CA2148255A1 - Preparation for therapeutic and especially prophylactic treatment of digestive tract disorders - Google Patents
Preparation for therapeutic and especially prophylactic treatment of digestive tract disordersInfo
- Publication number
- CA2148255A1 CA2148255A1 CA002148255A CA2148255A CA2148255A1 CA 2148255 A1 CA2148255 A1 CA 2148255A1 CA 002148255 A CA002148255 A CA 002148255A CA 2148255 A CA2148255 A CA 2148255A CA 2148255 A1 CA2148255 A1 CA 2148255A1
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- Prior art keywords
- preparation according
- permeabilizer
- preparation
- diseases
- indication
- 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.)
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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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- Neurosurgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT
The preparation serves in the therapy and prophylaxis of diseases of the digestive tract that occur in the presence of pathogenic and/or facultative-pathogenic bacteria, such as, for example, in the presence of Helicobacter pylori.
For this purpose, a concentration of at least 5 µg of a polypeptide antibiotic per ml of fluid must be achieved at the site to be affected. This occurs by the application of a pre-defined dose.
The preparation serves in the therapy and prophylaxis of diseases of the digestive tract that occur in the presence of pathogenic and/or facultative-pathogenic bacteria, such as, for example, in the presence of Helicobacter pylori.
For this purpose, a concentration of at least 5 µg of a polypeptide antibiotic per ml of fluid must be achieved at the site to be affected. This occurs by the application of a pre-defined dose.
Description
- 2 ~
" . ~ . "
These germs, which are distinct from Helicobacter pylori, are also further ` -transferred from hurnan being to human being. Infestation with non~
Helicobacter ~lori bacteria must not be underestimated. Most of these bacteria, lik0 Helicobacter pylori, live in the same ecological niche, that is, on and in the mucosa of the stomach, under the protective mucus layer. Those who keep dogs and cats are particularly at risk of infecting themselves with these germs (for example, with Flexispira rappini).
Clinical pictures in which the bacteria mentioned above play a part arediscussed in the following publications: "Chronic Alcoholic Gastritis,"
Rajiv Uppal, MD; Syed K. Lateef, MD; Mark A. Korsten, MD; Fiorenzo ` `
Paronetto, MD; Charles S. Lieber, MD, Archives of Internal Medicine, April 1991, Vol. 151, pages 760 -764; "Detection and identification of Helicobacter pylori by the polymerase chain reaction," C. Clayton, K.
Kleanthous, S. Tabaqchali, J. Clin Pathol 1991, 44, pages 5t5-516. An indication of a connection between Helicobacter pylori and stomach :
cancer is found in the essay "Helicobacter pylori and gastric carcinoma,"
R.J.L.F. Loffeld, I. Willems, J.A. Flendrig & Arends, J.W., Histopathology ~ -1990, 17, pages 537-541.
Preparations that have been known thus far for treating the diseas0s .mentioned in the publications cited above exhibit an unfavorable relationship o~ efficacy and side-effects. Due to the grave consequences of an infection with these pathogens, see above, an effective prophylaxis and treatment that poses no cause for concern is necessary.
The aforementioned di eases are treated according to therapeutic ~ ~
-' ~: ..
_2 1 4 8 2 ~
. . . ~ ':
~ `:,.... `
methods that havo been uGied thus fa;with preparations, whose pnncipal ~active ingredient is, for example, bisrnuth salts. Since a mono-therapy : "
with these salts proved to be insùfficient, by way of complement, a complicated antibiotic combination therapy had to be conducted (for exampls, with amoxicillin and metronidazole). Due to long years of the ~ ;
use of bismuth preparations, their profile of side-effects is sufficiently well-known: neurotoxic symptoms were noted in the foreground. For ` ` -`
quits some time, the benefit-to-risk ratio of bismuth preparations has been called to question. The spectrum of side-effects of the antibiotics ` : `
that have been used thus far is sufficiently well known.
: '.: ' . .:
Such methods of treatment are described, for example, in the essay ~.
"Diagnostic value of decreasing IgG, IgA, and IgM antibody titres after eradication of Helicobacter pylori," Timo U. Kosunen, Kari Seppala, Seppo Sarna, Pentti Sipponen, The Lancet, Vol 339, 11 April 1992, page :893, as well as in the survey article by J. Ormand and N. Talley~
"Helicobacter pylori: Controversies and an Approach to Management" -from Màyo Clin. Proc. 65: 414-426, 1990. ~ ;
Beyond that, symptomatic treatment involving antacids, H2-blockers, and `; ;`- -~
ATPase-inhibitors that has been used thus far generally leads to an `~ ~ -ovsrabundance of bacteria and/or fungi in the stomach (fecal flora), since the acidic protection of the hollow organ has been lost. In conjunction with the acidic inhibition, a massive decrease in the secretion of Iysozyme from the gastric`glands occurs. This anti-bacterially effective enzyme of the body's own is essential for the repression of pathogenic `~
germs. To that extent, the suppression of acid favors certain etiopathogenetic factors for diverse gastro-intestinal lesions (such as gastric carcinoma and carcinoids). Apart from special indications, acid ~.
suppression is obsolete, and for ethical and economic reasons, it should ~:
;: ~
- 4 - ~ ~ ~
-:-. - . ~, ...
be r~placed by lantibiotic prophylaxis and therapy.
. . . - .. -, It is th~r~fore the task of ths present invention to indicatc a preparation of the typ0 cit~d at thc outsot in such a way that It assures a high degree . ;
of efficacy without side-offects. ' This task is achieved according to the invention by virtue of the fact that a defined dose of a polypeptide antibiotic is contained as the active ` -ingredient, as a result of the application of which an active ingredient -~. ; ;
concentration of at least 5 ~g/ml is achieved at the affected site.
Ths anti-bacterial effectiveness of lantibiotics, especially of nisin, is ~ d already known. Use as a foodstuffs additive is described, for example, in the European patent application EP-A-0 453 972. In addition, the anti-bacterial effectiveness of nisin is also indicated in the United States `
patent 5 043 176. Th~ use of nisin in the cosmetic field is described in ~ ;
the published German patent application DE-OS 39 38 140.
. " ' The bacteria enumerated at the outset are the etiopathogenetic factor for ~ .chronic gastritis. The latter leads, over time, to atrophy of the mucosa, and to intestinal metaplasia. The final stage of these processes is, as a ~ `
rule, a gastric tumor.
, ~
- ~, As a result of timely prophylactic use of nisin, it would be possible to achieve a drastic reduction in the incidence of these tumors. The settlement of the stomach with pathogenic bacteria (such as Gastrospirillum hominis or Helicobacter pylori) can give rise to a weakening of the resistance of the mucosa, so that patients who are compelled to take corticosteroids and non-steroidal antiphlogistics `~
(NSAIDS) on a regular basis develop peptic ulcers.
-. . . ~ ~. .
~, ~
~, . 21~82~jS , -5~
Even among this group of patients, a considerable reduction of this : `ailment can be achieved by tha timely prophylactic use of nisin, for ~xample. In this regard, some thought should also be devoted to the addition of a nisinoid substance to alcoholic beverages, in order to ;; .
prevent stomach perforation, which is so feared among alcoholics, and ~ ;;
alcoholic gastritis. : ` `
, . . .
Approximately half of the world's population carries Helicobacter pylori. ; ~ ~ -Due to suitable screening programs (serology, breath test, and PCR), ~:
groups at risk may be readily identified. In these casesj an economic significance that should not be underestimated would be attached to the ~ "
prophylactic use of nisinoid substances.
- ~ .
The prophylactic use of nisin does not give cause for any medical concern, since it is not absorbed, and since it is inactivated by pancreatic" ~-:
enzymes, especially alpha-chymotrypsin. ~: ;
The medication is applied until the treatment goal, namely, the ;~ ~ ` ;``
0radication of the germs, has been achieved. Since many of the bacteria under discussion occur ubiquitously, reinfection must not be precluded, however.
From the therapeutic standpointl the foliowing indications result~
- Duodenal ulcer - Duodenal ulcerwith gastric metaplasia - Gastriculcer ~- ~ p~
- Stomach lesions with intestinal metaplasia - Erosions -- chronically active gastritis ~ -chronically inactive gastritis (e.g. atrophic) ~ ~
, -2 ~ ~ 8 2 ~
. . . ~ ~ . .
,. ~ :.```, ~... ..
i i, . . .
;, ~. . ` ` ... ~
- chronically inactive gastritis with metaplasia and/or dysplasia - oth~r forms of gastritis `~
- acute gastritis -- l~uodenitis -- non-ulcerolls dyspepsia and functional dyspapsia - other gastro-intestinal diseases - Barrett's esophagus with dysplasia or metaplasia ` ~
- Diseasc on ths basis of haterotopic gastric mucosa in the digestive ~ -- tract (e.g. in Meckel's diverticulum) Other indicatlons include~
- Diseases on the basis of settlement of the efferent pathways ~ -associated with the digestive tract by bacteria (Q~9. Brunner's glands) ~;
- endocrine disorders, such as hypergastrinemia and hyperpepsinogenernia - psychlatricdisorders (e~. depression) - Ménétrier's disease - Gastropathies, such as protein-losing hypertrophic gastropathy or gastric Iymphomas.
.. . - :~
The use of a lantibiotic, especially of a nisinoid active ingredient, proves to be an extremely effective measure for killing off aggressive gastric bactsria~ Nisinoid substances are resistant to gastric juice, because they : . . .
contain lanthionine and/or methyl lanthionine, and they can even develop their optimal effect in a pH of 1-2, which is typically extant in the stomach.
The use of nisinoid substances is also indicated in the case of pets and farm animals, as well as laboratory and zoo animals. In these animals, the ~xistence of bacteria that occur in the same ecological niche as - - ~
~, 2 ~ -8 ~
Heticobacter pylori in human beings was shown. Undar normal conditions, Helicobacter pylori is human-specific, and, with the exception of primates, it does not occur in the aforementioned animals. " ~
Given the lack of sufficient study findings and taxonomic turbulences in ` ~ ~ .
this special sector, these spiral-shapad organisms are currently being classified as in the publication "An Uncultured Gastric Spiral Organism Is a Newly Identified Helicobacter in Humans," Jay V. Solnick, Jani O'Rourke, Adrian Lee, Bruce J. Paster, Floyd E. Dewhirst and Lucy S.
Tomkins! The Journal of Infectious Diseases, 1993, 168, pages 379 ff.
The following bacteria were presented~
- Hclicobacterfelis DS3 - Helicobacterfelis CS1 - (Gaslrospirillum hominis) 2 - (Gastrospirillum hominis) 1 `~
- Helicobacterpylori . ~
- Helicobacteracinonyx : ~;: .`
- Helicobactersp. CL03 - Helicobacter mustelae - Helicobacier fennelliae :
- Helicobacter muridarum - Helicobacter cinaedi - (Flexispira rappini) - Wolinella succinogenes - Campylobacter fetus ss fetus ;~
- Campylobacter largi - Campylobactercoli ; :~
- Campylobacter jejuni ,. . ,., ~, ~ ~". ~ .
~ ~ 4 8 ~
- 8~
The bacteria of the Campylbacter-H01icobacter complex that are isolated from animals induce gastro-intestinal lesions that are comparable to those in human beings, so that here, too, the use of nisin seems to make `
economic sense. In addition, they are frequently transferred to human beings, and then produce the well known picture of Helicobacter pylori.
This germ spectrum, as well, should be attacked with nisinoid substances.
The most recent knowledge points to a bacterial etio-pathogenesis of Crohn's disease and ulcerous colitis (chronic inflammatory intestinal diseases). Here, too, some thought might be given to the use of lantibiotics, especiallythat of nisinoid substances.
In ~ha production and use of the preparation, nisin's solubility in water can be exploited. Solubility in water depends upon the pH value that is ;;
present in each case, and, for a quantity of water of 100 mill~liters, it is 12 grams in the cass of a pH value of 2.4, 1 gram in the case of a pH
value of 5.6, and 0.075 grams In the case of a pH value of 7Ø Thus, in the case of low pH values in particular, a high degree of water-solubility` ~
is given. In non-polar solvents, by contrast, a comparably pronounced `
Insolubility is given.
" , ~ ...
Nisin belongs to the group of polypeptide antibiotics, sub-group - - ~
lantibiotics, and it consists of 34 amino acids. This polypeptide is produced by certain strains of Lactococcus lactis ssp. `
Lantibiotics, whose preferred embodiment may be seen in subtilin, nisin, and nisinoid substances, are taken to mean, amon3 other things, those bactenocines as well, that contain lanthionine and/or methyl lanthionine. I
" '~ -;'~"' ---.. _ .. ....... .
2~5 :~
It is characteristic that within the nisin molecule, five ring structures are prss~nt, each of which exhibits a different number of amino acids. The .
molecular weight is approximately 3500. However, there are also ~ :;
molecular structures, especially dimers or multimers, that have become known, that exhibit molecular weights of up to 14000. This is indicated, for example, by B. Jarvis, Jeffsoat, Joan & Cheeseman, Bioch. Biophys.
Acta, 1968, 168 (1), page 153.
Production of an active ingredient with tried and true means can be ~ ` -accomp!ished by virtus of the fact that th~e nisinoid substance is embodied as nisin.
The structure of nisin, in principle, as well as possibilities for the production of nisin, result from the patents GB [Great Britainl 844 782, and DE [Germanyl 11 95 434. Additional production methods are , ;
indicated, for example, in the patents DE 16 17 580 as well as DE 20 00 ``
818. Nisinoid substances (anti-microbially effective peptide analogs) can be manufactured by bio-technological means, or produced synthetically.
By "genetic sngineering" or carefully directed mutagenesis, mutants that are superior to the natural substance can be produced. In particular, it is possible, by these means, to undertake an alteration of the chemical configuration, for example, by the introduction of new amino acids, or the substitution or deletion of amino acids, or certain chemical groups.
A combination of the nisinoid substance with preparations that lead to a reduction of the mucosal barrier enhances the effectiveness (for example, Iysezyme, cyclo-oxygenase inhibitors, cationic detergents, ~ `
chelators, etc.). The Iysozyme, for example, not only has a synergistic - ` -effect, it also causes a delay in the development of resistance, and, like - i, ,' ', -: .... . .
` 21482 -~lo-nisin, it is resistant to gastric juice. In particular, thought is given to a ~ -combination with permaabilizing agents.
` . . ', ~':~,"', ;~
The high relapse quotient, or exacerbation of gastro-intestinal ailments may be attributed, based upon our own investigations, to the fact, for example, that Helicobacter pylori persists intracellularly in the stomach's ~;
~pith~lial c~lls. These intracellular germs could not be reached`with thc methods of therapy used to data. With the aid of liposomes or proteo-liposomes, it is possible to sluice nisin into affected cells without any difficulties, leading, in this way, to a killing off of the bacteria. Thus, the danger of recidivism is eliminated.
In order to render the ingestion of the preparation easier, it is suggested that the dose to be administered be cmbodied as the filling of a capsule.
The amount of the dosa can be realized in the case of an arrangement within the capsule in such a way, for exa`mple, that the filling is embodied as a substance in the form of a powder. It is also possible, however, for the filllng to be embodied as a solution of the substances, or, for a dispersion (suspansion or emulsion) to be extant. `
- ~ ~
According to another preparation, it is possible for the amount of the dose to be provided within the area of a tablet. A delayed release of the preparation out of a special galenic formulation is conceivable. To this and, for example, liposomes or hydrogels that are in keeping with the publication "Hydrogels: Swelling, Drug Loading, and Release," S.W. Kim ~;
et al., Pharmaceutical Research, 9, 1992, pages 283-290, can be used, as can bio-aclhesive materials of natural and synthetic origin. Additional galenic formulations in this respect are described in the publication "Formulations releasing the drug proximal to the pylorus in the dog," J. `
. .:
~l~g2~
Hein~m~ki et al., International Journal of Pharmaceutics, 48 ~1988), ~ -pages 51-61.
. :
In order to render the development of the active ingredien~ in the area of ` ~ ~ `
the stomach possible, soma thought is also dcvoted to the fact that the ~;
quantity of the dose is contained in a dosable fluid, and that it is administered orally. A solution or a dispersion may be extant. The oral ;~ `
application is, as a matter of principle, used to good purpose in the case of gastric applications and applications to the small intestine. In applications in the region of the large intastine, application should be accomplished rectally. - ;
, ;`','~
The various possibilities for compounding the preparation can be complemented by the following inactive ingredients, such as, for exampla, preservative substances, buffer substances, carriers, flavor correctors, dyestuffs, binding agents, adhesives, lubricants, adsorbing agents, thickening agents, and thinners. As a result of use over decades in the preservation of foodstuffs without any cause for concern, it seems to be to good purposa to administer the composition of the active ingredient with acidic beverages (for example, fruit juices, colas), which would increase the compliance. In addition, other foodstuffs having a broad acceptance in the population are conceivable as carriers of the`~
preparation (for axample, milk). `
An additional fascinating possibility for the elimination of the bacteria enumerated at the outset would be Drobiotic therapy. In this process, ~ -living, bacteriocin-producing bacteria, such as, for example, lactobacilli, are used, which are, themselves, harmless, but which, as a result of competitive and bactericidal mechanisms, lead to an exclusion of the pathogenic/faculta1ive-pathogenic germs. ::
. .
, ; ~: . .
. . .
:.`.`
This principle can, obviously, also be exploited in a prophylactic manner.
An elegant method, for example, would be, in the case of the gastro~
intestinal region, to enrich yoghurt with lactococei that produce nisin; in correspondin~ preparation with additive inactive ingredients, the ~ -compliance problems of some patients, and their aggressive bacteria, can be eliminated.
- ,, In this or some similar manner, the criteria established in 1988 by the - ~;
WHO and listed by H. Cranz for an OTC ~over the counter] drug are met in an ideal way; they are described in the essay: Crantz, H. Over-the-counterdrugs: the issues. Drug Safety 5 (Suppl. 1): pages l20-125, 1 990.
"~
Ailments of ths digestive tract are taken to mean ailments of the gut, the stomach, and the esophagus.
~; .'~ ' .`''-,,, : . ~ . , ' 1 , .. :
2 ~ 3 ~ ~ ~
', " "~..
NISIN - Sensitivity Testing An ~xperimental test of the effects of nisin upon Helicobacter pylori took plac~ as follows.
1. Test strains Helicobacter pytori 1, origin MHH, ~110/92 ~ ` `
Helicobacter pylori ll, MHH, 8/17192 The strains were stored as frozen preserves (10% ~Iycerine added), or, they were stored in transport medium carrisrs (Transwab) at 172C. `
2. Nutritiva madia Columbia agar base (tha firm of Merck), with the addition of 10%
horse's blood (manufactured as a chocolate agar plate).
" . ~ . "
These germs, which are distinct from Helicobacter pylori, are also further ` -transferred from hurnan being to human being. Infestation with non~
Helicobacter ~lori bacteria must not be underestimated. Most of these bacteria, lik0 Helicobacter pylori, live in the same ecological niche, that is, on and in the mucosa of the stomach, under the protective mucus layer. Those who keep dogs and cats are particularly at risk of infecting themselves with these germs (for example, with Flexispira rappini).
Clinical pictures in which the bacteria mentioned above play a part arediscussed in the following publications: "Chronic Alcoholic Gastritis,"
Rajiv Uppal, MD; Syed K. Lateef, MD; Mark A. Korsten, MD; Fiorenzo ` `
Paronetto, MD; Charles S. Lieber, MD, Archives of Internal Medicine, April 1991, Vol. 151, pages 760 -764; "Detection and identification of Helicobacter pylori by the polymerase chain reaction," C. Clayton, K.
Kleanthous, S. Tabaqchali, J. Clin Pathol 1991, 44, pages 5t5-516. An indication of a connection between Helicobacter pylori and stomach :
cancer is found in the essay "Helicobacter pylori and gastric carcinoma,"
R.J.L.F. Loffeld, I. Willems, J.A. Flendrig & Arends, J.W., Histopathology ~ -1990, 17, pages 537-541.
Preparations that have been known thus far for treating the diseas0s .mentioned in the publications cited above exhibit an unfavorable relationship o~ efficacy and side-effects. Due to the grave consequences of an infection with these pathogens, see above, an effective prophylaxis and treatment that poses no cause for concern is necessary.
The aforementioned di eases are treated according to therapeutic ~ ~
-' ~: ..
_2 1 4 8 2 ~
. . . ~ ':
~ `:,.... `
methods that havo been uGied thus fa;with preparations, whose pnncipal ~active ingredient is, for example, bisrnuth salts. Since a mono-therapy : "
with these salts proved to be insùfficient, by way of complement, a complicated antibiotic combination therapy had to be conducted (for exampls, with amoxicillin and metronidazole). Due to long years of the ~ ;
use of bismuth preparations, their profile of side-effects is sufficiently well-known: neurotoxic symptoms were noted in the foreground. For ` ` -`
quits some time, the benefit-to-risk ratio of bismuth preparations has been called to question. The spectrum of side-effects of the antibiotics ` : `
that have been used thus far is sufficiently well known.
: '.: ' . .:
Such methods of treatment are described, for example, in the essay ~.
"Diagnostic value of decreasing IgG, IgA, and IgM antibody titres after eradication of Helicobacter pylori," Timo U. Kosunen, Kari Seppala, Seppo Sarna, Pentti Sipponen, The Lancet, Vol 339, 11 April 1992, page :893, as well as in the survey article by J. Ormand and N. Talley~
"Helicobacter pylori: Controversies and an Approach to Management" -from Màyo Clin. Proc. 65: 414-426, 1990. ~ ;
Beyond that, symptomatic treatment involving antacids, H2-blockers, and `; ;`- -~
ATPase-inhibitors that has been used thus far generally leads to an `~ ~ -ovsrabundance of bacteria and/or fungi in the stomach (fecal flora), since the acidic protection of the hollow organ has been lost. In conjunction with the acidic inhibition, a massive decrease in the secretion of Iysozyme from the gastric`glands occurs. This anti-bacterially effective enzyme of the body's own is essential for the repression of pathogenic `~
germs. To that extent, the suppression of acid favors certain etiopathogenetic factors for diverse gastro-intestinal lesions (such as gastric carcinoma and carcinoids). Apart from special indications, acid ~.
suppression is obsolete, and for ethical and economic reasons, it should ~:
;: ~
- 4 - ~ ~ ~
-:-. - . ~, ...
be r~placed by lantibiotic prophylaxis and therapy.
. . . - .. -, It is th~r~fore the task of ths present invention to indicatc a preparation of the typ0 cit~d at thc outsot in such a way that It assures a high degree . ;
of efficacy without side-offects. ' This task is achieved according to the invention by virtue of the fact that a defined dose of a polypeptide antibiotic is contained as the active ` -ingredient, as a result of the application of which an active ingredient -~. ; ;
concentration of at least 5 ~g/ml is achieved at the affected site.
Ths anti-bacterial effectiveness of lantibiotics, especially of nisin, is ~ d already known. Use as a foodstuffs additive is described, for example, in the European patent application EP-A-0 453 972. In addition, the anti-bacterial effectiveness of nisin is also indicated in the United States `
patent 5 043 176. Th~ use of nisin in the cosmetic field is described in ~ ;
the published German patent application DE-OS 39 38 140.
. " ' The bacteria enumerated at the outset are the etiopathogenetic factor for ~ .chronic gastritis. The latter leads, over time, to atrophy of the mucosa, and to intestinal metaplasia. The final stage of these processes is, as a ~ `
rule, a gastric tumor.
, ~
- ~, As a result of timely prophylactic use of nisin, it would be possible to achieve a drastic reduction in the incidence of these tumors. The settlement of the stomach with pathogenic bacteria (such as Gastrospirillum hominis or Helicobacter pylori) can give rise to a weakening of the resistance of the mucosa, so that patients who are compelled to take corticosteroids and non-steroidal antiphlogistics `~
(NSAIDS) on a regular basis develop peptic ulcers.
-. . . ~ ~. .
~, ~
~, . 21~82~jS , -5~
Even among this group of patients, a considerable reduction of this : `ailment can be achieved by tha timely prophylactic use of nisin, for ~xample. In this regard, some thought should also be devoted to the addition of a nisinoid substance to alcoholic beverages, in order to ;; .
prevent stomach perforation, which is so feared among alcoholics, and ~ ;;
alcoholic gastritis. : ` `
, . . .
Approximately half of the world's population carries Helicobacter pylori. ; ~ ~ -Due to suitable screening programs (serology, breath test, and PCR), ~:
groups at risk may be readily identified. In these casesj an economic significance that should not be underestimated would be attached to the ~ "
prophylactic use of nisinoid substances.
- ~ .
The prophylactic use of nisin does not give cause for any medical concern, since it is not absorbed, and since it is inactivated by pancreatic" ~-:
enzymes, especially alpha-chymotrypsin. ~: ;
The medication is applied until the treatment goal, namely, the ;~ ~ ` ;``
0radication of the germs, has been achieved. Since many of the bacteria under discussion occur ubiquitously, reinfection must not be precluded, however.
From the therapeutic standpointl the foliowing indications result~
- Duodenal ulcer - Duodenal ulcerwith gastric metaplasia - Gastriculcer ~- ~ p~
- Stomach lesions with intestinal metaplasia - Erosions -- chronically active gastritis ~ -chronically inactive gastritis (e.g. atrophic) ~ ~
, -2 ~ ~ 8 2 ~
. . . ~ ~ . .
,. ~ :.```, ~... ..
i i, . . .
;, ~. . ` ` ... ~
- chronically inactive gastritis with metaplasia and/or dysplasia - oth~r forms of gastritis `~
- acute gastritis -- l~uodenitis -- non-ulcerolls dyspepsia and functional dyspapsia - other gastro-intestinal diseases - Barrett's esophagus with dysplasia or metaplasia ` ~
- Diseasc on ths basis of haterotopic gastric mucosa in the digestive ~ -- tract (e.g. in Meckel's diverticulum) Other indicatlons include~
- Diseases on the basis of settlement of the efferent pathways ~ -associated with the digestive tract by bacteria (Q~9. Brunner's glands) ~;
- endocrine disorders, such as hypergastrinemia and hyperpepsinogenernia - psychlatricdisorders (e~. depression) - Ménétrier's disease - Gastropathies, such as protein-losing hypertrophic gastropathy or gastric Iymphomas.
.. . - :~
The use of a lantibiotic, especially of a nisinoid active ingredient, proves to be an extremely effective measure for killing off aggressive gastric bactsria~ Nisinoid substances are resistant to gastric juice, because they : . . .
contain lanthionine and/or methyl lanthionine, and they can even develop their optimal effect in a pH of 1-2, which is typically extant in the stomach.
The use of nisinoid substances is also indicated in the case of pets and farm animals, as well as laboratory and zoo animals. In these animals, the ~xistence of bacteria that occur in the same ecological niche as - - ~
~, 2 ~ -8 ~
Heticobacter pylori in human beings was shown. Undar normal conditions, Helicobacter pylori is human-specific, and, with the exception of primates, it does not occur in the aforementioned animals. " ~
Given the lack of sufficient study findings and taxonomic turbulences in ` ~ ~ .
this special sector, these spiral-shapad organisms are currently being classified as in the publication "An Uncultured Gastric Spiral Organism Is a Newly Identified Helicobacter in Humans," Jay V. Solnick, Jani O'Rourke, Adrian Lee, Bruce J. Paster, Floyd E. Dewhirst and Lucy S.
Tomkins! The Journal of Infectious Diseases, 1993, 168, pages 379 ff.
The following bacteria were presented~
- Hclicobacterfelis DS3 - Helicobacterfelis CS1 - (Gaslrospirillum hominis) 2 - (Gastrospirillum hominis) 1 `~
- Helicobacterpylori . ~
- Helicobacteracinonyx : ~;: .`
- Helicobactersp. CL03 - Helicobacter mustelae - Helicobacier fennelliae :
- Helicobacter muridarum - Helicobacter cinaedi - (Flexispira rappini) - Wolinella succinogenes - Campylobacter fetus ss fetus ;~
- Campylobacter largi - Campylobactercoli ; :~
- Campylobacter jejuni ,. . ,., ~, ~ ~". ~ .
~ ~ 4 8 ~
- 8~
The bacteria of the Campylbacter-H01icobacter complex that are isolated from animals induce gastro-intestinal lesions that are comparable to those in human beings, so that here, too, the use of nisin seems to make `
economic sense. In addition, they are frequently transferred to human beings, and then produce the well known picture of Helicobacter pylori.
This germ spectrum, as well, should be attacked with nisinoid substances.
The most recent knowledge points to a bacterial etio-pathogenesis of Crohn's disease and ulcerous colitis (chronic inflammatory intestinal diseases). Here, too, some thought might be given to the use of lantibiotics, especiallythat of nisinoid substances.
In ~ha production and use of the preparation, nisin's solubility in water can be exploited. Solubility in water depends upon the pH value that is ;;
present in each case, and, for a quantity of water of 100 mill~liters, it is 12 grams in the cass of a pH value of 2.4, 1 gram in the case of a pH
value of 5.6, and 0.075 grams In the case of a pH value of 7Ø Thus, in the case of low pH values in particular, a high degree of water-solubility` ~
is given. In non-polar solvents, by contrast, a comparably pronounced `
Insolubility is given.
" , ~ ...
Nisin belongs to the group of polypeptide antibiotics, sub-group - - ~
lantibiotics, and it consists of 34 amino acids. This polypeptide is produced by certain strains of Lactococcus lactis ssp. `
Lantibiotics, whose preferred embodiment may be seen in subtilin, nisin, and nisinoid substances, are taken to mean, amon3 other things, those bactenocines as well, that contain lanthionine and/or methyl lanthionine. I
" '~ -;'~"' ---.. _ .. ....... .
2~5 :~
It is characteristic that within the nisin molecule, five ring structures are prss~nt, each of which exhibits a different number of amino acids. The .
molecular weight is approximately 3500. However, there are also ~ :;
molecular structures, especially dimers or multimers, that have become known, that exhibit molecular weights of up to 14000. This is indicated, for example, by B. Jarvis, Jeffsoat, Joan & Cheeseman, Bioch. Biophys.
Acta, 1968, 168 (1), page 153.
Production of an active ingredient with tried and true means can be ~ ` -accomp!ished by virtus of the fact that th~e nisinoid substance is embodied as nisin.
The structure of nisin, in principle, as well as possibilities for the production of nisin, result from the patents GB [Great Britainl 844 782, and DE [Germanyl 11 95 434. Additional production methods are , ;
indicated, for example, in the patents DE 16 17 580 as well as DE 20 00 ``
818. Nisinoid substances (anti-microbially effective peptide analogs) can be manufactured by bio-technological means, or produced synthetically.
By "genetic sngineering" or carefully directed mutagenesis, mutants that are superior to the natural substance can be produced. In particular, it is possible, by these means, to undertake an alteration of the chemical configuration, for example, by the introduction of new amino acids, or the substitution or deletion of amino acids, or certain chemical groups.
A combination of the nisinoid substance with preparations that lead to a reduction of the mucosal barrier enhances the effectiveness (for example, Iysezyme, cyclo-oxygenase inhibitors, cationic detergents, ~ `
chelators, etc.). The Iysozyme, for example, not only has a synergistic - ` -effect, it also causes a delay in the development of resistance, and, like - i, ,' ', -: .... . .
` 21482 -~lo-nisin, it is resistant to gastric juice. In particular, thought is given to a ~ -combination with permaabilizing agents.
` . . ', ~':~,"', ;~
The high relapse quotient, or exacerbation of gastro-intestinal ailments may be attributed, based upon our own investigations, to the fact, for example, that Helicobacter pylori persists intracellularly in the stomach's ~;
~pith~lial c~lls. These intracellular germs could not be reached`with thc methods of therapy used to data. With the aid of liposomes or proteo-liposomes, it is possible to sluice nisin into affected cells without any difficulties, leading, in this way, to a killing off of the bacteria. Thus, the danger of recidivism is eliminated.
In order to render the ingestion of the preparation easier, it is suggested that the dose to be administered be cmbodied as the filling of a capsule.
The amount of the dosa can be realized in the case of an arrangement within the capsule in such a way, for exa`mple, that the filling is embodied as a substance in the form of a powder. It is also possible, however, for the filllng to be embodied as a solution of the substances, or, for a dispersion (suspansion or emulsion) to be extant. `
- ~ ~
According to another preparation, it is possible for the amount of the dose to be provided within the area of a tablet. A delayed release of the preparation out of a special galenic formulation is conceivable. To this and, for example, liposomes or hydrogels that are in keeping with the publication "Hydrogels: Swelling, Drug Loading, and Release," S.W. Kim ~;
et al., Pharmaceutical Research, 9, 1992, pages 283-290, can be used, as can bio-aclhesive materials of natural and synthetic origin. Additional galenic formulations in this respect are described in the publication "Formulations releasing the drug proximal to the pylorus in the dog," J. `
. .:
~l~g2~
Hein~m~ki et al., International Journal of Pharmaceutics, 48 ~1988), ~ -pages 51-61.
. :
In order to render the development of the active ingredien~ in the area of ` ~ ~ `
the stomach possible, soma thought is also dcvoted to the fact that the ~;
quantity of the dose is contained in a dosable fluid, and that it is administered orally. A solution or a dispersion may be extant. The oral ;~ `
application is, as a matter of principle, used to good purpose in the case of gastric applications and applications to the small intestine. In applications in the region of the large intastine, application should be accomplished rectally. - ;
, ;`','~
The various possibilities for compounding the preparation can be complemented by the following inactive ingredients, such as, for exampla, preservative substances, buffer substances, carriers, flavor correctors, dyestuffs, binding agents, adhesives, lubricants, adsorbing agents, thickening agents, and thinners. As a result of use over decades in the preservation of foodstuffs without any cause for concern, it seems to be to good purposa to administer the composition of the active ingredient with acidic beverages (for example, fruit juices, colas), which would increase the compliance. In addition, other foodstuffs having a broad acceptance in the population are conceivable as carriers of the`~
preparation (for axample, milk). `
An additional fascinating possibility for the elimination of the bacteria enumerated at the outset would be Drobiotic therapy. In this process, ~ -living, bacteriocin-producing bacteria, such as, for example, lactobacilli, are used, which are, themselves, harmless, but which, as a result of competitive and bactericidal mechanisms, lead to an exclusion of the pathogenic/faculta1ive-pathogenic germs. ::
. .
, ; ~: . .
. . .
:.`.`
This principle can, obviously, also be exploited in a prophylactic manner.
An elegant method, for example, would be, in the case of the gastro~
intestinal region, to enrich yoghurt with lactococei that produce nisin; in correspondin~ preparation with additive inactive ingredients, the ~ -compliance problems of some patients, and their aggressive bacteria, can be eliminated.
- ,, In this or some similar manner, the criteria established in 1988 by the - ~;
WHO and listed by H. Cranz for an OTC ~over the counter] drug are met in an ideal way; they are described in the essay: Crantz, H. Over-the-counterdrugs: the issues. Drug Safety 5 (Suppl. 1): pages l20-125, 1 990.
"~
Ailments of ths digestive tract are taken to mean ailments of the gut, the stomach, and the esophagus.
~; .'~ ' .`''-,,, : . ~ . , ' 1 , .. :
2 ~ 3 ~ ~ ~
', " "~..
NISIN - Sensitivity Testing An ~xperimental test of the effects of nisin upon Helicobacter pylori took plac~ as follows.
1. Test strains Helicobacter pytori 1, origin MHH, ~110/92 ~ ` `
Helicobacter pylori ll, MHH, 8/17192 The strains were stored as frozen preserves (10% ~Iycerine added), or, they were stored in transport medium carrisrs (Transwab) at 172C. `
2. Nutritiva madia Columbia agar base (tha firm of Merck), with the addition of 10%
horse's blood (manufactured as a chocolate agar plate).
3. Culture conditions Culture in anaerobic pot after Brewer, using BBL CampyPae Plus of the firm of Becton Dickinson (standardized H2-, CO2- atmosphere) 4. Production ofthe Test Solution Pure nisin, made by the firm of "Aplin & Barrett LTD~' was used as the test substance. The testing of the substance took place at two different solvent pH values, pH 4.43 and pH 2Ø
~;.'`,.:,',~".
The following concentrations were used in the first trial batch~
260 micrograms/ml 1,000 micrograms/ml 10,000 micrograms/ml. ~ ; ;;
Since the first trial yielded no refsrence point for a varied effect in the case of plt 2.0 or pH 4.42, the repeat trial was conducted with the diluent, which had been adjusted to 2.0, and with the following concentrations:
500 micrograms/ml 1,000 micrograms/ml :
2,600 microgramslml 5,000 micrograms/ml ~ ~
10,000 micrograms/ml. ~ ;
' ~
5. Sensitivity testing according to DIN [German Industrial Norm] 58940, ~ ~ -Part 6, agar dilution method ......
The exception to the performance of this test: the test was not conducted on Mueller-Hinton nutritive medium (free of blood and s~rum), but rather on 10% horse's blood chocolate agar, because thus far, the germs could not be cultured on serum-free nutritive media.
In the agar dilution method, the concentraUons to be tested were ;
added to th~ as yet liquid nutritive media as 10-fold concentrated solution, and carefully mixed with the nutritive medium in a ratio of 1:10. Aftsr tho solidification of the agar, the test strains, as a ~ ~823~ ~
.. ...
-15- ~ ~`
massive inoculum, were inoculated onto the agar plates, and, as the DIN demands, they were inoculated onto the agar plates of various nisin concentrations. The results were read after 4 days of incubation at 37 [presumably Centigrade].
~;.'`,.:,',~".
The following concentrations were used in the first trial batch~
260 micrograms/ml 1,000 micrograms/ml 10,000 micrograms/ml. ~ ; ;;
Since the first trial yielded no refsrence point for a varied effect in the case of plt 2.0 or pH 4.42, the repeat trial was conducted with the diluent, which had been adjusted to 2.0, and with the following concentrations:
500 micrograms/ml 1,000 micrograms/ml :
2,600 microgramslml 5,000 micrograms/ml ~ ~
10,000 micrograms/ml. ~ ;
' ~
5. Sensitivity testing according to DIN [German Industrial Norm] 58940, ~ ~ -Part 6, agar dilution method ......
The exception to the performance of this test: the test was not conducted on Mueller-Hinton nutritive medium (free of blood and s~rum), but rather on 10% horse's blood chocolate agar, because thus far, the germs could not be cultured on serum-free nutritive media.
In the agar dilution method, the concentraUons to be tested were ;
added to th~ as yet liquid nutritive media as 10-fold concentrated solution, and carefully mixed with the nutritive medium in a ratio of 1:10. Aftsr tho solidification of the agar, the test strains, as a ~ ~823~ ~
.. ...
-15- ~ ~`
massive inoculum, were inoculated onto the agar plates, and, as the DIN demands, they were inoculated onto the agar plates of various nisin concentrations. The results were read after 4 days of incubation at 37 [presumably Centigrade].
6. Test Results 6.1 Results of the first orienting t~st with the pure nisin substance ~ -, , ~., ~., Table 1 Gro~h after4 days, 37C ~-Helicobacter pylori I Helicobacter pylori ll Massive Dilution Massive `~
......... ................. ......................... .... ... ........ ..
Dilution sowing sowing ` ~.
... ... .. . '.. ' ':~ . , pH 4.42 Control +++ +++ +++ +++ .
250 ~lg/ml +++ +++
1,000,ug/ml +
10,000 ~Ig/ml DH 2.0 `: `
Control +++ +++ ++~ +++
250 ,ug/ml ++-+++ ++-+++
~,000 llg/ml +-++ +/-10,000 ~g/ml Control ~++ +++ +++ +++
pH neutral . ~
. ~.... ..
~ . - . ,. - ~ ,~
" :~ '` :", 2-14 8 ?. ~ 5 - 16~
In this case :; -+++ signifies confluence of growth, :~
+/-, +, ~+ si~nifies reduced growth - signifies no growth.
~'` '``
6.2 Repeat test ` ~:
Table 2 Growth after 4 days, 37C
Helicobacter pylori I Helicobacter pylori ll . : ` " `- ' Massive Dilution Massive Dilution sowing sowing pH 2.0 Control +++ +++ +++ ~++
500~Ig/ml ++++ ++~
1,000 ~g/ml + +/~
2,500 ~,Ig/ml - - - - :
5,000 llg/rnl - - - - . : .
10,000 ~lg/ml ~ n ~ ~.
Control +++ +++ +++ +++
pH neutral 7. Summary H.p. I: The substance's effect begins at 1,000 Ilg/ml, inhibition is complete at 2,500 llg/ml, :: .
H.p. Il: The sensitivity of this strain, or rather, its minimal inhibiting :: .
concentration, lies at ~ 250 ~,lg/ml. -""
',`,"' '~ '~'~.'`
- - 2 1 ~ ~ 2 ~
~ ` .. - .
- 17~
In a test of this substance that had taken place previously (SIGMA
preparation, not ~he Pure substance~, there were indications that the . . -, - ~
substance worked on all 5 strains that were tested at 250 llg/ml i (complete inhibition was not achieved).
~, ~
.
Overall, depending upon the species of bacteria that are extant in concrete terms, and, depending upon the concrete realization of the -, ~
lantibiotic, and especially of the nisinoid substance, an effect could `
be achi~ved in a pharmaceutical composition beginning at a concentration of active ingredient of 5 ~g/ml. -: ~: , ...:. . ~
~...... ... ... :
The permeabilizing agents for reducing the mucosal barrier and for enhancing the active ingredient that hava already been mentioned in ` `
examplary fashion, may be divided into the following groups in : ` "i `
principle~
~ . ~
1. Lysine polymers and protamines, `~
.~ , . . .i -. . - .
- .:
2. Polycationic peptides, such as, for example, lactoferrin, Iysozyme, cathepsin G, ,: : ~.:,~
3. Amimoglycosides, carboxylic ionophors, 4. cationic, anionic, and amphoteric detergents, such as, for example, benzalkonium chloride or SDS, 5. polymyxins, PMBM, and corresponding derivatives, ~ `
6. chelating agents, for example, various EDTA's, HMP, NTA, citrate -::. , -, ~.,~
.... ,. ~...
2 1 ~
-18 - 1 -~
7. surfactants, such as Tweens, Tritons, glycerides, for example, .
~. gen~ral permeabilizers, for example, Tris, Ca~2, Mg~2, Na+, `
9. Carbohydrate fatty acid esters, for example, saccharose mono ~ -fattyacid ester, :
10. bioadhesive substances, .. - . .~. ~,~
11. Iiposomes for the intracellular killing of internalized bacteria, ~ ~ -' 12. cyclo-oxygenase inhibitors, such as 5-ASA, for example, ; ~.
13. prot~ctive antioxidants, such as vitamin C, for example, ~ `
14. other substances that reduce the hydrophobicity of the stomach mucosa.
As a matter of principle, instead of an isolated permeabilizer, random combinations of two or more permeabilizers from among the groups Iisted above may be used, but the combination in question depends upon - -the underlying conditions surrounding their use. ~ . -. . .:. -:.: .
,..." :,.;,."......
'., ~ .~'.' ' ,"., - ... . - -. -,,. . ~,~
. :- -:~ .,..,. :,....
......... ................. ......................... .... ... ........ ..
Dilution sowing sowing ` ~.
... ... .. . '.. ' ':~ . , pH 4.42 Control +++ +++ +++ +++ .
250 ~lg/ml +++ +++
1,000,ug/ml +
10,000 ~Ig/ml DH 2.0 `: `
Control +++ +++ ++~ +++
250 ,ug/ml ++-+++ ++-+++
~,000 llg/ml +-++ +/-10,000 ~g/ml Control ~++ +++ +++ +++
pH neutral . ~
. ~.... ..
~ . - . ,. - ~ ,~
" :~ '` :", 2-14 8 ?. ~ 5 - 16~
In this case :; -+++ signifies confluence of growth, :~
+/-, +, ~+ si~nifies reduced growth - signifies no growth.
~'` '``
6.2 Repeat test ` ~:
Table 2 Growth after 4 days, 37C
Helicobacter pylori I Helicobacter pylori ll . : ` " `- ' Massive Dilution Massive Dilution sowing sowing pH 2.0 Control +++ +++ +++ ~++
500~Ig/ml ++++ ++~
1,000 ~g/ml + +/~
2,500 ~,Ig/ml - - - - :
5,000 llg/rnl - - - - . : .
10,000 ~lg/ml ~ n ~ ~.
Control +++ +++ +++ +++
pH neutral 7. Summary H.p. I: The substance's effect begins at 1,000 Ilg/ml, inhibition is complete at 2,500 llg/ml, :: .
H.p. Il: The sensitivity of this strain, or rather, its minimal inhibiting :: .
concentration, lies at ~ 250 ~,lg/ml. -""
',`,"' '~ '~'~.'`
- - 2 1 ~ ~ 2 ~
~ ` .. - .
- 17~
In a test of this substance that had taken place previously (SIGMA
preparation, not ~he Pure substance~, there were indications that the . . -, - ~
substance worked on all 5 strains that were tested at 250 llg/ml i (complete inhibition was not achieved).
~, ~
.
Overall, depending upon the species of bacteria that are extant in concrete terms, and, depending upon the concrete realization of the -, ~
lantibiotic, and especially of the nisinoid substance, an effect could `
be achi~ved in a pharmaceutical composition beginning at a concentration of active ingredient of 5 ~g/ml. -: ~: , ...:. . ~
~...... ... ... :
The permeabilizing agents for reducing the mucosal barrier and for enhancing the active ingredient that hava already been mentioned in ` `
examplary fashion, may be divided into the following groups in : ` "i `
principle~
~ . ~
1. Lysine polymers and protamines, `~
.~ , . . .i -. . - .
- .:
2. Polycationic peptides, such as, for example, lactoferrin, Iysozyme, cathepsin G, ,: : ~.:,~
3. Amimoglycosides, carboxylic ionophors, 4. cationic, anionic, and amphoteric detergents, such as, for example, benzalkonium chloride or SDS, 5. polymyxins, PMBM, and corresponding derivatives, ~ `
6. chelating agents, for example, various EDTA's, HMP, NTA, citrate -::. , -, ~.,~
.... ,. ~...
2 1 ~
-18 - 1 -~
7. surfactants, such as Tweens, Tritons, glycerides, for example, .
~. gen~ral permeabilizers, for example, Tris, Ca~2, Mg~2, Na+, `
9. Carbohydrate fatty acid esters, for example, saccharose mono ~ -fattyacid ester, :
10. bioadhesive substances, .. - . .~. ~,~
11. Iiposomes for the intracellular killing of internalized bacteria, ~ ~ -' 12. cyclo-oxygenase inhibitors, such as 5-ASA, for example, ; ~.
13. prot~ctive antioxidants, such as vitamin C, for example, ~ `
14. other substances that reduce the hydrophobicity of the stomach mucosa.
As a matter of principle, instead of an isolated permeabilizer, random combinations of two or more permeabilizers from among the groups Iisted above may be used, but the combination in question depends upon - -the underlying conditions surrounding their use. ~ . -. . .:. -:.: .
,..." :,.;,."......
'., ~ .~'.' ' ,"., - ... . - -. -,,. . ~,~
. :- -:~ .,..,. :,....
Claims (49)
1. Preparation for the therapy and especially the prophylaxis of diseases of the gullet or the stomach or the duodenum or for diseases, which are based on endocrinal or mental disorders, which occur in the presence of bacteria of the genus helicobacter or flexispira, characterized in that it contains as the active ingredient a defined dose of at least one lantibioticum, which contains the atypical amino acids lanthionine and/or methyl lanthionine and that the lantibioticum is combined with at least one permeabilizer for the reduction of the mucosa barrier.
This is to certify that the translation of this document from German into English is a true and accurate rendition of the original document to the best of our knowledge and ability.
This is to certify that the translation of this document from German into English is a true and accurate rendition of the original document to the best of our knowledge and ability.
2. Preparation for the therapy and especially the prophylaxis of diseases of the gullet or the stomach of the duodenum or diseases, which are based on endocrinal or mental disorders, and which occur in the presence of bacteria of the genus helicobacter or flexispira, characterized in that it contains as the active ingredient a defined dosage of a mixture of at least two lantibiotica, which contain the atypical amino acids lanthionine and/or methyl lanthionine.
3. Preparation according to claim 2, characterized in that the dose is combined with at least one permeabilizer.
4. Preparation according to one of the claims 1 to 3, characterized in that - in the case of applications in the intestinal area - a combination of active ingredients with a ph-reducing agent for providing an acidic medium at the location where it is active is provided.
5. Preparation according to one of the claims 1 to 4, characterized in that the ph-reducing agent consists of 5-amino salicylic acid.
6. Preparation according to one of the claims 1 to 5, characterized in that the permeabilizer consists of a carbohydrate fatty acid ester.
7. Preparation according to one of the claims 1 to 6, characterized in that the permeabilizer consists of cyclo-oxygenase inhibitor.
8. Preparation according to claim 7, characterized in that the cyclo-oxygenase inhibitor consists of acetylsalicyclic acid.
9. Preparation according to claim 7, characterized in that the cyclo-oxygenase inhibitor consists of 5-ASA.
10. Preparation according to one of the claims 1 to 9, characterized in that the permeabilizer consists of lysozyme.
11. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of a lysin polymer.
12. Preparation according to one of the claim 1 to 10, characterized in that the permeabilizer consists of Protamine.
13. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of a polycationis peptide.
14. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of an aminoglycoside.
15. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of a carboxylic ionophore.
16. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of a cationic detergent.
17. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of an anionic detergent.
18. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of an amphoteric detergent.
19. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of Polymyxin.
20. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of PMBM.
21. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of a derivative of a Polymyxin.
22. Preparation according to one of the claims 1 to 10, characterized in that the permeabilizer consists of a bioadhesive substance.
23. Preparation according to one of the claims 1 to 22, characterized in that the lantibioticum consists of a nisinoide substance.
24. Preparation according to claim 23, characterized in that the nisinoide substance consists of nisin.
25. Preparation according to one of the claims 1 to 24, characterized in that active multimeres are formed by the nisinoide substance with molecular weights of about 7,000 and 14,000.
26. Preparation according to one of the claims 1 to 25, characterized in that that dose consists of the content of a capsule.
27. Preparation according to claim 26, characterized in that the content consists of a powdery substance.
28. Preparation according to claim 26, characterized in that the filling consists of the dispersion of a substance.
29. Preparation according to one of the claims 1 to 25, characterized in that the dose is provided within the confines of a tablet.
30. Preparation according to one of the claims 1 to 25, characterized in that the dose is dissolved in a liquid, which can be administered in exact doses.
31. Preparation according to one of the claims 1 to 25, characterized in that the dose is dispersed in a liquid.
32. Preparation according to one of the claims 1 to 31, characterized in that the dose is provided in a special galenic formulation with a delayed release of the active ingredient and/or an extended period of retention in the stomach.
33. Preparation according to one of the claims 1 to 32, characterized in that by means of the applied dose a concentration of the active ingredient of at least 50 µg/ml is achieved at the point, where it is to act.
34. Preparation according to one of the claims 1 to 32, characterized in that by means of the applied dose a concentration of the active ingredient of at least 250 µg/ml is achieved at the point, where it is to act.
35. Preparation according to one of the claims 1 to 32, characterized in that by means of the applied dose a concentration of the active ingredient of at least 1000 µg/ml is achieved at the point, where it is to act.
36. Preparation according to one of the claims 1 to 35, characterized in that an indication in the veterinary field is contemplated.
37. Preparation according to one of the claims 1 to 36, characterized in that an indication for the treatment of certain mental disorders is present, which are caused endocrinologically or toxically by the helicobacter species.
38. Preparation according to one of the claims 1 to 37, characterized in that an indication for the treatment of certain types of hypergastrinemia is present, in which the helicobacter species is involved.
39. Preparation according to one of the claims 1 to 37, characterized in that as an indication during the treatment of endocrine disorders a hyperpepsinogenemia is present.
40. Preparation according to one of the claims 1 to 37, characterized in that as an indication during the treatment of mental disorders a depression is present.
41. Preparation according to one of the claims 1 to 40, characterized in that an indication for the prophylaxis and therapy of gastropathic and duodenopathic disorders, which are induced by corticosteroid and NSAID, is present.
42. Preparation according to one of the claims 1 to 41, characterized in that as an indication during the treatment of diseases of the gullet a Barrett's Gullet is present.
43. Preparation according to one of the claims 1 to 39, characterized in that an indication of a heterotopic stomach mucosa is present in the Meckel's Diverticle, which reacts positively to helicobacter bacteria.
44. Preparation according to one of the claims 1 to 39, characterized in that an indication for the prophylaxis and therapy of stomach cancer is present.
45. Preparation according to one of the claims 1 to 39, characterized in that as an indication during the treatment of the disease of the stomach a Menetrier's Disease is present.
46. Preparation according to one of the claims 1 to 39, characterized in that as an indication a disease of the duodenum is present, which is caused by the presence of helicobacter species in the Brunner's Glands.
47. Preparation according to one of the claims 1 to 46, characterised in that the effective ingredient is administered with the help of beverages and/or other food.
48. Preparation for the therapy and particularly for the prophylaxis of diseases of the gullet or the stomach or the duodenum or diseases, which are based on endocrine or mental disorders, and which occur in the presence of bacteria of the helicobacter or flexispira species, characterized in that live bacteria, which produce bacteriozine, are present as the effective ingredient, and which produce a lantibioticum as a product of their metabolism, which contains the atypical amino acids lanthionine and/or methyllanthionine.
49. Preparation for the therapy and particularly for the prophylaxis of diseases of the gullet or the stomach or the duodenum or diseases, which are based on endocrine or mental disorders, and which occur in the presence of bacteria of the helicobacter or flexispira species, characterized in that the effective ingredient is a lantibioticum, which is produced with a genetically modified or mutated species of lactococcus lactis, and which is combined with at least one permeabilizer for the reduction of the mucose barrier.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4236469 | 1992-10-29 | ||
| DEP4236469.8 | 1992-10-29 | ||
| DE4304640 | 1993-02-16 | ||
| DEP4304640.1 | 1993-02-16 | ||
| DE4307352A DE4307352A1 (en) | 1992-10-29 | 1993-03-09 | Preparation for therapy and especially prophylaxis of diseases of the digestive tract |
| DEP4307352.2 | 1993-03-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2148255A1 true CA2148255A1 (en) | 1994-05-11 |
Family
ID=27204393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002148255A Abandoned CA2148255A1 (en) | 1992-10-29 | 1993-10-22 | Preparation for therapeutic and especially prophylactic treatment of digestive tract disorders |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0666759A1 (en) |
| JP (1) | JPH08504401A (en) |
| AU (1) | AU5174593A (en) |
| CA (1) | CA2148255A1 (en) |
| WO (1) | WO1994009806A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4432262A1 (en) * | 1994-01-13 | 1995-07-20 | Denecke Rainer Dr Med Vet | Combination prepn. for treatment of digestive tract disorders |
| US5804549A (en) * | 1996-01-05 | 1998-09-08 | Ambi Inc. | Compositions with activity against helicobacter |
Family Cites Families (7)
| 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 (en) * | 1984-04-11 | 1985-10-29 | Terumo Corp | Intestinally absorbable urokinase liposome composition |
| EP0545911B1 (en) * | 1988-06-22 | 1996-09-11 | Applied Microbiology, Inc. | Lanthionine-containing bacteriocin compositions for use as bactericides |
| 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 |
| DK0589893T3 (en) * | 1991-04-15 | 1996-09-09 | Applied Microbiology Inc | Use of a bacteriocin as an antimicrobial agent for the manufacture of a medicament for the treatment of gastric disorders associated with helicobacter pylori |
| IL104364A (en) * | 1992-01-17 | 1997-09-30 | Applied Microbiology | Pharmaceutical compositions containing bacteriocins |
-
1993
- 1993-10-22 CA CA002148255A patent/CA2148255A1/en not_active Abandoned
- 1993-10-22 EP EP93922890A patent/EP0666759A1/en not_active Withdrawn
- 1993-10-22 JP JP6510549A patent/JPH08504401A/en active Pending
- 1993-10-22 AU AU51745/93A patent/AU5174593A/en not_active Abandoned
- 1993-10-22 WO PCT/DE1993/001006 patent/WO1994009806A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08504401A (en) | 1996-05-14 |
| EP0666759A1 (en) | 1995-08-16 |
| AU5174593A (en) | 1994-05-24 |
| WO1994009806A1 (en) | 1994-05-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |