WO2000007571A2 - Formulations having probiotically active microorganisms - Google Patents
Formulations having probiotically active microorganisms Download PDFInfo
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- WO2000007571A2 WO2000007571A2 PCT/AT1999/000192 AT9900192W WO0007571A2 WO 2000007571 A2 WO2000007571 A2 WO 2000007571A2 AT 9900192 W AT9900192 W AT 9900192W WO 0007571 A2 WO0007571 A2 WO 0007571A2
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- WO
- WIPO (PCT)
- Prior art keywords
- formulation according
- microorganisms
- lactobacillus
- formulation
- stabilized
- Prior art date
Links
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- 238000002360 preparation method Methods 0.000 claims description 12
- 244000199866 Lactobacillus casei Species 0.000 claims description 10
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- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 claims description 7
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
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- 240000001046 Lactobacillus acidophilus Species 0.000 claims description 2
- 235000013956 Lactobacillus acidophilus Nutrition 0.000 claims description 2
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- 238000001179 sorption measurement Methods 0.000 abstract 1
- 238000011534 incubation Methods 0.000 description 28
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 28
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
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- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 6
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- 229960001699 ofloxacin Drugs 0.000 description 6
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
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- 230000004888 barrier function Effects 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/04—Preserving or maintaining viable microorganisms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/065—Microorganisms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention relates to formulations with probiotic microorganisms.
- probiotics A General View in: “The Lactic Acid Bacteria, Volume 1", BJB Wood ed. (1992), the probiotic microorganisms (common synonym “probiotics”) are , Elsevier Applied Science, 155/156) describes individual or mixed cultures of living microorganisms which are applied to humans and animals and which have a beneficial effect on the host by supporting the properties of the naturally present intestinal microflora. This means that only products that contain living or viable microorganisms, e.g. as freeze-dried cells, improve the health status of humans and animals and which can develop their effects in the mouth or the gastrointestinal tract.
- MSB lactic acid bacteria
- lactic acid bacteria of the genera Lactobacillus, Streptococcus, Lactococcus, Leuconostoc, Enterococcus, Bifidobacterium, Carnobacterium and Sporolactobacillus are in pharmaceutical preparations and food supplements according to the current state of knowledge and current taxonomy. increasingly found.
- Many subspecies of the genera Lactobacillus, Bifidobacterium and Enterococcus are considered to be necessary natural intestinal inhabitants of humans and animals. They occur - depending on nutritional status, age, state of health and intestinal tract - in dynamically changing amounts.
- Lactic acid bacteria are assessed according to their abilities in a similar way to other microorganisms. These are: 1. biochemical (eg the utilization of carbohydrate utilization)
- physiological e.g. stimulation of intestinal peristalsis
- the microflora of the intestine can be specifically supported by the application of certain MSB via medical indications or the way of supplementing food.
- MSB medical indications or the way of supplementing food.
- microorganisms are difficult to stabilize. In preparations, they are usually used dried as viable, lyophilized microorganisms. The display is the responsibility of the culture producers. The continuous production of the microorganisms in the required qualities, as well as their further processing into physiologically effective forms. Definitions and the subsequent storage period determine the biological activity of the material (Brennan et al., J. Food Prot. 46 (1983), 887-892).
- the object of the present invention is to provide formulations containing probiotic microorganisms which, when properly administered in suspension form, guarantee that physiologically relevant germ contents enter the human or animal intestine and which can therefore be highly effective in the intestinal physiology. Linked to this is the task of maintaining the viability of the probiotics, especially the MSB, in the product itself.
- formulations themselves can be produced on a large scale and reproducibly as medical formulations for therapeutic indications or as an additional or preventive food supplement for humans and animals.
- a formulation comprising buffer substances and microorganisms stabilized by lyophilization and. optionally technologically necessary auxiliaries, wherein the microorganisms stabilized by lyophilization are dry incorporated into the matrix-forming buffer substances and these formulations can be dry, for example either in powder form or as tablets.
- the preparations according to the invention develop their effect, which are predominantly in powder form or as a tablet, after appropriate dissolution and ingestion by the patient or consumer.
- the phase of the disintegration of the formulation can be carried out, for example, in water without a substantial loss of the number of bacteria, even if acidic reactions occur when dissolved.
- the (spatial) close contact between microorganisms and buffer substances is sufficient to survive even the acidic processes during the dissolution process if the formulation according to the invention is formulated as effervescent powder and substances such as organic acids (e.g. tartaric acid, citric acid), acidifying agents, various (acidic) ) Flavors, etc.
- the buffer substances are also able to exert this protective effect when passing through the stomach.
- the formulation according to the invention guarantees protection of the microorganisms stabilized by lyophilization from the natural acid barrier of the stomach, the microorganisms being protected by the action of the buffer substances of the formulation after their reconstitution.
- the microorganisms therefore enter the intestine in a viable form, where they can develop their effectiveness.
- formulations according to the present invention are outstandingly suitable for the production of preparations for a wide variety of medical indications and as an additional or preventive food supplement for humans and animals.
- the microorganisms stabilized by lyophilization preferably contain auxiliaries for lyophilization, as well as residues from the nutrient medium. These lyophilisate compositions determine the hygroscopic properties of the lyophilisate.
- Preferred lyophilisates have a w values in the range from 0.2 or below, in particular from 0.1 to 0.2, after the freeze-drying process. As a result, they are long-lasting, but they are also able to absorb large quantities of water quickly from the ambient air, which of course must be avoided during storage got to.
- This problem can be technologically solved by further processing - tableting, filling, packaging - immediately after the introduction of lyophilized microorganisms into the effervescent matrix, so that contact with the ambient air is minimized.
- the packaging must have an a w value of 0.1 to 0.2 in the long term so that free water is not available for active life processes in cells.
- Packaging in composite films, sachets or for tablets in aluminum sleeves with desiccants are particularly suitable for this.
- the storage temperature should be chosen so that 20 ° C is not exceeded.
- the formulation according to the invention advantageously has an a w value of 0.1 to 0.2, in particular 0.1 to 0.15. Therefore, buffer matrices which are composed of completely anhydrous mineral constituents are preferably also used according to the invention. In principle, these are easy to prepare, but have so far not been used in the production of probiotic formulations.
- Preferred buffer systems in the context of the present invention are phosphate buffers, citrate buffers, carbonate buffers, malate buffers and tartrate buffers with alkalis and alkaline earths (pH 4-7.5).
- Strains from the families Lactobacillus, Enterococcus, Bifidobacterium and Enterobacteriaceae, preferably from the genera Enterobacter and Escherichia, are used in the formulations according to the invention as microorganisms stabilized or preserved by lyophilization, in particular strains from the genera Lactobacillus delbschreibii subs. bulgaricus, Lactobacillus acidophilus, Lactobacillus casei GG, Lactobacillus casei subsp. casei, Lactobacillus helveticus, Lactobacillus lactis, Lactobacillus salivarius, Lactobacillus plantarum, Streptococcus salivarius subsp.
- thermophilus Enterococcus faecium, Bifidobacterium bifidum, Bifidobacterium infantis, Bififobacterium longum (as well as other Bifidobacterium species) and physiologically important subspecies of Escherichia coli and mixtures of two or more species of these microorganisms are particularly preferred.
- yeast strains in particular Saccharomyces bulardii for the human field, or other probiotic yeasts, for example Kluyveromyces marxianus for animals, are suitable for the production of the formulations according to the invention.
- microorganisms are those whose effects can be used for oral active immunization.
- the formulations according to the invention advantageously comprise further formulation auxiliaries or technically necessary combinations of adjuvants.
- antioxidants and amino acids may be necessary.
- the substance classes mentioned are typically part of all natural systems of organic origin and are therefore also obtained on an industrial scale and used as additives. They are present in the concentrations used for the formulation according to the invention below the limit values permitted in medications and nutritional supplements and are completely harmless.
- Auxiliaries used with preference are L-ascorbic acid and L-cysteine.
- the decisive technological step for the formulations according to the invention lies in the use of buffer substances which, after being dissolved in a suitable solvent, such as water, fruit juices, mineral waters, etc., offer the microorganisms, which were also dry until then, optimal conditions for cell wall reconstitution and these then allow passage through the upper digestive tract, in particular the stomach, with the hydrochloric acid present in the stomach being buffered for a short time.
- a suitable solvent such as water, fruit juices, mineral waters, etc.
- composition When dispersing the pharmaceutical form, a composition should preferably be produced which corresponds to the currently valid WHO recipe for rehydration during or after diarrhea.
- the formulation according to the invention is made available as a shower, the buffer substances being part of the dry shower bases.
- the formulation according to the invention disintegrates, CO 2 is formed , which displaces the oxygen present in the solution, and thus leads to more favorable survival conditions for anaerobic and microaerophilic germs.
- the effervescent basics are preferably divided as effervescent granules (cf., for example, European Pharmacopoeia, 3rd edition (1997), 1847/1848 and Hagers Handbook of Pharmaceutical Practice, 5th edition, page 723).
- the buffer granules are manufactured using the technologically customary granulation methods, e.g. by thermal granulation in heatable mixers, by granulation with reactive or non-reactive liquids in suitable commercial devices, whereby granulation can also be carried out in a vacuum (e.g. evacuable mixer with chopper with subsequent drying and screening, the TOPO® process or fluidized bed granulation) . Spiked with the intended microorganisms, these granules can then be tableted or filled into sachets.
- a vacuum e.g. evacuable mixer with chopper with subsequent drying and screening, the TOPO® process or fluidized bed granulation
- the formulation according to the invention preferably contains one or more active pharmaceutical ingredients, in particular an antidarrheal active ingredient, as a result of which a superadditive, anti-diarrhetic effect results from the combination of these substances while at the same time restoring a healthy intestinal flora.
- active ingredients for the formulation according to the invention can be, for example, loperamide, domperidone and ofloxacin, which themselves have no germ-damaging effect on lactic acid bacteria.
- the active formulation according to the invention preferably preferably comprises
- 0.1 - 30% by weight of microorganisms stabilized by lyophilization in particular 0.1 to 5% by weight, and - 10 - 99.9% by weight, in particular 70 to 99% by weight of buffer substances (shower base) and, if necessary, 0 - 80% by weight, in particular 0 to 2% by weight, of auxiliaries.
- the buffer substances, but also auxiliary substances and lyophilisates, are preferably in granular form or in powder form.
- a particularly preferred formulation contains microorganisms of the genus Lactobacillus casei GG stabilized by lyophilization.
- the present invention relates to the use of the formulations of the intestinal physiologically active according to the invention for the preparation of preparations for medical indications, in particular for gastrointestinal disorders, or as a food supplement and animal food supplement.
- formulations according to the invention are particularly suitable in all cases in which the natural intestinal flora has been impaired or destroyed, for example in the effective accompanying and aftertreatment during or after administration of antibiotics.
- formulations according to the invention can also include glucose and / or oligosaccharides and / or other saccharides which are favorable for the growth of germs in the intestinal lumen, as well as polysaccharides and related substances (inulins, dietary fibers).
- Example 1 Stable formulations of effervescent granules (tablets) with lactic acid bacteria as an effective principle
- Lactobacillus casei GG (LGG, Valio, Finland) approx. 10 8 CfU (colony forming units) / dose
- Enterococcus faecium (Ef) (strain M74, Medipharm, Sweden) approx.
- Bifidobacterium lactis (strain Bb 12, Hansen 's Biosystems / Denmark) approx. 10 10 CfU / dose
- Example 2 Incubation of the Formulations According to the Invention in Artificial Gastric Juice (aMS)
- the buffer substances are mixed with bacterial lyophilisates in a weight ratio of 249: 1.
- One part of lyophilisate is sufficient to achieve a germ density of approximately 10 8 -10 9 CfU / g of formulation mass.
- germ densities in ranges above 10 12 CfU / g are achieved, which are of course preferred for commercial products according to the invention.
- the incubation is carried out at a body temperature of 37 ° C to simulate as physiological conditions as possible.
- SWB shaking water bath
- REF reference sample
- the course of the reduction in the number of bacteria is shown in Table 1.
- Column 2 of Table 1 shows the course of the bacterial count as it results from the use of the buffer substance and LGG according to the invention in the case of incubation in aMS.
- Column 3 contains the REF data.
- Column 4 shows how aMS affects unprotected lactic acid bacteria in the form of a lyophilisate (Lyo).
- composition of the effervescent mixture (according to Bauer et al. "Pharmaceutical Technology", 5th edition, page 316):
- Table 4 below lists the survival germ counts of LGG after incubation in artificial gastric juice and in parallel after incubation in water (REF).
- Example 4 Effect of domperidone on the survivability of lactic acid bacteria
- Table 6 shows that the active ingredient domperidone has very little influence on the survivability of the lactic acid bacteria during the incubation. -The combination of domperidone and artificial gastric juice causes a slightly greater decrease in the number of bacteria than water. E.g. Effect of ofloxacin on the survivability of lactic acid bacteria
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Abstract
Description
Formulierungen mit probiotisch wirksamen Mikroorganismen Formulations with probiotic microorganisms
Die Erfindung betrifft Formulierungen mit probiotisch wirksamen Mikroorganismen .The invention relates to formulations with probiotic microorganisms.
Als probiotisch wirksame Mikroorganismen (häufiges Synonym "Pro- biotika") werden nach einer modernen Definition (Havenaar et al . , "Probiotics: A General View" in: "The Lactic Acid Bacteria, Volume 1", B.J.B. Wood ed. (1992), Elsevier Applied Science, 155/156) Einzel- oder Mischkulturen lebender Mikroorganismen bezeichnet, die an Mensch und Tier angewendet werden und den Wirt durch die Unterstützung der Eigenschaften der natürlich vorhandenen intestinalen Mikroflora vorteilhaft beeinflussen. Das bedeutet, daß nur Produkte die Darmphysiologie positiv beeinflussen können, die lebende oder lebensfähige Mikroorganismen enthalten, z.B. als gefriergetrocknete Zellen, den Gesundheitsstatus von Mensch und Tier verbessern und die ihre Wirkung im Mund oder dem gastrointestinalen Trakt entfalten können.According to a modern definition (Havenaar et al., "Probiotics: A General View" in: "The Lactic Acid Bacteria, Volume 1", BJB Wood ed. (1992), the probiotic microorganisms (common synonym "probiotics") are , Elsevier Applied Science, 155/156) describes individual or mixed cultures of living microorganisms which are applied to humans and animals and which have a beneficial effect on the host by supporting the properties of the naturally present intestinal microflora. This means that only products that contain living or viable microorganisms, e.g. as freeze-dried cells, improve the health status of humans and animals and which can develop their effects in the mouth or the gastrointestinal tract.
Besonders aus der Gruppe der Milchsäurebakterien (MSB) sind nach intensiven Forschungen spezielle Keime, die humanspezifisch und lebensmitteltechnologisch wertvolle Eigenschaften aufweisen, in das wissenschaftliche Interesse gerückt.From the group of lactic acid bacteria (MSB), in particular, after intensive research, special germs that have valuable properties in terms of human and food technology have become of scientific interest.
In pharmazeutischen Präparationen und Nahrungs-Ergänzungen sind nach derzeitigem Wissensstand und geltender Taxonomie Milchsäurebakterien der Gattungen Lactobacillus, Streptococcus, Lacto- coccus, Leuconostoc, Enterococcus, Bifidobacterium, Carnobacte- rium und Sporolactobacillus (Bergey's Manual of Systematic Bac- teriology, IX; Aufl.) zunehmend zu finden. Von den Gattungen Lactobacillus, Bifidobacterium und Enterococcus gelten viele Subspecien als notwendige natürliche Darmbewohner von Mensch und Tier. Sie kommen - in Abhängigkeit vom Ernährungsstatus, Alter, Gesundheitszustand und Darmabschnitt - in sich dynamisch ändernden Mengen vor.According to the current state of knowledge and current taxonomy, lactic acid bacteria of the genera Lactobacillus, Streptococcus, Lactococcus, Leuconostoc, Enterococcus, Bifidobacterium, Carnobacterium and Sporolactobacillus (Bergey's Manual of Systematic Bacteri) are in pharmaceutical preparations and food supplements according to the current state of knowledge and current taxonomy. increasingly found. Many subspecies of the genera Lactobacillus, Bifidobacterium and Enterococcus are considered to be necessary natural intestinal inhabitants of humans and animals. They occur - depending on nutritional status, age, state of health and intestinal tract - in dynamically changing amounts.
Milchsäurebakterien werden analog zu anderen Mikroorganismen nach ihren Fähigkeiten beurteilt. Diese sind: 1. biochemische (z.B. die Verwertung von Kohlehydratverwertung)Lactic acid bacteria are assessed according to their abilities in a similar way to other microorganisms. These are: 1. biochemical (eg the utilization of carbohydrate utilization)
2. physiologische (z.B. die Stimulation der Darmperistaltik)2. physiological (e.g. stimulation of intestinal peristalsis)
3. antimikrobielle (z.B. die Hemmung anderer Mikroorganismen)3.antimicrobial (e.g. inhibition of other microorganisms)
4. kompetitive (z.B. die Hemmung bzw. den Abbau von Entero- toxinen) .4. competitive (e.g. inhibition or degradation of enterotoxins).
(Volker Rusch, "Mikrobiologische Therapie", Therapeutikum 6 (1992), Seiten 292-298; K. Zimmermann, "Magen-Darm-Passage Mikrobiologische Präparate und ihr Zugang zum Immunsystem bei oraler Verabreichung", top-medizin 8 (1994), Seiten 29-31; Petra Kolb-Jaeckel, "Die Mikrobiologische Therapie und ihre Möglichkeiten bei entzündlichen Darmerkrankungen", Erfahrungsheilkunde 43(9) (1994), Seiten 502-504.(Volker Rusch, "Microbiological Therapy", Therapeutikum 6 (1992), pages 292-298; K. Zimmermann, "Gastrointestinal Passage Microbiological Preparations and Their Access to the Immune System with Oral Administration", top-medicine 8 (1994), Pages 29-31; Petra Kolb-Jaeckel, "Microbiological Therapy and Its Possibilities for Inflammatory Bowel Diseases", empirical medicine 43 (9) (1994), pages 502-504.
Die Mikroflora des Darmes kann durch die Applikation bestimmter MSB über medizinale Indikationen oder den Weg der Nahrungs-Ergänzung zielgerichtet unterstützt werden. Im Vordergrund stehen heute sowohl diätetische als auch prophylaktische und therapeutische Indikationen, wie u.a. bei Reisediarrhoe, Behandlung von Ostipationen, Restitution einer gestörten Darmflora nach Antibiotikaeinnahme, regulierende Funktion bei Stress-Situationen, Erniedrigung des Cholesterinspiegels, Krebstherapie, Zahnfleischentzündungen, Ergänzung von Diätformen, etc..The microflora of the intestine can be specifically supported by the application of certain MSB via medical indications or the way of supplementing food. Today, the focus is on both dietary and prophylactic and therapeutic indications, such as for traveler's diarrhea, treatment of osteipation, restitution of a disturbed intestinal flora after taking antibiotics, regulating function in stressful situations, lowering the cholesterol level, cancer therapy, gingivitis, supplementing diet forms, etc.
Die Funktionalität lebensfähiger bzw. lebender MSB ist nur dann gesichert, wenn die bevorzugt verabreichten Keime in hoher Dichte in den Darm gelangen. Natürliche physiologische Barrieren können Mikroorganismen bei ungeschützten Aufnahmeformen abtöten. Insbesondere bei der direkten peroralen Verabreichungsform lebensfähiger Mikroorganismen ist zu beachten, daß je nach Gattung bzw. Stamm der größte Teil der Bakterien bereits im Magen, der mit seinem sauren Milieu eine natürliche Barriere für fast alle Gattungen von Bakterien darstellt, zerstört wird.The functionality of viable or living MSB is only ensured if the preferred germs get into the intestine in high density. Natural physiological barriers can kill microorganisms in unprotected forms of intake. Especially with the direct oral administration form of viable microorganisms, it should be noted that, depending on the genus or strain, the majority of the bacteria are already destroyed in the stomach, which with its acidic milieu is a natural barrier for almost all types of bacteria.
Hinzu kommt, daß lebende Mikroorganismen schwer zu stabilisieren sind. In Präparationen werden sie üblicherweise getrocknet als lebensfähige, lyophilisierte Mikroorganismen angewendet. Die Darstellung obliegt den Kulturenherstellern. Die kontinuierliche Produktion der Mikroorganismen in den geforderten Qualitäten, sowie deren Weiterverarbeitung zu physiologisch wirksamen Formu- lierungen und die anschließende Lagerperiode entscheiden über die biologische Aktivität des Materials (Brennan et al . , J.Food Prot. 46 (1983) , 887-892) .In addition, living microorganisms are difficult to stabilize. In preparations, they are usually used dried as viable, lyophilized microorganisms. The display is the responsibility of the culture producers. The continuous production of the microorganisms in the required qualities, as well as their further processing into physiologically effective forms. Definitions and the subsequent storage period determine the biological activity of the material (Brennan et al., J. Food Prot. 46 (1983), 887-892).
Eine Verabreichung solcher probiotisch wirksamer Präparationen in flüssiger Form, beispielsweise in Getränken, wurde bislang noch nicht in Erwägung gezogen, da solche Kulturen im Magenbereich derart inaktiviert werden, daß sie im Darm keine positiven Wirkungen mehr hervorrufen können. Weiters können gebrauchsfertige Probiotika nicht über ausreichend lange Zeiträume in flüssiger Form gelagert werden. Das Vorsehen von Mikroorganismen in Gemengen mit (trockenen) Brausepulvern (Weinsäure oder Zitronensäure; Entwicklung von C02 aus Natriumhydrogencarbonat ) wurde bis jetzt auch nicht in Betracht gezogen, da es beim Auflösungs- vorgang von Brausepulvern zu aziden Reaktionen kommen kann, bei welchen die Mikroorganismen - analog zur Magenpassage - irreversibel geschädigt werden.The administration of such probiotic preparations in liquid form, for example in beverages, has not previously been considered, since such cultures are inactivated in the stomach area in such a way that they can no longer produce positive effects in the intestine. Furthermore, ready-to-use probiotics cannot be stored in liquid form for sufficiently long periods. The provision of microorganisms in mixtures with (dry) effervescent powders (tartaric acid or citric acid; development of C0 2 from sodium hydrogen carbonate) has not been considered until now, since acidic reactions can occur during the dissolution process of effervescent powders, in which the microorganisms - analogous to the gastric passage - are irreversibly damaged.
Die Aufgabe der vorliegenden Erfindung besteht darin, Formulierungen, enthaltend probiotisch wirksame Mikroorganismen, zur Verfügung zu stellen, welche bei vorschriftsmäßiger Verabreichung in suspendierter Form garantieren, daß physiologisch relevante Keimgehalte in den menschlichen bzw. tierischen Darm gelangen und die daher darmphysiologisch hochwirksam sein können. Verbunden ist die Aufgabe des Erhalts der Lebensfähigkeit der Probiotika, insbesondere der MSB, im Produkt selbst.The object of the present invention is to provide formulations containing probiotic microorganisms which, when properly administered in suspension form, guarantee that physiologically relevant germ contents enter the human or animal intestine and which can therefore be highly effective in the intestinal physiology. Linked to this is the task of maintaining the viability of the probiotics, especially the MSB, in the product itself.
Die Formulierungen selbst sind als medizinische Formulierungen für therapeutische Indikationen oder aber als zusätzlich oder vorbeugend verabreichbare Nahrungs-Ergänzung für Mensch und Tier großtechnologisch und reproduzierbar herstellbar.The formulations themselves can be produced on a large scale and reproducibly as medical formulations for therapeutic indications or as an additional or preventive food supplement for humans and animals.
Diese Aufgabe wird erfindungsgemäß gelöst durch eine Formulierung umfassend Puffersubstanzen und durch Lyophilisation stabilisierte Mikroorganismen und. gegebenenfalls technologisch notwendige Hilfsstoffe, wobei die durch Lyophilisation stabilisierten Mikroorganismen trocken in die matrixbildenden Puffersubstanzen eingearbeitet sind und diese Formulierungen trocken, z.B. entweder in Pulverform oder als Tabletten, ausgeformt sein können. Ihre Wirkung entfalten die erfindungsgemäßen Präparate, welche vorwiegend in Pulverform oder als Tablette vorliegen, nach entsprechender Auflösung und Einnahme durch den Patienten bzw. Konsumenten. Überraschenderweise kann mit Hilfe der Puffersubstanzen die Phase des Zerfalls der Formulierung z.B. in Wasser durchgeführt werden, ohne daß es zu einem wesentlichen Verlust der Keimzahl kommt, selbst wenn beim Auflösen azide Reaktionen auftreten. Offenbar reicht der (räumlich) enge Kontakt zwischen Mikroorganismen und Puffersubstanzen aus, um selbst die aziden Prozesse beim Auflösungsvorgang zu überstehen, wenn die erfindungsgemäße Formulierung als Brausepulver formuliert ist und Substanzen, wie organische Säuren (z.B. Weinsäure, Zitronensäure) , Säuerungsmittel, verschiedene (säurehaltige) Aromen, etc., enthalten. Weiters sind die Puffersubstanzen auch in der Lage, bei der Magenpassage ebenfalls diese protektive Wirkung auszuüben.This object is achieved according to the invention by a formulation comprising buffer substances and microorganisms stabilized by lyophilization and. optionally technologically necessary auxiliaries, wherein the microorganisms stabilized by lyophilization are dry incorporated into the matrix-forming buffer substances and these formulations can be dry, for example either in powder form or as tablets. The preparations according to the invention develop their effect, which are predominantly in powder form or as a tablet, after appropriate dissolution and ingestion by the patient or consumer. Surprisingly, with the help of the buffer substances, the phase of the disintegration of the formulation can be carried out, for example, in water without a substantial loss of the number of bacteria, even if acidic reactions occur when dissolved. Apparently, the (spatial) close contact between microorganisms and buffer substances is sufficient to survive even the acidic processes during the dissolution process if the formulation according to the invention is formulated as effervescent powder and substances such as organic acids (e.g. tartaric acid, citric acid), acidifying agents, various (acidic) ) Flavors, etc. Furthermore, the buffer substances are also able to exert this protective effect when passing through the stomach.
Die erfindungsgemäße Formulierung garantiert nach der Dispergie- rung in Wasser oder anderen zweckmäßigen Flüssigkeiten den durch Lyophilisation stabilisierten Mikroorganismen einen Schutz vor der natürlichen Säure-Barriere des Magens, wobei die Mikroorganismen nach deren Rekonstitution durch die Wirkung der Puffersubstanzen der Formulierung geschützt werden. Mit den erfindungsgemäßen Formulierungen gelangen daher die Mikroorganismen nach Verabreichung und nachfolgender Magenpassage in lebensfähiger Form in den Darm, wo sie ihre Wirksamkeit entfalten können.After dispersion in water or other suitable liquids, the formulation according to the invention guarantees protection of the microorganisms stabilized by lyophilization from the natural acid barrier of the stomach, the microorganisms being protected by the action of the buffer substances of the formulation after their reconstitution. With the formulations according to the invention, after administration and subsequent gastric passage, the microorganisms therefore enter the intestine in a viable form, where they can develop their effectiveness.
Die Formulierungen gemäß der vorliegenden Erfindung eignen sich hervorragend zur Herstellung von Präparaten für verschiedenste medizinische Indikationen und als zusätzlich oder vorbeugend verabreichbare Nahrungs-Ergänzung für Mensch und Tier.The formulations according to the present invention are outstandingly suitable for the production of preparations for a wide variety of medical indications and as an additional or preventive food supplement for humans and animals.
Die durch Lyophilisierung stabilisierten Mikroorganismen enthalten vorzugsweise Hilfsstoffe zur Lyophilisation, sowie Nährbodenreste. Diese Lyophilisat-Kompositionen bedingen die hygroskopischen Eigenschaften des Lyophilisats . Bevorzugte Lyophilisate weisen nach dem Gefriertrocknungsprozeß aw-Werte im Bereich von 0,2 oder darunter, insbesondere von 0,1 bis 0,2, auf. Dadurch sind sie zwar lange haltbar, jedoch auch in der Lage, aus der Umgebungsluft Wasser rasch in großer Menge aufzunehmen, was selbstverständlich bei der Lagerung unbedingt vermieden werden muß. Diese Problematik kann insoferne technologisch gelöst werden, indem unmittelbar nach der Einbringung von lyophilisierten Mikroorganismen in die Brausematrix die Weiterverarbeitung - Tablettierung, Abfüllung, Abpackung - erfolgt, sodaß der Kontakt zur Umgebungsluft minimiert wird. Die Verpackung muß einen aw- Wert von 0,1 bis 0,2 langfristig erhalten, damit für aktive Lebensvorgänge in Zellen kein freies Wasser zur Verfügung steht. Geeignet sind hierfür besonders Verpackungen in Verbundfolien, Beuteln (Sachets) bzw. für Tabletten in Aluminium-Hülsen mit Trocknungsmittel. Die Lagertemperatur sollte so gewählt werden, daß 20 °C nicht überschritten werden.The microorganisms stabilized by lyophilization preferably contain auxiliaries for lyophilization, as well as residues from the nutrient medium. These lyophilisate compositions determine the hygroscopic properties of the lyophilisate. Preferred lyophilisates have a w values in the range from 0.2 or below, in particular from 0.1 to 0.2, after the freeze-drying process. As a result, they are long-lasting, but they are also able to absorb large quantities of water quickly from the ambient air, which of course must be avoided during storage got to. This problem can be technologically solved by further processing - tableting, filling, packaging - immediately after the introduction of lyophilized microorganisms into the effervescent matrix, so that contact with the ambient air is minimized. The packaging must have an a w value of 0.1 to 0.2 in the long term so that free water is not available for active life processes in cells. Packaging in composite films, sachets or for tablets in aluminum sleeves with desiccants are particularly suitable for this. The storage temperature should be chosen so that 20 ° C is not exceeded.
Demgemäß weist die erfindungsgemäße Formulierung vorteilhafterweise einen aw-Wert von 0,1 bis 0,2, insbesondere von 0,1 bis 0,15, auf. Daher werden erfindungsgemäß auch bevorzugterweise Puffermatrices verwendet, die aus vollständig wasserfreien mineralischen Bestandteilen zusammengesetzt sind. Diese sind prinzipiell zwar leicht herzustellen, wurden aber bislang bei der Herstellung von probiotisch wirksamen Formulierungen nicht verwendet.Accordingly, the formulation according to the invention advantageously has an a w value of 0.1 to 0.2, in particular 0.1 to 0.15. Therefore, buffer matrices which are composed of completely anhydrous mineral constituents are preferably also used according to the invention. In principle, these are easy to prepare, but have so far not been used in the production of probiotic formulations.
Bevorzugte Puffersysteme im Rahmen der vorliegenden Erfindung sind Phosphatpuffer, Citratpuffer, Carbonatpuffer, Malatpuffer sowie Tartratpuffer mit Alkalien und Erdalkalien (pH 4 - 7,5) .Preferred buffer systems in the context of the present invention are phosphate buffers, citrate buffers, carbonate buffers, malate buffers and tartrate buffers with alkalis and alkaline earths (pH 4-7.5).
Als durch Lyophilisation stabilisierte bzw. haltbar gemachte Mikroorganismen werden im besonderen Stämme aus den Familien Lactobacillus, Enterococcus, Bifidobacterium und Enterobacteria- ceae, vorzugsweise aus den Gattungen Enterobacter und Escheri- chia in den erfindungsgemäßen Formulierungen verwendet, wobei die Arten Lactobacillus delbrückii subs . bulgaricus, Lactobacillus acidophilus, Lactobacillus casei GG, Lactobacillus casei subsp. casei, Lactobacillus helveticus, Lactobacillus lactis, Lactobacillus salivarius, Lactobacillus plantarum, Streptococcus salivarius subsp. thermophilus, Enterococcus faecium, Bifidobacterium bifidum, Bifidobacterium infantis, Bififobacterium longum (sowie weitere Bifidobacterium-Arten) und physiologisch bedeut- ame Subspecies von Escherichia coli sowie Mischungen von zwei oder mehreren Arten dieser Mikroorganismen besonders bevorzugt sind. Weiters eignen sich Hefestämme, insbesondere Saccharomyces bou- lardii für den Human-Bereich, oder andere probiotisch wirksame Hefen, z.B. Kluyveromyces marxianus für Tiere, zur Herstellung der erfindungsgemäßen Formulierungen.Strains from the families Lactobacillus, Enterococcus, Bifidobacterium and Enterobacteriaceae, preferably from the genera Enterobacter and Escherichia, are used in the formulations according to the invention as microorganisms stabilized or preserved by lyophilization, in particular strains from the genera Lactobacillus delbrückii subs. bulgaricus, Lactobacillus acidophilus, Lactobacillus casei GG, Lactobacillus casei subsp. casei, Lactobacillus helveticus, Lactobacillus lactis, Lactobacillus salivarius, Lactobacillus plantarum, Streptococcus salivarius subsp. thermophilus, Enterococcus faecium, Bifidobacterium bifidum, Bifidobacterium infantis, Bififobacterium longum (as well as other Bifidobacterium species) and physiologically important subspecies of Escherichia coli and mixtures of two or more species of these microorganisms are particularly preferred. Furthermore, yeast strains, in particular Saccharomyces bulardii for the human field, or other probiotic yeasts, for example Kluyveromyces marxianus for animals, are suitable for the production of the formulations according to the invention.
Bei den erwähnten Arten ist ihre physiologisch bedeutsame Wirkung ( "probiotische" Eigenschaften) schon hinlänglich beschrieben worden. Ihre Bedeutung macht sie zu bevorzugten Mikroorganismen im Rahmen der vorliegenden Erfindung.The physiologically significant effects ("probiotic" properties) of the species mentioned have already been sufficiently described. Their importance makes them preferred microorganisms in the context of the present invention.
Als Mikroorganismen eignen sich auch solche, deren Wirkung zu einer oralen aktiven Immunisierung verwendet werden kann.Also suitable as microorganisms are those whose effects can be used for oral active immunization.
Die erfindungsgemäßen Formulierungen umfassen günstigerweise weitere Formulierungshilfsstoffe oder technisch notwendige Hilfsstoffkombinationen. Notwendig sein können je nach Mikroorganismenart Antioxidantien und Aminosäuren. Die genannten Stoff- klassen sind typischerweise Bestandteil in allen natürlichen Systemen organischen Ursprungs, und werden daher auch großtechnisch gewonnen und als Zusatzstoffe verwendet. Sie sind in den für die erfindungsgemäße Formulierung angewendeten Konzentrationen unter den in Medikationen und Nahrungs-Ergänzungen zugelassenen Grenzwerten vorhanden und vollkommen unbedenklich.The formulations according to the invention advantageously comprise further formulation auxiliaries or technically necessary combinations of adjuvants. Depending on the type of microorganism, antioxidants and amino acids may be necessary. The substance classes mentioned are typically part of all natural systems of organic origin and are therefore also obtained on an industrial scale and used as additives. They are present in the concentrations used for the formulation according to the invention below the limit values permitted in medications and nutritional supplements and are completely harmless.
Bevorzugt genutzte Hilfsstoffe sind L-Ascorbinsäure und L-Cy- stein.Auxiliaries used with preference are L-ascorbic acid and L-cysteine.
Der entscheidende technologische Schritt für die erfindungsgemäßen Formulierungen liegt in der Verwendung von Puffersubstanzen, die nach der Lösung in einem geeigneten Lösungsmittel, wie z.B. Wasser, Fruchtsäften, Mineralwässern, etc., den bis dahin ebenfalls trocken vorliegenden Mikroorganismen optimale Bedingungen zur Zellwandrekonstitution bieten und diesen in weiterer Folge eine Passage durch den oberen Verdauungskanal, insbesondere den Magen, ermöglichen, wobei insbesondere die im Magen vorhandene Salzsäure kurzfristig abgepuffert wird. Ein unbescha- deter und rascher Durchtritt der mit der Lösung aufgenommenen Mikroorganismen in den Dünndarm wird damit gewährleistet. Bevorzugterweise wird die erfindungsgemäße Formulierung zu einer etwa isotonen Lösung (zwischen 150 und 350 mosmol, insbesondere 300 mosmol) aufgelöst.The decisive technological step for the formulations according to the invention lies in the use of buffer substances which, after being dissolved in a suitable solvent, such as water, fruit juices, mineral waters, etc., offer the microorganisms, which were also dry until then, optimal conditions for cell wall reconstitution and these then allow passage through the upper digestive tract, in particular the stomach, with the hydrochloric acid present in the stomach being buffered for a short time. This ensures that the microorganisms absorbed with the solution pass through the small intestine quickly and without damage. The formulation according to the invention is preferably dissolved into an approximately isotonic solution (between 150 and 350 mosmol, in particular 300 mosmol).
Vorzugsweise sollte beim Dispergieren der Arzneiform eine Zusammensetzung entstehen, die der jeweils gültigen WHO-Rezeptur für die Rehydratation während oder nach Diarrhöe entspricht.When dispersing the pharmaceutical form, a composition should preferably be produced which corresponds to the currently valid WHO recipe for rehydration during or after diarrhea.
Nach einer bevorzugten Ausführungsform wird die erfindungsgemäße Formulierung als Brause zur Verfügung gestellt, wobei die Puffersubstanzen Teil der trockenen Brausegrundlagen sind. Beim Zerfall der erfindungsgemäßen Formulierung bildet sich C02, das den in der Lösung vorhandenen Sauerstoff verdrängt, und somit zu günstigeren Überlebensbedingungen für anaerobe und mikroaero- phile Keime führt. Bevorzugterweise werden die Brausegrundlagen als Brausegranulat zur Verfügung geteilt (vgl. z.B. Europäisches Arzneibuch, 3. Auflage (1997), 1847/1848 und Hagers Handbuch der pharmazeutischen Praxis, 5. Auflage, Seite 723).According to a preferred embodiment, the formulation according to the invention is made available as a shower, the buffer substances being part of the dry shower bases. When the formulation according to the invention disintegrates, CO 2 is formed , which displaces the oxygen present in the solution, and thus leads to more favorable survival conditions for anaerobic and microaerophilic germs. The effervescent basics are preferably divided as effervescent granules (cf., for example, European Pharmacopoeia, 3rd edition (1997), 1847/1848 and Hagers Handbook of Pharmaceutical Practice, 5th edition, page 723).
Die Puffergranulate werden nach den technologisch üblichen Gra- nulierungsmethoden hergestellt, so z.B. durch thermische Granulierung in heizbaren Mischern, durch Granulierung mit reaktiven oder nicht reaktiven Flüssigkeiten in geeigneten handelsüblichen Geräten, wobei auch im Vakuum granuliert werden kann (z.B. evakuierbare Mischer mit Zerhacker mit anschließender Trocknung und Siebung, dem TOPO®-Verfahren oder der Wirbelschicht-Granulierung) . Versetzt mit den vorgesehenen Mikroorganismen können diese Granulate anschließend tablettiert oder in Sachets abgefüllt werden.The buffer granules are manufactured using the technologically customary granulation methods, e.g. by thermal granulation in heatable mixers, by granulation with reactive or non-reactive liquids in suitable commercial devices, whereby granulation can also be carried out in a vacuum (e.g. evacuable mixer with chopper with subsequent drying and screening, the TOPO® process or fluidized bed granulation) . Spiked with the intended microorganisms, these granules can then be tableted or filled into sachets.
Vorzugsweise enthält die erfindungsgemäße Formulierung ein oder mehrere pharmazeutische Wirkstoffe, insbesondere einen antidiar- rhöetisch wirksamen Bestandteil, wodurch ein überadditiver, an- tidiarrhöetischer Effekt durch die Kombination dieser Substanzen bei gleichzeitiger Wiederherstellung einer gesunden Darmflora entsteht. Pharmazeutische Wirkstoffe für die erfindungsgemäße Formulierung können z.B. Loperamid, Domperidon und Ofloxacin sein, die selbst keine keimschädigende Wirkung auf Milchsäurebakterien ausüben. Die erfindungsgemäße wirksame Formulierung umfaßt vorzugsweise in der RegelThe formulation according to the invention preferably contains one or more active pharmaceutical ingredients, in particular an antidarrheal active ingredient, as a result of which a superadditive, anti-diarrhetic effect results from the combination of these substances while at the same time restoring a healthy intestinal flora. Pharmaceutical active ingredients for the formulation according to the invention can be, for example, loperamide, domperidone and ofloxacin, which themselves have no germ-damaging effect on lactic acid bacteria. The active formulation according to the invention preferably preferably comprises
0,1 - 30 Gew.% durch Lyophilisation stabilisierte Mikroorganismen, insbesondere 0,1 bis 5 Gew.%, und - 10 - 99,9 Gew.%, insbesondere 70 bis 99 Gew.% Puffersubstanzen (Brausegrundlagen) sowie bei Bedarf 0 - 80 Gew.%, insbesondere 0 bis 2 Gew.%, Hilfsstoffe. Die Puffersubstanzen, aber auch Hilfsstoffe und Lyophilisate, liegen vorzugsweise in granulierter Form oder in Pulverform vor.0.1 - 30% by weight of microorganisms stabilized by lyophilization, in particular 0.1 to 5% by weight, and - 10 - 99.9% by weight, in particular 70 to 99% by weight of buffer substances (shower base) and, if necessary, 0 - 80% by weight, in particular 0 to 2% by weight, of auxiliaries. The buffer substances, but also auxiliary substances and lyophilisates, are preferably in granular form or in powder form.
Eine besonders bevorzugte Formulierung beinhaltet durch Lyophilisation stabilisierte Mikroorganismen der Gattung Lactobacillus casei GG .A particularly preferred formulation contains microorganisms of the genus Lactobacillus casei GG stabilized by lyophilization.
Gemäß einem weiteren Aspekt betrifft die vorliegende Erfindung die Verwendung der erfindungsgemäßen darmphysiologisch wirksamen Formulierungen zur Herstellung von Präparationen für medizinische Indikationen, insbesondere für Magen-/Darm-Erkrankungen, bzw. als Nahrungs-Ergänzung und Tiernahrungs-Ergänzung.According to a further aspect, the present invention relates to the use of the formulations of the intestinal physiologically active according to the invention for the preparation of preparations for medical indications, in particular for gastrointestinal disorders, or as a food supplement and animal food supplement.
Besonders geeignet sind die erfindungsgemäßen Formulierungen bei allen Fällen, in denen die natürliche Darmflora beeinträchtigt bzw. zerstört worden ist, beispielsweise bei der effektiven Begleit- und Nachbehandlung während bzw. nach einer Antibiotikagabe .The formulations according to the invention are particularly suitable in all cases in which the natural intestinal flora has been impaired or destroyed, for example in the effective accompanying and aftertreatment during or after administration of antibiotics.
Weiters können erfindungsgemäße Formulierungen auch Glucose und/oder Oligosaccharide und/oder andere für das Keimwachstum im Darmlumen günstige Saccharide sowie Polysaccharide und artverwandte Stoffe (Inuline, Ballaststoffe) umfassen.Furthermore, formulations according to the invention can also include glucose and / or oligosaccharides and / or other saccharides which are favorable for the growth of germs in the intestinal lumen, as well as polysaccharides and related substances (inulins, dietary fibers).
Die Erfindung wird anhand der folgenden Beispiele, auf die sie selbstverständlich nicht beschränkt sein soll, näher erläutert.The invention is illustrated by the following examples, to which it is of course not intended to be limited.
B e i s p i e l 1: Stabile Formulierungen von Brausegranulaten (-tabletten) mit Milchsäurebakterien als wirksames PrinzipExample 1: Stable formulations of effervescent granules (tablets) with lactic acid bacteria as an effective principle
Mischung 1.1.: Lactobacillus casei GG (LGG, Valio, Finnland) ca. 108 CfU (Co- lony forming Units) /DosisMix 1.1 .: Lactobacillus casei GG (LGG, Valio, Finland) approx. 10 8 CfU (colony forming units) / dose
Natriumhydrogencarbonat 984 mgSodium bicarbonate 984 mg
Kaliumhydrogencarbonat 900 mgPotassium hydrogen carbonate 900 mg
Zitronensäure 1416 mgCitric acid 1416 mg
Dinatriumhydrogenphosphat 180 mgDisodium hydrogen phosphate 180 mg
Natriumcarbonat 600 mgSodium carbonate 600 mg
Aroma 120 mgAroma 120 mg
Mischung 1.2:Mix 1.2:
Enterococcus faecium (Ef) (Stamm M74, Medipharm, Schweden) ca.Enterococcus faecium (Ef) (strain M74, Medipharm, Sweden) approx.
108 CfU/Dosis10 8 CfU / dose
Natriumhydrogencarbonat 984 mgSodium bicarbonate 984 mg
Kaliumhydrogencarbonat 900 mgPotassium hydrogen carbonate 900 mg
Zitronensäure 1416 mgCitric acid 1416 mg
Dinatriumhydrogenphosphat 180 mgDisodium hydrogen phosphate 180 mg
Natriumcarbonat 600 mgSodium carbonate 600 mg
Aroma 120 mgAroma 120 mg
Mischung 1.3:Mix 1.3:
Bifidobacterium lactis (Stamm Bb 12, Hansen' s Biosystems/ Dänemark) ca. 1010 CfU/DosisBifidobacterium lactis (strain Bb 12, Hansen 's Biosystems / Denmark) approx. 10 10 CfU / dose
Glucose 2953 mgGlucose 2953 mg
Natriumcarbonat 1107 mgSodium carbonate 1107 mg
Zitronensäure 1036 mg Kaliumcarbonat 203 mgCitric acid 1036 mg potassium carbonate 203 mg
Dinatriumhydrogenphosphat 584 mg Aroma 94 mgDisodium hydrogen phosphate 584 mg aroma 94 mg
B e i s p i e l 2 : Inkubation der erfindungsgemäßen Formulierungen in artifiziellem Magensaft (aMS)Example 2: Incubation of the Formulations According to the Invention in Artificial Gastric Juice (aMS)
Im Rahmen der vorliegenden Beispiele werden jeweils die Puffersubstanzen mit Bakterienlyophilisaten im Gewichtsverhältnis 249 : 1 gemischt. Ein Teil Lyophilisat genügt, um eine Keimdichte von etwa 108-109 CfU/g Formulierungs-Masse zu erzielen. Mit modernen Lyophilisaten werden Keimdichten in Bereichen über 1012 CfU/g erzielt, die selbstverständlich bei erfindungsgemäßen Handelsprodukten bevorzugt sind. Die Inkubation wird bei Körpertemperatur von 37°C durchgeführt, um möglichst physiologische Bedingungen zu simulieren.In the context of the present examples, the buffer substances are mixed with bacterial lyophilisates in a weight ratio of 249: 1. One part of lyophilisate is sufficient to achieve a germ density of approximately 10 8 -10 9 CfU / g of formulation mass. With modern lyophilisates, germ densities in ranges above 10 12 CfU / g are achieved, which are of course preferred for commercial products according to the invention. The incubation is carried out at a body temperature of 37 ° C to simulate as physiological conditions as possible.
Die Inkubation in aMS wird durch Mischung der erfindungsgemäßen Präparate mit 150 ml Wasser und 100 ml aMS (= 100 ml 0,1 normale HC1) gestartet und unter Bewegung im Schüttelwasserbad (SWB) durchgeführt .The incubation in aMS is started by mixing the preparations according to the invention with 150 ml of water and 100 ml of aMS (= 100 ml of 0.1 normal HCl) and carried out with agitation in a shaking water bath (SWB).
Eine Probe, die nur in Wasser inkubiert wird, nicht jedoch in aMS, dient als Referenzprobe (REF) .A sample that is only incubated in water, but not in aMS, serves as a reference sample (REF).
Beispiel 2.1:Example 2.1:
Die Lactobacillus casei GG enthaltende Zubereitung (Formulierungsmasse = 4,20 g) gemäß Mischung 1.1, wird hinsichtlich ihrer stabilisierenden Wirkung gegenüber den Mikroorganismen während Inkubation in aMS untersucht. Der Verlauf der Keimzahlreduktion ist in Tabelle 1 dargestellt.The preparation containing Lactobacillus casei GG (formulation mass = 4.20 g) according to mixture 1.1 is examined for its stabilizing effect against the microorganisms during incubation in aMS. The course of the reduction in the number of bacteria is shown in Table 1.
Tabelle 1 Überlebensraten von Lactobacillus casei GG-Bakterien nach Inkubation in artifiziellen MagensaftTable 1 Survival rates of Lactobacillus casei GG bacteria after incubation in artificial gastric juice
In Spalte 2 der Tabelle 1 ist der Keimzahlverlauf dargestellt, wie er sich aus dem erfindungsgemäßen Einsatz der Puffersubstanz und LGG bei Inkubation in aMS ergibt. In Spalte 3 sind die Daten der REF enthalten. Spalte 4 -zeigt, wie sich aMS auf ungeschützte Milchsäurebakterien in Form eines Lyophilisates (Lyo) auswirkt.Column 2 of Table 1 shows the course of the bacterial count as it results from the use of the buffer substance and LGG according to the invention in the case of incubation in aMS. Column 3 contains the REF data. Column 4 shows how aMS affects unprotected lactic acid bacteria in the form of a lyophilisate (Lyo).
Beispiel 2.2:Example 2.2:
Die Enterococcus faecium enthaltende Zubereitung gemäß MischungMix containing Enterococcus faecium
1.2 (Formulierungsmasse 4,20 g) wird hinsichtlich ihrer stabili- sierenden Wirkung gegenüber den Mikroorganismen während Inkubation in aMS untersucht. Der Verlauf der Keimzahlreduktion ist in Tabelle 2 dargestellt.1.2 (formulation mass 4.20 g) is effect on the microorganisms during incubation in aMS was examined. The course of the bacterial count reduction is shown in Table 2.
Tabelle 2 Überlebensraten von Enterococcus faecium-Bakterien nach Inkubation in artifiziellem MagensaftTable 2 Survival rates of Enterococcus faecium bacteria after incubation in artificial gastric juice
Wie in Mischung 2.1 bei LGG verhält sich Ef in vergleichbarer Weise. In Spalte 1 wird anhand der Keimzahl deutlich, daß nach Inkubation in aMS über 2 Stunden praktisch kein Keimverlust eintrat. Ohne Puffersubstanzen (Spalte 4) können Ef-Keime in aMS nicht überleben.As in Mix 2.1 for LGG, Ef behaves in a comparable way. In column 1 it is clear from the bacterial count that practically no bacterial loss occurred after incubation in aMS for 2 hours. Without buffer substances (column 4), Ef germs cannot survive in aMS.
Beispiel 2.3:Example 2.3:
Die Bifidobacterium ssp. enthaltende Zubereitung (Formulierungs- masse 5,98 g) gemäß Mischung 1.3 wird hinsichtlich ihrer stabilisierenden Wirkung gegenüber den Mikroorganismen während Inkubation in aMS untersucht. Der Verlauf der Keimzahlreduktion ist in Tabelle 3 dargestellt.The Bifidobacterium ssp. Preparation containing (formulation mass 5.98 g) according to mixture 1.3 is examined for its stabilizing effect against the microorganisms during incubation in aMS. The course of the bacterial count reduction is shown in Table 3.
Tabelle 3 Überlebensraten von Bifidobacterium ssp. Nach Inkubation in ar- tifiziellem Magensaft
Auch für Bifidobacterium ssp. ist bei einer Inkubation in aMS kein wesentlicher Keimverlust über 2 Stunden festzustellen.Also for Bifidobacterium ssp. there is no significant loss of germs over 2 hours when incubated in aMS.
Beispiel 2.4: (Vergleich mit herkömmlichen Brauseformulierungen)Example 2.4: (Comparison with conventional shower formulations)
Zusammensetzung der Brausemischung (gemäß Bauer et al . „Pharmazeutische Technologie" , 5. Auflage, Seite 316):Composition of the effervescent mixture (according to Bauer et al. "Pharmaceutical Technology", 5th edition, page 316):
1560 mg Zitronensäure 940 mg NaHC03 10 mg LGG1560 mg citric acid 940 mg NaHC0 3 10 mg LGG
Anwendungsmenge: 2510 mgApplication amount: 2510 mg
Für die Untersuchung in aMS wurden 2,510 g bakterienhältige Brausemischung in 150 ml Wasser suspendiert und weitere 100 ml artifizieller Magensaft zugesetzt; danach erfolgte die Inkubation im SWB (37°C) .For the investigation in aMS, 2.510 g of bacteria-containing effervescent mixture were suspended in 150 ml of water and a further 100 ml of artificial gastric juice were added; the incubation then took place in the SWB (37 ° C.).
Für die Referenzuntersuchung wurden 2,510 g bakterienhältige Brausemischung in 250 ml Wasser suspendiert und anschließend bei 37°C im SWB inkubiert.For the reference investigation, 2.510 g of bacteria-containing effervescent mixture were suspended in 250 ml of water and then incubated at 37 ° C in the SWB.
In der nachfolgenden Tabelle 4 sind die Überlebenskeimzahlen von LGG nach Inkubation in artifiziellem Magensaft sowie parallel dazu nach Inkubation in Wasser (REF) aufgelistet.Table 4 below lists the survival germ counts of LGG after incubation in artificial gastric juice and in parallel after incubation in water (REF).
Tabelle 4 Überlebensraten von Lactobacillus casei GG nach Inkubation in artifiziellem Magensaft und reinem Wasser
Die Inkubation von Milchsäurebakterien in Lösungen, die nur Brausemischungen enthalten, zeigt, daß diese Hilfsstoffkomponen- ten alleine überhaupt keinen Schutz gegenüber artifiziellem Magensaft bieten. Darüberhinaus ist auch eine nicht ausreichende Stabilisierung der Keime nach Inkubation in reinem Wasser zu verzeichnen.The incubation of lactic acid bacteria in solutions that only contain effervescent mixtures shows that these auxiliary components alone do not offer any protection against artificial gastric juice at all. In addition, there is also insufficient stabilization of the germs after incubation in pure water.
B e i s p i e l Wirkung von Lopera id auf die Überlebens- fähigkeit von MilchsäurebakterienExample of the effect of Lopera id on the survivability of lactic acid bacteria
Für die Untersuchung in aMS wurden 6,0 g Brausemischung (Mischung 1.3; jedoch anstelle von Bifidobacterium lactis LGG) und 2 mg Loperamid in 150 ml Wasser dispergiert und 100 ml artifizi- eller Magensaft zugesetzt; danach erfolgte die Inkubation im SWB (37°C) .For the investigation in aMS, 6.0 g of effervescent mixture (mixture 1.3; however instead of Bifidobacterium lactis LGG) and 2 mg of loperamide were dispersed in 150 ml of water and 100 ml of artificial gastric juice were added; the incubation then took place in the SWB (37 ° C.).
Für die Referenzprobe wurden 6,0 g Brausemischung und 2 mg Loperamid in 250 ml Wasser dispergiert; anschließend erfolgte die Inkubation im SWB (37 °C) .6.0 g of effervescent mixture and 2 mg of loperamide were dispersed in 250 ml of water for the reference sample; the incubation then took place in the SWB (37 ° C.).
Tabelle 5 Überlebensrate von Bifidobacterium lactis nach Inkubation in artifiziellem Magensaft in Anwesenheit von LoperamidTable 5 Survival rate of Bifidobacterium lactis after incubation in artificial gastric juice in the presence of loperamide
B e i s p i e l 4 : Wirkung von Domperidon auf die Überlebensfähigkeit von MilchsäurebakterienExample 4: Effect of domperidone on the survivability of lactic acid bacteria
Für die Untersuchung in aMS wurden 6,0 g Brausemischung (Mischung 1.3; jedoch anstelle von Bifidobacterium lactis LGG) und 10 mg Domperidon in 150 ml Wasser dispergiert und 100 ml artifi- zieller Magensaft zugesetzt; danach erfolgte die Inkubation im SWB (37°C) .For the investigation in aMS, 6.0 g of effervescent mixture (mixture 1.3; however instead of Bifidobacterium lactis LGG) and 10 mg domperidone were dispersed in 150 ml water and 100 ml artificial gastric juice were added; the incubation then took place in the SWB (37 ° C.).
Für die Referenzprobe wurden 6,0 g Brausemischung und 10 mg Domperidon in 250 ml Wasser gelöst, anschließend erfolgte die Inkubation im SWB (37°C) .For the reference sample, 6.0 g of effervescent mixture and 10 mg of domperidone were dissolved in 250 ml of water, followed by incubation in the SWB (37 ° C).
Tabelle 6 Überlebensraten von LGG nach Inkubation in artifiziellem Magensaft in Anwesenheit von DomperidonTable 6 Survival rates of LGG after incubation in artificial gastric juice in the presence of domperidone
Tabelle 6 zeigt, daß der Wirkstoff Domperidon einen sehr geringen Einfluß auf die Überlebensfähigkeit der Milchsäurebakterien während der Inkubation hat. -Die Kombination von Domperidon und artifizellem Magensaft bedingt eine geringfügig stärkere Abnahme der Keimzahl als Wasser. B e i s p i e l Wirkung von Ofloxacin auf die Überlebensfähigkeit von MilchsäurebakterienTable 6 shows that the active ingredient domperidone has very little influence on the survivability of the lactic acid bacteria during the incubation. -The combination of domperidone and artificial gastric juice causes a slightly greater decrease in the number of bacteria than water. E.g. Effect of ofloxacin on the survivability of lactic acid bacteria
Für die Untersuchung in aMS wurden 6,0 g Brausemischung (Mischung 1.3; jedoch anstelle von Bifidobacterium lactis LGG) und 200 mg Ofloxacin in 150 ml Wasser dispergiert und 100 ml artifi- zieller Magensaft zugesetzt; danach erfolgte die Inkubation im SWB (37°C) .For the investigation in aMS, 6.0 g of effervescent mixture (mixture 1.3; however instead of Bifidobacterium lactis LGG) and 200 mg ofloxacin were dispersed in 150 ml of water and 100 ml of artificial gastric juice were added; the incubation then took place in the SWB (37 ° C.).
Für die Referenzprobe wurden 6,0 g Brausemischung und 200 mg Ofloxacin in 250 ml Wasser dispergiert und anschließend im SWB (37°C) inkubiert.For the reference sample, 6.0 g of effervescent mixture and 200 mg ofloxacin were dispersed in 250 ml of water and then incubated in the SWB (37 ° C).
Tabelle 7 Überlebensraten von LGG nach Inkubation in artifiziellem Magensaft in Anwesenheit von OfloxacinTable 7 Survival rates of LGG after incubation in artificial gastric juice in the presence of ofloxacin
Die Ergebnisse in Tabelle 7 zeigen, daß der Wirkstoff Ofloxacin die Milchsäurebakterien während der Inkubation in artifiziellem Magensaft nur geringfügig beeinflußt. The results in Table 7 show that the active ingredient ofloxacin only slightly influences the lactic acid bacteria during the incubation in artificial gastric juice.
Claims
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU52704/99A AU5270499A (en) | 1998-08-06 | 1999-07-29 | Formulations having probiotically active microorganisms |
| EP99938048A EP1102580A2 (en) | 1998-08-06 | 1999-07-29 | Formulations having probiotically active microorganisms |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0136098A AT407008B (en) | 1998-08-06 | 1998-08-06 | FORMULATIONS WITH PROBIOTALLY EFFECTIVE MICROORGANISMS |
| ATA1360/98 | 1998-08-06 |
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| WO2000007571A2 true WO2000007571A2 (en) | 2000-02-17 |
| WO2000007571A3 WO2000007571A3 (en) | 2000-05-11 |
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| PCT/AT1999/000192 WO2000007571A2 (en) | 1998-08-06 | 1999-07-29 | Formulations having probiotically active microorganisms |
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|---|---|
| EP (1) | EP1102580A2 (en) |
| AT (1) | AT407008B (en) |
| AU (1) | AU5270499A (en) |
| WO (1) | WO2000007571A2 (en) |
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| WO2002005829A2 (en) * | 2000-07-17 | 2002-01-24 | Chr. Hansen A/S | Methods and formultations with probiotic microorganisms and medicaments |
| WO2002007741A1 (en) * | 2000-07-25 | 2002-01-31 | Borody Thomas J | Probiotic recolonisation therapy |
| EP1287745A1 (en) | 2001-08-24 | 2003-03-05 | The Procter & Gamble Company | Chewable compositions with probiotic agents |
| WO2007098924A2 (en) * | 2006-02-28 | 2007-09-07 | Lohmann Animal Health Gmbh & Co. Kg | Composition comprising an agent for stabilizing active substances in drinking water, effervescent mixture, method for the production thereof, and use thereof |
| WO2010094727A1 (en) * | 2009-02-23 | 2010-08-26 | Chr. Hansen A/S | Method for making lactid acid bacteria composition |
| US20110223251A1 (en) * | 2008-08-28 | 2011-09-15 | Chr-Hansen A/S | Bacterial composition |
| FR2963239A1 (en) * | 2010-08-02 | 2012-02-03 | Vetalis | SOLAR EFFERVESCENT GALENIC FORMS FOR ANIMALS |
| WO2012035454A1 (en) * | 2010-09-16 | 2012-03-22 | Yeditepe Universitesi | Lyophilized biopesticide effervescent granule and production method thereof |
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| WO2015154140A1 (en) * | 2014-04-09 | 2015-10-15 | Kambouris Shares Pty Ltd | Methods and compositions for delivering a probiotic |
| US9649343B2 (en) | 2011-03-09 | 2017-05-16 | National Institutes of Health (NIH); U.S. Department of Health and Human Services (DHHS); The United States of America, NIH Division of Extramural Inventions and Tehnology Resources (DEITR) | Compositions and methods for transplantation of colon microbiota |
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Also Published As
| Publication number | Publication date |
|---|---|
| ATA136098A (en) | 2000-04-15 |
| WO2000007571A3 (en) | 2000-05-11 |
| EP1102580A2 (en) | 2001-05-30 |
| AU5270499A (en) | 2000-02-28 |
| AT407008B (en) | 2000-11-27 |
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