane resistance, so that patients who regularly take corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDS) are dependent to develop peptic ulcers.
  • pathogenic bacteria e.g. Gastrospirillum hominis or Helicobacter pylori
  • NSAIDS non-steroidal anti-inflammatory drugs
  • nisin is medically harmless since it is not absorbed and is inactivated by pancreatic enzymes, in particular alpha-chymotrypsin.
  • the medication is applied until the aim of the treatment, namely germination, has been achieved. Since many of the bacteria discussed occur ubiquitously, reinfection cannot be ruled out.
  • Erosions chronically active gastritis chronically inactive gastritis chronically inactive gastritis (e.g. atrophic) chronically inactive gastritis with metaplasia and / or dyplasia other gastritis acute gastritis
  • Bacteria e.g. Brunner's glands
  • endocrine disorders such as hypergastrinemia
  • Hyperpepsinogenemia mental disorders e.g. depression
  • Gastropathies e.g. protein-losing hypertrophic gastropathy or gastric lymphoma
  • Nisinoid substances are resistant to gastric juice because they contain lanthionine and / or methyllathionine and can even exert their optimal effect at a pH of 1-2, which is typically present in the stomach.
  • nisinoid substances are also indicated in domestic and farm animals as well as laboratory and zoo animals. Bacteria were found in these animals that occur in the same ecological niche as Helicobacter pylori in humans. Helicobacter pylori is human-specific under normal conditions and, with the exception of the monkey, does not occur in the animals mentioned above.
  • the bacteria of the Campylobacter-Helicobacter complex isolated from animals induce gastrointestinal lesions which are comparable to humans, so that the use of nisine also appears to be economically sensible here. In addition, they are often transferred to humans and then generate the image known from Helicobacter pylori. This spectrum of germs should also be tackled with nisinoid substances.
  • the water solubility of nisin can be used in the manufacture and use of the preparation.
  • the water solubility is dependent on the respective pH value and is 12 grams for a quantity of water of 100 milliliters at a pH of 2.4, 1 gram at a pH of 5.6 and 0.075 grams at a pH of Value of 7.0. This means that water solubility is particularly high at low pH values.
  • non-polar water 100 milliliters at a pH of 2.4, 1 gram at a pH of 5.6 and 0.075 grams at a pH of Value of 7.0.
  • REPLACEMENT LEAF Solvents have a comparatively pronounced insolubility.
  • Nisin belongs to the group of polypeptide antibiotics, subgroup Lantibiotica, and consists of 34 amino acids. This polypeptide is used by certain strains of Lactococcus lactis ssp. produced.
  • Lantibiotics the preferred formation of which can be seen in subtilin, nisin and nisinoid substances, are also understood to mean, inter alia, bacteriocins which contain lanthionine and / or methyl lanthionine.
  • nisinoid substance is formed as nisin.
  • Nitinoid substances can be produced biotechnologically or generated synthetically.
  • mutants superior to the natural substance can be produced.
  • this makes it possible to change the chemical configuration, for example by introducing new amino acids or replacing or deleting amino acids or certain chemical groups.
  • a combination of the nisinoid substance with preparations that lead to a reduction of the mucosal barrier potentiates the effectiveness (e.g. lysozyme, cyclooxygenase inhibitor, cationic detergents, chelators, etc.).
  • the lysozyme acts e.g. not only synergistic, it also delays the development of resistance and, like nisin, is enteric-resistant.
  • a combination with permeabilizers is intended.
  • gastrointestinal diseases can be attributed to the fact that, for example, Helicobacter pylori persists intracellularly in gastric epithelial cells. These intracellular germs could not be reached with previous therapy methods. With the help of liposomes or proteoliposomes, nisin can be easily infiltrated into the infected cells and thus kills the bacteria. This eliminates the risk of recurrence.
  • the dose to be administered be designed as a capsule filling.
  • the dosing amount can be realized in an arrangement within a capsule, for example, such that the filling is in the form of a powdery substance
  • ER SA TZBLATT is. But it is also possible that the filling is designed as a solution of the substances or that a dispersion (suspension or emulsion) is present.
  • the metered amount it is possible for the metered amount to be arranged in the area of a tablet.
  • a delayed release of the preparation from a special galenical formulation is conceivable.
  • liposomes or hydrogels can be used in accordance with the publication "Hydrogels: Swelling, Drug Loading, and Release", SW Kim et al. , Pharmaceutical Research, 9, 1992, pages 283-290, bioadhesive materials of natural and synthetic origin are also used. Further galenical formulations in this regard can be found in 1 of the publication "Formulations releasing the drug proximal to the pylorus in the dog", J. Heinämäki et al. , International Journal of Pharmaceuticals, 48 (1988), pages 51-61.
  • the metered amount is contained in a meterable liquid and is administered orally.
  • a meterable liquid for example, there may be a solution or dispersion.
  • Oral administration is generally expedient in gastric and small intestine applications.
  • the application should be rectal.
  • composition of the preparation can be supplemented by the following auxiliaries, e.g. Preservatives, buffer substances, carriers, flavoring agents, colorants, binders, adhesives, lubricants, adsorbents, thickeners and thinners. Due to the decades-long, safe use in food preservation, it seems appropriate to include the active ingredient composition
  • acidic beverages e.g. fruit juices, cola drinks
  • Other foods with broad acceptance among the population are also conceivable as carriers of the preparation (eg milk).
  • Diseases of the digestive tract are understood to mean diseases of the intestine, stomach and esophagus.
  • Helicobacter pylori I origin MHH, 10.8.92 Helicobacter pylori II, MHH, 17.8.92
  • the strains were stored as frozen foods (10% glycerine additive) or on transport medium carriers (Transwab) at -172 ° C.
  • the concentrations to be tested were added to the still liquid culture medium as a 10-fold concentrated solution and mixed thoroughly with the culture medium in a ratio of 1:10. After the agar had solidified, the test strains were inoculated onto the agar plates of different nisin concentration as a solid inoculum and, as required in the DIN, as a germ suspension. The result was read after 4 days of incubation at 37 °.
  • +++ means confluent growth, + / -, +, ++ reduced growth, - no growth.
  • H.p.I The substance effect starts at 1,000 ⁇ g / ml, the inhibition is completely at 2,500 ⁇ g / ml
  • H.p.II The sensitivity of this strain or its minimum inhibitory concentration is ⁇ 250 ⁇ g / ml.
  • an effect can be achieved in a pharmaceutical composition from an active substance concentration of 5 ⁇ g / ml.
  • permeabilizers already mentioned by way of example for reducing the mucosal barrier and as an active ingredient booster can basically be divided into the following groups:
  • Polycationic peptides for example lactoferrin, lysozyme, cathepsin G,
  • cationic, anionic and amphoteric detergents for example benzalkonium chloride or SDS,
  • Chelators for example various EDTA's, HMP, NTA, citrate
  • surfactants for example tweens, tritons, glycerides,
  • REPLACEMENT LEAF 8 general permeabilizers, for example Tris, C _., A 2+, M_, g 2+, N x ⁇ a +,
  • carbohydrate fatty acid esters for example sucrose mono fatty acid esters
  • Cyclooxygenase inhibitors such as 5-ASA,
  • any combination of two or more permeabilizers from the groups given above can be used instead of an isolated permeabilizer, the particular combination being dependent on the conditions of use.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Communicable Diseases (AREA)
  • Neurosurgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette préparation permet d'assurer la thérapie et la prophylaxie de maladies du tractus digestif qui surviennent en présence de bactéries pathogènes et/ou pathogènes secondaires, par exemple en présence d'Helicobacter pylori. A cet effet, il faut arriver à obtenir une concentration d'au moins 5 νg d'un antibiotique polypeptidique par ml de liquide au point d'intervention, ce qui est possible par administration d'une dose définie.
EP93922890A 1992-10-29 1993-10-22 Preparation permettant d'assurer la therapie et notamment la prophylaxie de maladies du tractus digestif Withdrawn EP0666759A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE4236469 1992-10-29
DE4236469 1992-10-29
DE4304640 1993-02-16
DE4304640 1993-02-16
DE4307352 1993-03-09
DE4307352A DE4307352A1 (de) 1992-10-29 1993-03-09 Präparat zur Therapie und insbesondere Prophylaxe von Erkrankungen des Verdauungstraktes
PCT/DE1993/001006 WO1994009806A1 (fr) 1992-10-29 1993-10-22 Preparation permettant d'assurer la therapie et notamment la prophylaxie de maladies du tractus digestif

Publications (1)

Publication Number Publication Date
EP0666759A1 true EP0666759A1 (fr) 1995-08-16

Family

ID=27204393

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93922890A Withdrawn EP0666759A1 (fr) 1992-10-29 1993-10-22 Preparation permettant d'assurer la therapie et notamment la prophylaxie de maladies du tractus digestif

Country Status (5)

Country Link
EP (1) EP0666759A1 (fr)
JP (1) JPH08504401A (fr)
AU (1) AU5174593A (fr)
CA (1) CA2148255A1 (fr)
WO (1) WO1994009806A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4432262A1 (de) * 1994-01-13 1995-07-20 Denecke Rainer Dr Med Vet Präparatkombination zur Therapie und Prophylaxe von Erkrankungen des Verdauungstraktes
US5804549A (en) * 1996-01-05 1998-09-08 Ambi Inc. Compositions with activity against helicobacter

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2264558A1 (en) * 1974-03-20 1975-10-17 Niviere Pierre Polymixin-methyl tetracycline salt antibiotics - active against Gram positive and negative bacteria, viruses and protozoa
JPS60215633A (ja) * 1984-04-11 1985-10-29 Terumo Corp 腸管吸収性ウロキナ−ゼリポソ−ム組成物
DE68913189T2 (de) * 1988-06-22 1994-05-19 Applied Microbiology Inc Nisin-zusammensetzungen zur anwendung als erhöhte breit-spektrum-bakterizide.
US4980163A (en) * 1989-03-01 1990-12-25 Public Health Research Institute Of The City Of New York Novel bacteriocin compositions for use as enhanced broad range bactericides and methods of preventing and treating microbial infection
US5043176A (en) * 1990-06-13 1991-08-27 Haarmann & Reimer Corp. Synergistic antimicrobial compositions
DE69213010T2 (de) * 1991-04-15 1997-01-23 Applied Microbiology Inc Verwendung eines Bakteriozin antibiotischen Agenten zur Herstellung eines Arzneimittels zur Behandlung von Magenverstimmungen, die durch Helicobacter pylori verursacht werden.
IL104364A (en) * 1992-01-17 1997-09-30 Applied Microbiology Pharmaceutical compositions containing bacteriocins

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9409806A1 *

Also Published As

Publication number Publication date
WO1994009806A1 (fr) 1994-05-11
JPH08504401A (ja) 1996-05-14
CA2148255A1 (fr) 1994-05-11
AU5174593A (en) 1994-05-24

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