WO2005017095A2 - A stable liquid probiotic composition, preparation and applications thereof - Google Patents
A stable liquid probiotic composition, preparation and applications thereof Download PDFInfo
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- WO2005017095A2 WO2005017095A2 PCT/IL2004/000749 IL2004000749W WO2005017095A2 WO 2005017095 A2 WO2005017095 A2 WO 2005017095A2 IL 2004000749 W IL2004000749 W IL 2004000749W WO 2005017095 A2 WO2005017095 A2 WO 2005017095A2
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- 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
- C12N1/20—Bacteria; Culture media therefor
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- 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
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- 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
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Definitions
- the present invention relates to probiotic compositions, and more particularly to a method of preparing a liquid probiotic composition comprising a non-pathogenic bacterial strain which may be stored in biologically active form for long periods of time, as well as compositions and methods of treatment thereof.
- Probiotic bacteria are those which are beneficial to humans and/or animals.
- probiotic bacteria is known in the art for improving the microbial balance in the intestinal tract of mammals, in order to prevent or treat gastro-enteric infections and other diseases or disorders involving and/or causing changes in or to the intestinal microflora composition, and/or resulting in any change to the microflora composition, and/or maintaining such changes, as well as changes to the microflora composition which actively cause or potentiate such diseases or disorders.
- results of studies carried out to date have been inconsistent and/or ambiguous.
- the use of probiotic bacteria alone to treat "traveler's diarrhea" was not sufficient to provide a significant effect in patients as opposed to placebo, yet the combination of the probiotic treatment with antibiotics proved to be highly effective.
- Pathogenic bacteria which may cause various diseases or disorders, also occupy their own particular environmental niches or habitats.
- Competition between pathogenic and probiotic bacteria may occur under various conditions, but maximal competitive effect occurs when the conditions for optimal survival and multiplication rate of both pathogenic and probiotic bacteria are similar. Under such conditions, survival depends upon more stringent competition for nutrients or growth factors, a well as upon synergistic nutrient utilization and competition for receptor sites.
- Factors such as production of antimicrobial substances, intensity of multiplication, and creation of restrictive environment, including induction of immunological processes and stimulation of epithelial cell turnover also have great significance under such conditions.
- Probiotic compositions have been developed using cultures of non-pathogenic E. coli with other non-pathogenic bacteria (US Patent No. 5,340,577; US Patent No. 5,443,826; US Patent No. 5,478,557; US Patent No. 5,604,127).
- Lactose-positive non-pathogenic E. coli strain having high antagonistic activity have been produced as freeze-dried preparations in Germany and Russia (e.g. use of freeze-dried preparation Colibacterin siccum of E. coli Ml 7, described in Vidal Handbook: Pharmaceutical preparations in Russia, Astra Pharm Service, 1997, Moscow).
- probiotic preparations comprising a large number (up to 30) different kinds of bacteria and bacteroids (for example, US Patent No.
- 4,518,696 teaches a liquid suspension of Lactobacili using an oil-cell mixture with sunflower seed oil.
- the viable cells are dried prior to combining with the oil, and are further characterized by having low internal concentrations of water.
- None of the background art patents teaches or suggests a liquid probiotic medium in which the bacterial cells maintain a high level of biological activity. Such a medium is clearly needed, for example for such diseases as inflammatory bowel disease.
- IBD Inflammatory bowel disease
- IBS irritable bowel syndrome
- IBD affects an estimated two million people in the United States alone.
- the exact causes of IBD and IBS are not yet understood.
- Common hypotheses include, for example, disorders in the immune system and actions of pro- inflammatory cytolines and selective activation of lymphocyte subsets, which perpetuate unrestrained activation of an inflammatory response in the intestine.
- Metabolites generated by pathogenic and potentially pathogenic bacteria may cause disorders in the immune system.
- these bacteria may be implicated in disturbances of this nature, related to disturbances in the microbiological balance in the intestine.
- Such disturbances may themselves be a cause, or alternatively (or in combination), it is believed that this disturbance may in turn lead to auto-immune reactions and/or other reactions of the immune system.
- IBD and IBS have no cure.
- Patients afflicted with IBD or IBS are generally treated currently with therapies that are directed at reducing the inflammatory processes, and at reducing the effects of the inflammatory processes on the patients.
- the presently known medical treatment of IBD is intended to decrease the number, frequency and severity of acute exacerbations of inflammatory bowel disease and to preventing secondary complications, but at best, the results are disappointing.
- the presently known methods for treating IBD or IBS may fail to provide a solution for at least some IBD or IBS sufferers as these methods (i) fail to provide a substantial cure for IBD, but rather provide treatment of the symptoms; and (ii) include either drug therapy that is accompanied by severe adverse side effects or invasive surgical treatments, both affecting the sufferer's quality of life.
- the background art does not teach or suggest a stable, effective liquid probiotic composition.
- the background art also does not teach or suggest such a composition for treatment of various intestinal disorders, including but not limited to, microbial infection, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).
- IBS irritable bowel syndrome
- IBD inflammatory bowel disease
- the present invention overcomes this deficiency of the background art by providing a method for preparing a liquid probiotic composition, comprising bacteria having at least a basal biologic activity, wherein said bacteria have been selected according to at least one selection pressure, and wherein the composition is substantially free from substances suitable for bacterial growth but not similarly suitable for mammals, and particularly not suitable for human beings, hereinafter defined as "non-suitable substances”.
- the selection pressure may comprise at least one of temperature, time (stability when stored for a period of time), and osmotic pressure.
- the present invention also provides a method for preparing a liquid probiotic composition, comprising: selecting bacteria according to a selection pressure; and maintaining said bacteria having at least a basal biologic activity for a period of time in storage.
- the present invention also provides a method for treating a subject, comprising administering the liquid probiotic composition to the subject in need of treatment thereof.
- the liquid formulation is therapeutically active immediately following oral administration, as no biomass generation in the gut is required.
- the method is for treating a gastrointestinal disease or disorder for which treatment is desired or required, which may optionally and more preferably comprise a microbial infection, such as a bacterial infection, and/or IBD and or IBS.
- a microbial infection such as a bacterial infection, and/or IBD and or IBS.
- the present invention is also useful for treatment of AAD (antibiotic associated diarrhea), as well as any form of acute diarrhea, for example caused by microbes (including but not limited to, enterotoxigenic E.
- Bowel Syndrome whether mucous or inflammatory, and of diarrhea caused by radiation or chemotherapy.
- the present invention is also useful for treatment of the various disease states related to the presence of "abnormal” or an "abnormal” distribution of microflora in the gastrointestinal tract; IBD (inflammatory bowel disease) whether mucous or inflammatory, spastic colon, mucous colitis, antibiotic-associated colitis, idiopathic or simple constipation, and chronic gastrointestinal infections with specific microorganisms such as Clostridium difficile, Campylobacter jejuni/coli etc.
- IBD inflammatory bowel disease
- composition and method are optionally useful for treating food intoxication, dyspeptic symptoms or episodes of acute diarrhea, or diarrhea caused by undetected pathogens or unknown etiology.
- present invention is also optionally useful for treating diseases and disorders of the digestive tract caused or maintained by disturbance of the microbial balance of the intestinal microflora, and/or by a bacterial overgrowth in the small intestine.
- the present invention is also optionally useful for preventing or decreasing a level of disturbance microbial balance of the digestive tract microflora resulting from antibiotic therapy, radiotherapy or chemotherapy, diseases or disorders of the digestive tract, including digestive tract surgery.
- the composition and method are optionally useful for preventing or treating disturbances in microbial balance of the digestive tract microflora resulting from diseases outside of the digestive tract, certain dietary and environmental factors.
- the present invention is also useful for improving or normalizing the physiological activity of the gastrointestinal tract in elderly and in the compromised patients.
- a liquid probiotic composition comprising bacteria having at least a basal biologic activity, in which the bacteria have been selected according to at least one selection pressure, selected from temperature, time stability (stability in storage) and osmotic pressure, and wherein the composition is substantially free from substances suitable for bacterial growth, including bacterial peptones, salts, and also lacking inhibition factors produced by the cells themselves during growth phase.
- the composition comprises an autolysate prepared from the bacteria themselves during an earlier preparation stage, which provides the necessary nutrients for being suitable for maintaining the bacteria in a living state with minimal biological activity, but which are not harmful to lower mammals or humans.
- the pH of the composition is adjusted to be suitable for maintaining the viability of the bacteria, more preferably from about pH 6 to about pH 7.
- a method of treating an inflammatory bowel disease/irritable bowel syndrome IBD or IBS, and others
- the method comprising orally administering to the subject a therapeutically effective amount of a probiotic Escherichia coli strain in a liquid formulation.
- the therapeutically effective amount preferably ranges between about 10 6 and about 10 12 viable bacteria per administration, ranging from 1 to 10, preferably about 2-4 administrations per day.
- a probiotical pharmaceutical composition comprising, as an active ingredient, a probiotic Escherichia coli strain in a liquid formulation.
- method of treatment for microbial infection comprising orally administering to the subject a therapeutically effective amount of a probiotic strain in a liquid formulation, preferably an Escherichia coli strain.
- the table below shows suggested doses of the composition according to the present invention for treatment of various diseases and disorders, and is meant for illustrative purposes only, without wishing to be limiting in any way. Table of Exemplary Diseases/Disorders and Suggested Dosing Regimens
- the present invention is also useful for improvement or normalizing of the immune system in subjects suffering from an immune system disorder including disorders as side effect caused by therapy of other diseases, as well as being useful for treating domestic animals.
- the probiotic non-pathogenic lactose-positive strain such as the Escherichia coli strain M- 17, alone or optionally with one or more E. coli strains and/or other bacterial strains.
- the liquid formulation comprises between about 10 6 and about 10 12 CFU per ml of the probiotic Escherichia coli strain, more preferably from about 10 7 and about 10 10 CFU per ml of the probiotic Escherichia coli strain.
- the present invention successfully addresses the shortcomings of the presently known configurations by providing a method and a probiotic pharmaceutical composition for treating bacterial infections, inflammatory bowel disease/irritable bowel syndrome (IBD or IBS, or others) with a probiotic E. coli strain.
- Such probiotic treatment is highly advantageous as is compared with the present methods of treating such diseases or disorders as described above, or other diseases or disorders as it is efficacious, safe, non-invasive and side effect-free.
- a feature of the present invention is that the E. coli or other bacteria are preserved in biologically active form.
- An advantage of the present invention is that the probiotic action of the bacteria commences immediately upon reaching the gastrointestinal tract.
- a further advantage of the present invention is that the preparation may be stored for long periods of time without significant loss of bacterial viability.
- An additional advantage of the present invention is that the preparation composition of the present invention shows higher stability than dried preparations during passage through the stomach.
- An additional advantage of the present invention is that the preparation shows a much more increased effect with larger doses when compared with known probiotic preparations.
- Probiotic compositions which are known in the art are clearly inferior, because of the manner in which they have been prepared and stored; for example, as noted above, many such compositions rely upon freeze-drying, which results in a severely decreased level of biological activity.
- the present invention also has the advantage that the wide spectrum of efficacy of the liquid probiotic composition enables intestinal infections to allows to be treated effectively without first identifying the pathogen and defining its sensitiveness to antibacterial preparations.
- FIG. 1 shows a comparison of the rate of growth of bacteria taken from the liquid composition according to the present invention with the rate of growth of bacteria taken from a freeze-dried composition; the former clearly shows a superior rate of growth as compared to the latter.
- the present invention is of a method for preparing a composition that comprises a non-pathogenic probiotic microorganism, and the composition and the use thereof in the treatment of microbial infections of the gastrointestinal tract, as well as IBS, IBD, antibiotic associated diarrhea (AND) and any other type of diarrhea or syndrome.
- the present invention comprises use of a liquid composition containing probiotic bacteria.
- Bacterial cells are initially selected by application of selection pressure factors, in order to select those cells which remain viable upon being subjected to conditions unfavorable to metabolism. These selection pressure factors may optionally and preferably include at least one of time stability (stability in storage), temperature, and osmotic pressure conditions. Hence, bacteria having maximum survival ability are selected.
- Temperature selection conditions may optionally and preferably comprise subjecting the cells to temperatures which exceed the optimum range for active vital cell metabolism, preferably to temperatures of 40°C for a period of between 4 and 5 days.
- cells may be selected by subjecting to temperatures which are below the optimum temperature range for active vital cell metabolism, preferably temperatures of between 2 and 15°C for a period of between 1-12 months, and more preferably, for between 3 and 12 months.
- selected bacteria are preferably used to inoculate a growth medium, for production of a biomass in order to prepare a liquid probiotic formulation conta-ining selected, viable non-pathogenic bacteria, optionally and preferably comprising between about 10 7 and about 10 8 colony forming units of the selected probiotic Escherichia coli per ml.
- the suspension medium is essentially free from growth medium.
- the suspension medium may further comprise a complex of substances which can be used for bacterial cells for maintaining their basal biologic activity with minimum expenditure of energy and plastic metabolism, by being supplied with such substances from the cell suspension itself as a result of autolysis under conditions which prevent production of biodegrading components of bacterial cells.
- Autolysis may optionally be increased by application of mechanical actions and/or through the composition of the environment.
- autolysis may be induced by provision of an osmotic imbalance between the osmotic pressure inside the bacterial cell and that of the suspension medium.
- autolysis may be induced by use of a suitable suspension medium having low osmotic pressure, most preferably 0.3-0.4% sodium chloride solution.
- autolysis may be induced through changes to the density of the bacterial suspension, for example by causing the density to preferably be from about 10 11 to about 10 12 number of bacterial per ml (CFU; it should be noted that these two terms are used interchangeably in the application).
- CFU bacterial per ml
- another method may be used, to prevent the production of biodegradation components of the bacteria.
- the bacterial suspension is subjected to conditions favoring autolysis for between 3-7 days in order for accumulation of autolysate to occur, then subjected to conditions of osmotic balance between the interior of the cells and a suitable suspension medium, preferably in the range of from about 0.6 % to about 0.7 % , most preferably about 0.6 % sodium chloride solution.
- Cellular components such as nucleic acid components, accumulate under conditions favorable for autolysis, in quantities preferably of up to 90-110 ⁇ g/ml, with cell concentrations of 10 ⁇ -10 12 number of bacteria per ml.
- the suspension medium maintains the cells under conditions which are not only viable, but which also maintain the cells in a biologically active condition.
- the medium also preferably includes necessary ingredients for maintaining bacteria substantially without further growth or multiplication (as described above), and the medium is essentially free of inhibiting agent normally generated by microorganisms during growth.
- the formulation is stored under conditions which maintain the bacteria under viable, biologically active conditions at basal biological activity rate, for maximum time periods. These conditions include pH of between about 6.0 and about 7.0, preferably between about 6.5 and about 6.8, and temperatures of from about 2 to about
- the liquid formulation of the present invention may be used in treatment of humans and of animals. Preferably, doses of between 10 ml and 20 ml of the formulation are administered to a subject between 2 and 4 times a day.
- the term "substantially free” from a particular substance preferably refers to a condition in which the substance is present in a minor or trace amount, more preferably less than about 5% weight per weight.
- the term "method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
- the term “treating” includes abrogating, substantially i- ⁇ hibiting, slowing or reversing the progression of a disease, substantially ameliorating clinical symptoms of a disease or substantially preventing the appearance of clinical symptoms of a disease.
- the term “preventing” refers to barring a subject from acquiring a disorder or disease in the first place.
- the phrase “inflammatory bowel disease (IBD)” refers to a disorder or disease characterized by inflammatory activity in the GI tract, and may include mucosal forms of IBD.
- IBDs examples include, without limitation, Crohn's disease (both distal and proximal), ulcerative colitis, mdeterminate colitis, microscopic colitis, collagenous colitis, idiopathic inflammation of the small and/or proximal intestine and IBD-related diarrhea.
- administering refers to a method for bringing the probiotic E. coli strain(s) or other strain(s) into an area or a site in the GI tract that is affected by the disease or disorder.
- therapeutically effective amount refers to that amount of a probiotic E.
- compositions for oral administration include suspensions or solutions in water or non-aqueous media or Hquid-cont ⁇ ining capsules. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable. Dosing is dependent on the severity of the symptoms and on the responsiveness of the subject to the therapeutic agent. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies and repetition rates.
- a therapeutically effective amount preferably ranges between about 10 6 and about 10 12 viable bacteria per administration, more preferably between about 10 7 and about 10 10 viable bacteria per administration, more preferably between about 10 8 and about 10 10 viable bacteria per administration and most preferably it is between about 5 x 10 9 and about 2 x 10 viable bacteria per administration.
- the number of administrations according to the present invention preferably ranges between 1 and 10 administrations per day, more preferably between 1 and 5 administrations per day and most preferably between 2 and 4 administrations per day.
- the overall amount of viable bacteria that is administered daily preferably ranges between about 10 9 and about 10 11 viable bacteria per day, although it may optionally range between about 10 6 and about 10 12 viable bacteria per day.
- the probiotic strain of the present invention is preferably formulated and administered as a liquid formulation, as is described in detail hereinbelow and is further exemplified in the Examples section that follows.
- the formulation of the probiotic strains of the present invention in a liquid formulation is highly advantageous. Being under biologically active conditions, the formulation serves also as a supportive medium for living bacteria, as opposed to lyophilized formulations, such as the commercial Ml 7 preparation, where the bacteria are under anabiotic conditions.
- the liquid formulation of the invention for example, is therapeutically active immediately following oral administration, as no biomass generation in the gut is required.
- the liquid formulation of the probiotic E. coli strain typically comprises a suspension of the bacteria in an aqueous solution.
- the aqueous solution is typically mainly comprised of distilled water, preferably including autolysate from bacteria, salt in an isotonic amount and can further comprise other ingredients, as is further detailed hereinbelow.
- the solution is adjusted for pH which is favorable for maintaining viability.
- the solution also comprises a nitrogen source, but more preferably in a relatively small amount, most preferably less than about 0.3 %, and even more preferably less than about 0.03%. It should be noted that unless stated otherwise, all percents herein are given as weight per volume.
- the liquid formulation of the probiotic E is typically mainly comprised of distilled water, preferably including autolysate from bacteria, salt in an isotonic amount and can further comprise other ingredients, as is further detailed hereinbelow.
- the solution is adjusted for pH which is favorable for maintaining viability.
- the solution also comprises a nitrogen source, but more preferably in a relatively small amount, most preferably less than about 0.3 %, and even more preferably less than about 0.03%. It should be noted
- the coli strain typically comprises between about 10 5 and about 10 12 CFU (colony forming units) of the probiotic Escherichia coli strain, per ml.
- the liquid formulation comprises between about 10 ⁇ and about 10 10 CFU per ml, more preferably between about 10 7 and about 10 s CFU per ml.
- between 10 ml and 20 ml per day of the liquid formulation is administered to a subject, between 2 and 4 times a day.
- the liquid formulation used in context of the present invention is orally administered and as such, it preferably further comprises one or more flavoring agent(s), and/or one or more plant extracts.
- Non-pathogenic lactose-positive E is orally administered and as such, it preferably further comprises one or more flavoring agent(s), and/or one or more plant extracts.
- strain Nisle and other strains comprise the main group of healthy aerobic microflora in the intestine of humans and animals, providing microbiological balance and playing an important role in alimentation and immunity.
- This strain of bacteria belongs to the same phylogenetic group as the majority of intestinal pathogens responsible for causing diarrhea, therefore their survival conditions are largely similar, resulting in a high level of competitive exclusion between the strains.
- This competitive effect includes production of antimicrobial substances during growth of probiotic bacteria, competition for nutrients and growth factors, synergistic nutrient utilization, and competition for receptor sites.
- the speed of multiplication which is a major factor in competitive antagonism, is higher with the bacterial strain of the present invention, than with, for example, Lactobacillus or R.
- the bacterial strain of the present invention is much less selective than strains such as Lactobacillus or B. Bifidus with regard to nutritional requirements.
- probiotic preparations use dried bacteria, such that the bacteria remain alive, but in anabiotic condition. Upon administration of such a preparation, a lag period occurs before biological activity is recovered. Since the contents of the intestine are rapidly expelled in the event of diarrhea, only a small percentage of administered dried bacterial preparation is retained in the colon to multiply and acquire biological activity.
- the liquid probiotic composition of the present invention enables preservation of the bacteria in biologically active form, such that the probiotic action of the bacteria commences immediately upon reaching the gastrointestinal tract, with no adaptation time required.
- the time taken for bacterial growth to commence is therefore much faster with the liquid composition of the present invention than with preparations using freeze-dried bacteria.
- the antagonistic effect of the probiotic composition of the present invention on bacterial pathogens was found to be considerably higher than that of probiotic bacteria from freeze-dried preparations.
- antagonistic it is meant the ability of a particular bacterial strain to antagonize growth of other bacteria or other micro-organisms. It is known that the action of gastric juice, largely comprising hydrochloric acid, causes death of many bacteria. Bacteria in dried form are weaker than those contained in liquid medium, and are therefore more susceptible to the effects of gastric juice.
- the bacteria contained in the liquid composition of the present invention are therefore more stable upon passage through the stomach than those in freeze-dried preparations. Bacteria entering the colon begin to multiply and exert their antagonistic properties. However, the site of primary action for the majority of intestinal pathogens is not the colon but the upper part of the gastro-intestinal tract.
- Known probiotic preparations do not enable delivery of a competitive concentration of live bacteria to the upper portions of the intestine, and are therefore practically ineffective in eliminating acute bacterial diarrhea and conditions caused by disturbance of the micro-ecological balance in upper sections of the intestine.
- increasing the bacterial quantity of the preparation is problematic. In such methods, the bacteria are dried together with the culture medium and various stabilizing agents are added to increase bacterial stability.
- the composition of the present invention comprises liquid suspension of biologically pure bacteria, such that the number of bacteria administered per day may be varied, from several tens of millions, up to about 200 billion bacteria, in a volume preferably up to about 150 ml, and at a concentration as previously stated.
- This enables a working competitive concentration of bacteria to be provided which begin with the upper sections of digestive tract, i.e. the site at which the majority of intestinal pathogens act.
- the target site determines the concentration which is required to treat the disease or disorder.
- the effectiveness of the liquid probiotic composition of the present invention is also increased due to the fact that it may be administered in accordance with the dosing frequency determined as providing maximum dose dependant efficacy according to the disease or disorder to be treated.
- the liquid probiotic composition of the present invention can be administered in a quantity 10-100 times higher than the effective quantity used for treatment of constipation.
- E. coli bacterial cells having the highest antagonistic activity and the most persistent bacterial cells under storage for long periods of time, preferably up to about 12 months, are more preferably first selected from lactose- positive non-pathogenic E. coli species having beneficial probiotic properties.
- E. coli cells or other bacteria for use in the probiotic composition of the present invention are selected by exerting selection pressure on the cells such that only selected cells remain viable.
- Application of selection pressure may be achieved by use of time pressure (stability over time), such that cells having long-term survival ability are selected; application of osmotic pressure; decrease of basal metabolism; or increase in temperature.
- Temperature selection optionally and preferably comprises subjecting the cells to temperature of 40°C for at least 4 days, and/or to higher temperatures for a shorter period of time. By these means, only cells having high survival abilities are selected from the initial culture.
- the selected bacterial cells were used for inoculation of growth medium, as described in greater detail below, with reference to Examples 6 and 7.
- the nutrient composition of the present invention may comprise various factors such as described with reference to the examples, for example from yeast extract and or yeast autolysate.
- the nutrient composition of the growth medium of the present invention may optionally include growth factors and provides a considerable increase in the accumulated bacterial biomass relative to that obtained with conventional growth media because of the addition of such growth factors, for example from yeast extract, which results in an economic benefit.
- the yeast extract is preferably present in an amount from about 5 gram per liter to about 25 gram per liter, and more preferably from about 15 gram per liter to about 20 gram per liter.
- Other sources of the nutrient composition are possible, but preferably include all of the necessary nutrients, growth factors etc as are known in the background art, such as described for example in "Manual of Methods for General Bacteriology", P.
- the method of the present invention provides biologically pure bacteria, free from culture medium, with its associated side-effects upon administration of large quantities, and from the inhibiting agents normally produced by the microorganism during growth, which delay commencement of growth and activity of bacteria. It is known that osmotic pressure inside cells of Gram-negative bacteria, particularly E. coli, may reach up to 15 atmospheres in the log phase of growth, and 2- 3 atmospheres in the stationary phase of growth. In a preferred embodiment of the method of the present invention, a suspension medium having low osmotic pressure, preferably below 1 atmosphere, more preferably from about 0.3 to about 0.4 atmospheres, is used.
- Osmotic imbalance and high bacterial density during the first preparation stage of the liquid probiotic composition of the present invention creates conditions for autolysis of the weakest and smallest stable bacterial cells in the log phase. These lysed cells provide an accumulation of cellular components from bacteria in the suspension medium, which provide nutritional requirements of remaining cells. Using this procedure, cell concentrations of from 10 11 to about 10 12 bacteria per ml (CFU) were obtained, although again cell concentrations may optionally be present in a broader range.
- the pH of the suspension medium of the present invention for maximum cell stability is optionally and preferably in the range of from about 6.0 to about 7.0. More preferably, the pH of the suspension medium is about 6.5.
- the bacterial cells of the present invention are optionally and preferably stored at temperatures in the range of from about 2 to about 20°C. More preferably, the storage temperature is in the range of from about 20 to about 10°C. Most preferably, the storage temperature is in the range of from about 2 to about 4°C.
- the liquid probiotic composition of the present invention creates a combination of factors which preserve the bacteria not only in a viable condition, but also in an immediately active biological form, for at least 12 months.
- concentration of bacteria for this stage may optionally range from about 10 6 to about 10 12 bacteria per ml.
- This complex of substances preferably includes nucleic acids, nucleic acid components, bacterial lipopolysaccharides, peptidoglycans, phospholipids and many other desirable substances.
- the probiotic composition of the present invention may be used in treatment of humans and of animals.
- Example 1 Process for the preparation of the liquid probiotic composition
- the selected bacteria were first prepared for growth to form the biomass in the form of concentrates ranging from 10 ⁇ -10 12 CFU per ml in 0.3%-0.4% NaCl solution, to produce the autolysate.
- cell concentrates were diluted in 0.6%-0.8% NaCl solution at a cell concentration of 10 7 cells/ml (although again optionally the concentration of bacteria may range from about 10 ⁇ to about 10 12 bacteria per ml).
- the liquid probiotic composition was adjusted to a pH favorable to cell survival. The prefeired pH was from about 6.5 up to 6.8.
- one or more plant extracts, flavoring agents and or other additives may be added, which do not decrease viability of bacteria preserved for long periods of time.
- a description is provided below of an exemplary method for preparing the plant extracts in Example 15.
- the liquid probiotic composition may be preserved under refrigerated conditions for at least 12 months without significant loss of biological properties.
- Example 2 Viability of bacteria E. coli M-17* (CFU/ml) depending on pH of the suspension medium (0.7 % Sodium Chloride solution with the autolysate, which together provides an osmotically balanced solution) at temperature + 2 + 8° C.
- the number of viable cells greatly decreases within one month upon storage in suspension medium having pH of 8.5. A significant decrease is seen within 2 months of storage at pH of less than 5.5 or greater than 7.5. By the end of 12 months, significant numbers of viable cells remain only in those media having pH of between 6.0 and 7.0.
- the number of viable bacteria in suspension decreases very little over a 12 month period of storage at temperatures of between 2 and 10°C, while a significant decrease is seen in the same time period with storage at 18-20°C. At temperatures of 25-30°C, almost no viable cells remain after 12 months.
- Example 4 The same quantity of bacteria E. coli M-17 (1ml 10 8 CFU per each sample) from freeze-dried live bacteria (commercial preparation Colibacterin) and from liquid probiotic composition (bacteria are present in biologically active form) was introduced into nutrient broth samples (200 ml). The mixture was incubated at 37°C for 90 minutes. The rate at which bacterial metabolic activity was reduced, i.e. their adaptation to the conditions of the new environmental medium, was evaluated in relation to the rate of their initial growth. To obtain this value, the quantity of bacteria (C.F.U. per 1 ml) was determined immediately after introducing bacteria into the nutrient broth, and subsequently at intervals of 30 minutes during the incubation process.
- Example 5 10-20 hour cultures of S. flexneri and S. sonnei were diluted in saline to a concentration of 10 5 CFU/ml. These were then seeded (1 ml) either alone or in combination with cultures of E. coli Ml 7 (diluted in saline to a concentration of 10 CFU/ml) from freeze dried probiotic (Colibacterin) or from liquid probiotic (Bio-Co) in test tubes containing Nutrient Broth (5 ml). The tubes were incubated for 24 hours at 37°C. The number of colony-forming units (CFU) of the pathogens and of E. coli Ml 7 from both probiotic preparations was determined by plate counts on nutrient agar. These data are shown in the table below.
- Antagonistic activity of probiotic organism E. coli Ml 7 from freeze dried and from liquid probiotic composition in relation to various strains of Shigella.
- Example 6 Culture medium (solid and liquid), shown as tryptic soy agar (TSA) and tryptic soy broth (TSB) was seeded with the same quantity of bacterial culture E. coli Ml 7.
- TSA tryptic soy agar
- TB tryptic soy broth
- the microorganism was cultivated under aerobic conditions at the optimum temperature (36°C) for 24 hours (solid culture media) and for 18 hours (liquid culture media). The concentration of bacteria per 1 ml was then determined by plate counts on nutrient agar.
- a comparison of accumulation of biomass of non-pathogenic E. coli (E. coli Ml 7) on an optimum growth medium (T.S.A. and T.S.B.) and on a growth medium in accordance with the invention is illustrated in table below.
- Example 7 An analysis of nucleic acid components was carried out on samples of a 10 11 - 10 12 CFU suspension of the bacteria in 0.4% sodium chloride solution after preservation of samples for 3 and 30 days at temperature + 2 ⁇ 4 °C. Initially, the samples were filtered through a 0.45 ⁇ microbiological filter in order to obtain a cell-free filtrate. The filtrates were checked for presence of nucleic acid components (adenine and uracil). According to the sensitivity of the methods, the limit of detection is These data are shown in the table below.
- Example 8 Production of bacterial biomass using liquid culture media.
- a standard fermentation vessel with aeration can be used. Nutrients necessary for bacterial growth are added in two stages.
- a medium may consist of soy peptone at 10.0 g/1, yeast extract at 18.0 g/1, glucose at 2.5 g/1, sodium chloride at 3.0 g/1, and a combination of disodium phosphate and monopotassium phosphate sufficient to provide a neutral or slightly basic pH (7.2 ⁇ 0.2). Additional nutrients are automatically supplied into the nutrient medium during the process of bacterial growth. Additional glucose should be continuously added following the growth of the culture in such way that the glucose concentration in the fermentation broth is kept at the level of 2.5 g/1.
- the pH of the fermentation broth may be kept neutral by the continuous addition of 4N NH-jOH.
- the broth is incubated at temperatures of from about 32 to about 36° C until the stationary phase of the growth cycle is reached.
- the cells are harvested by centrifugation or ultrafiltration, up to a level at which residual quantities of total nitrogen are not more than 0.3%, and preferably not more than 0.03% for cell concentration of 10 7 -10 8 microbial cells per ml of suspension, resuspended in saline and re-precipitated.
- a 10 ⁇ -10 12 suspension of the bacteria is prepared in 0.4%-0.6% NaCl solution cooled to 4-8° C and, stored under refrigerated conditions. It should be noted that the concentration of bacteria for this stage (and/or for administration to the subject) may optionally range from about 10 6 to about 10 12 bacteria per ml.
- Example 9 Production of bacterial biomass using a solid culture media
- Non-pathogenic E. coli were grown on a solid culture medium, using a composition of nutrients providing maximum accumulation of bacterial biomass according to the present invention.
- the composition of the medium is as follows: Formula (in g/1) Soy peptone 10.0 Yeast extract 18.0 Dextrose 2.5 Sodium chloride 4.0 Agar 12.0 Final pH 7.0 ( 0.2 approx. )
- Prepared medium is poured into corresponding matrices with layer thickness of 5-7 millimeters. After cooling, the culture medium is seeded with bacterial culture E. coli M-17. Matrices are placed in an incubator and incubated under aerobic conditions at the optimum temperature (34-38° C) for about 24-28 hours.
- Example 10 Treatment of diarrhea
- a total of 64 patients were treated with different therapeutically effective amounts of the liquid probiotic composition of the present invention. These quantities were in the range of 10-200 billion live bacteria per day, divided into 4-6 doses.
- a first group of patients were prescribed the liquid probiotic composition of the invention containing a therapeutically effective amount of 10 million bacteria per day. In 85% of these patients, the symptoms of acute diarrhea were still present after 3 days. From the 4 th day, these patients were prescribed the therapeutically active amount of 200 billion bacteria per day.
- Example 11 Effect of liquid probiotic composition on the character of intestinal microflora changes in patients treated with anti-helicobacter therapy.
- a group of 104 patients treated with anti-helicobacter therapy was randomly divided into 2 sub-groups.
- the patients of the 2 nd group were administered the liquid probiotic composition of the present invention.
- the quantitative composition of bacteria considered to be the main representatives of healthy microflora was determined in all the patients. The results are shown in the Table below.
- Non-pathogenic E. coli of the type Ml 7 serves as the leading representative of aerobic microflora in the intestine.
- the total number of E. coli in the intestine is normalized, and their quality improved (i.e. the level of lactose-positive bacteria is increased, and the level of lactose-negative bacteria and E. coli with low fermentative activity is decreased).
- the number of bifidobacteria which are the most important representatives healthy anaerobic intestinal microflora, is increased.
- Example 12 Preparation of the probiotic composition - exemplary method
- the composition according to the present invention may optionally be prepared according to the following exemplary method.
- Probiotic E. coli (10 8 - 10 9 cells), optionally from a seed stock, are inoculated into liquid or solid culture medium components using standard microbial fermentation techniques. Growth conditions preferably include continuous aeration, maintenance of neutral pH and supplementation with glucose. This organism has preferably not been genetically engineered in any way, but rather has been isolated from microflora obtained from a normal human gastrointestinal tract.
- Manufacturing is optionally and preferably controlled with respect to the following critical control points: • Precautions to be taken receiving and handling cultures • Control procedures to assure appropriate culture conditions • Maintenance of sterility • Control procedures to assure correct levels of probiotic in finished product
- the seed stock itself may be prepared as follows.
- One frozen vial of E. coli M-17 strain is removed from storage at -80° C, thawed at room temperature, and then transferred aseptically into a sterile baffled shake flask containing sterilized Tryptic Soy broth (Difco). After 15-20 hour's growth, the culture is examined microscopically and streaked onto a Bacto m ⁇ ndo Agar L ⁇ S plates to check for purity.
- Reactor Preparation Each reactor is batched and sterilized with the medium in place. Dextrose is sterilized separately and added to a concentration of 2.5 g/L before culture inoculation.
- the seed culture is aseptically transferred to the bioreactor, and the culture grown under established conditions of temperature, pH, agitation and dissolved oxygen.
- a glucose feed of 3.5 to 3.9 g/L is started fours hours post inoculation. After 18-22 hour's growth, the culture is examined microscopically and streaked onto a Bacto m Endo Agar LES plates to check for purity. The reactor is then cooled to ⁇ 10° C for harvest.
- Microfiltration Bioreactor contents are harvested by concentration using a 0.2 ⁇ pore size tangential flow microfiltration unit. Concentrate is diafiltered with 5 volumes of sterile saline and then placed into sterile bottles for storage at 4-6° C. The sample is examined microscopically and streaked onto a Bacto m Endo Agar LES plate to check for purity and enumerated by plating onto Tryptic Soy agar plates.
- An upper GI endoscopy revealed a normal appearing small bowel.
- a random biopsy from the second part of the duodenum documented the presence of normal small bowel mucosa.
- a capsule endoscopy study was preformed and revealed inflammatory changes in the proximal small bowel including a few erosions, mucosal hemorrhages, edema and loss of villi.
- the patient was treated with a probiotic composition prepared as described in
- Example 12 at a regimen of one tablespoon twice daily, approximately half an hour before meals. After 2 weeks there was no improvement in the patient's condition.
- the probiotic treatment of the patient was continued while raising the daily dose to four tablespoons daily. Following this treatment, the patient reported substantial improvement, for the first time in two years.
- a second capsule endoscopy of the small bowel demonstrated improvement of the inflammatory process of the proximal small bowel.
- Example 14 Methods of treatment with the liquid probiotic composition
- the liquid probiotic composition of the present invention have been shown to be effective treatments for gastrointestinal diseases and conditions, including but not limited to, microbial infection, IBS and IBD.
- the following example is an illustration only of a method of treating such a gastrointestinal disease or disorder (or condition in need of treatment), and any other suitable condition with the liquid probiotic composition of the present invention, and is not intended to be limiting.
- the method includes admi-tnstering the liquid probiotic medium to a subject to be treated.
- the liquid probiotic composition is administered in a pharmaceutically effective amount according to an effective dosing methodology, preferably until a predefined endpoint is reached, such as the absence of a symptom of a gastrointestinal disease, disorder or condition and any other suitable condition in the subject, or the prevention of the appearance of such a disease, disorder, condition or symptom in the subject.
- the biologically active edible extract may be prepared from any suitable fruit, vegetable, leaf, stem, or root of a plant, or from herbs.
- the plant can be cabbage, garlic, parsley, dill, lemon and etc, or a herb such as mint and so forth.
- the plant extract may optionally be prepared by distillation under reduced pressure providing boiling temperature up to 40° C .
- equipment existing in the market can be used , for instance the "Rotovapor" device.
- a process for preparing a plant extract for being added to the composition of the present invention preferably includes:
- This fraction may be --urther diluted with water.
- the plant extract can optionally be stored for 12 months under refrigerated conditions without loosing its capacity.
- This fraction itself constitutes a food / feed additive and may also optionally be prepared by mixing more than one plant extract.
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Priority Applications (7)
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CA002535892A CA2535892A1 (en) | 2003-08-18 | 2004-08-16 | A stable liquid probiotic composition, preparation and applications thereof |
BRPI0412979-2A BRPI0412979A (en) | 2003-08-18 | 2004-08-16 | liquid probiotic composition, method for the preparation of liquid probiotic composition and method for treating a patient |
AU2004265511A AU2004265511A1 (en) | 2003-08-18 | 2004-08-16 | A stable liquid probiotic composition, preparation and applications thereof |
EP04745086A EP1656025A4 (en) | 2003-08-18 | 2004-08-16 | A stable liquid probiotic composition, preparation and applications thereof |
JP2006523747A JP2007518693A (en) | 2003-08-18 | 2004-08-16 | Stable liquid probiotic composition, its preparation and application |
MXPA06001821A MXPA06001821A (en) | 2003-08-18 | 2004-08-16 | A stable liquid probiotic composition, preparation and applications thereof. |
IL173691A IL173691A0 (en) | 2003-08-18 | 2006-02-13 | A stable liquid probiotic composition, preparation and applications thereof |
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BRPI0412979A (en) | 2006-10-03 |
AU2004265511A1 (en) | 2005-02-24 |
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EP1656025A4 (en) | 2007-12-05 |
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ZA200601391B (en) | 2007-04-25 |
EP1656025A2 (en) | 2006-05-17 |
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