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WO2010114864A1 - Formes posologiques orales probiotiques - Google Patents

Formes posologiques orales probiotiques Download PDF

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Publication number
WO2010114864A1
WO2010114864A1 PCT/US2010/029294 US2010029294W WO2010114864A1 WO 2010114864 A1 WO2010114864 A1 WO 2010114864A1 US 2010029294 W US2010029294 W US 2010029294W WO 2010114864 A1 WO2010114864 A1 WO 2010114864A1
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Prior art keywords
composition
vitamin
probiotic
group
tablets
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Inventor
Frank E. Hodal, Jr.
Karl P. Weinrich
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Little Calumet Holdings LLC
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Little Calumet Holdings LLC
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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
    • 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
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • 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
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • 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

  • This invention relates generally to probiotic formulations and more specifically to probiotic oral dosage forms that remain stable under storage conditions.
  • the gastrointestinal (“GI”) tract is a complex micro-ecosystem in which the mucosal lining of the host coexists with billions of microorganisms that live on or are attached to the lining.
  • microorganisms that inhabit the GI tract are "probiotic" bacteria, which help to maintain the health of the GI tract of the host organism.
  • probiotic bacteria are provided with shelter and support, and copious amounts of food substrates and in return, they offer the host a variety of potential therapeutic uses including replacing intestinal bacteria destroyed by antibiotics; aiding digestion and suppressing disease-causing bacteria; preventing and treating diarrhea, including infectious diarrhea, particularly from rotavirus (a virus that commonly causes diarrhea in children); treating overgrowth of "bad" organisms in the gastrointestinal tract (a condition that tends to cause diarrhea and may occur from use of antibiotics); alleviating symptoms of irritable bowel syndrome and, possibly, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); preventing and/or reducing the recurrence of vaginal yeast infections, urinary tract infections, and cystitis (bladder inflammation); improving lactose absorption digestion in people who are lactose intolerant; and enhancing the immune response.
  • rotavirus a virus that commonly causes diarrhea in children
  • overgrowth of "bad" organisms in the gastrointestinal tract a condition that tends to cause diarrhea and may occur from use of antibiotics
  • probiotics have many beneficial uses, there is a need in the art for probiotic supplements.
  • probiotics that may be included in a supplement, are Lactobacillus acidophilus, L. bulgaricus, L. casei, L.fermentum, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius, Bifidobacterium bifidum, B. infantis, B. animalis subsp. lactis, B.
  • Streptococcus thermophilis Enterococcus faecalis
  • E.faecium Bifidobacterium breve
  • Lactobacillus brevis Lactococcus lactis
  • Pediococcus acidilactici Lactobacillus helveticus
  • Bacillus coagulans and Streptococcus salivarius, all of which are found in the GI and vaginal tracts of humans.
  • Streptococcus salivarius is included in a supplement.
  • the lactobacillus species are gram-positive lactic acid bacteria that absorb lactose and other monosaccharides in the intestinal tract to produce lactic acid, which has the beneficial effect of lowering the pH of the organs making the environment of the organs hostile for the growth of harmful bacterial.
  • the bifidobacterium species are the first species of microorganisms to colonize the sterile colon of a newborn baby that is nursed by its mother. Bifidobacteria use the mechanism of crowding to digest the nutrients that otherwise harmful bacteria would use for reproduction.
  • Probiotic supplements may have up to approximately 10 billion colony forming units per supplement.
  • L. acidophilus in particular has the additional beneficial effect of producing the anti-microbial substances (i.e., natural antibiotics) acidolin, acidolphilin, lactocidin, and bacteriocin, which increase the immune system's resistance against fungus, such as Candida albican, and the harmful bacterial species Escherichia coli, Staphylococcus aureus, and salmonella.
  • anti-microbial substances i.e., natural antibiotics
  • acidolin i.e., natural antibiotics
  • acidolphilin i.e., lactocidin
  • bacteriocin bacteriocin
  • L. bulgaricus enhances the digestibility of proteins and milk products, aids in the production of natural antibiotics, and has been used to treat gastrointestinal disorders such as enterocolitis.
  • L. plantarum helps produce lactolin, a natural antibiotic, and synthesizes L-
  • L. salivarius is a facultative bacterium (i.e., a bacterial species that survives and grows in both anaerobic and aerobic environments) that is most abundant in the mouth and gums.
  • L. salivarius has several advantages as a probiotic: it has the ability to break down undigested protein and disengage the toxins produced by protein putrefactions; it is useful to prevent and fight Helicobacter pylori, which is known to be a cause of ulcers); and because its population doubles every 20 minutes, smaller amounts of the probiotic may be administered to a patient thus lending an economic advantage to the use of the probiotic.
  • L. rhamnosus has excellent stability over a wide range of temperatures and pH levels; it relieves hypersensitivity reactions and intestinal inflammation in individuals with eczema and food allergies.
  • B. animalis is a probiotic bacterium that plays a role in intestinal mucosal defense.
  • B. animalis has two subspecies: B. animalis subsp. animalis and B. animalis subsp. lactis, both of which prior to 2004 were referred to as B. animalis and B. animalis subsp. lactis. Masco et al, INT'L J SYST EVOL BIOL 54: 1137-1143 (2004). Because B. animalis subsp.
  • B. animalis subsp. lactis which is a lactic acid bacterium characterized by its high oxygen resistance and production of considerable amounts of formate, grows well in milk cultures and thus, is a useful probiotic.
  • B. animalis subsp. lactis is added to infant formulas to ensure that newborn babies not being nursed have sufficient colonization of bifidobacteria and is the only bifidobacterium species that is found in yogurt cultures.
  • B. bifidum inhibits the growth of the harmful bacterial species salmonella, listeria, shigella, E. coli, and Clostridium perfringens by consuming their nutrients, such as for example, ferrous ions, which many harmful bacterial species require for growth. B. bifidum also synthesizes some vitamins and aids in the absorption of minerals such as calcium, magnesium, and zinc.
  • infantis is the first probiotic to colonize the sterile digestive tract of an infant that is nursed by its mother.
  • this probiotic may be administered in supplemental form in order to ensure that the newborn has the proper intestinal flora.
  • B. longum biovar longum (referred to as B. longum) has been found to be able to eliminate nitrates from the intestinal tract.
  • thermophilis generates lactase activity, facilitating the digestion of lactose in milk.
  • E. faecalis and E. faecium are both lactic acid bacteria that have inhibitory effects against enteropathogens such as E. coli, salmonellae, shigellae and Clostridia.
  • U.S. Patent No. 4,518,696 to Gehrman et al. teaches the use of sunflower oil as a liquid suspending medium for preparing dry viable lactobacillus cells that are stable at room temperature.
  • U.S. Patent No. 5,466,463 to Ford teaches a vaginal suppository containing an antimicrobial agent and a viable colony of microencapsulated lactobacilli bacteria; the bacteria are microencapsulated to protect them from the action of the antimicrobial agent.
  • U.S. Patent Nos. 5,614,209; 5,633,012; 5,635,202; and 5,733,568 all to Ford teach microencapsulated lactobacilli bacteria for oral and topical administration to mammals that have 10 3 viable microencapsulated lactobacilli in each unit dose.
  • U.S. Patent No. 6,706,287 to Ranganathan et al. teaches microencapsulated and/or enteric-coated probiotics, such as lactobacillus and bif ⁇ dium bacteria species, that are capable of metabolizing urea and ammonia to amino acids.
  • a disadvantage of many of the probiotic formulations on the market is the poor shelf life of the formulations; accordingly, there is a need in the art for improved shelf life of probiotic formulations having live colonies of probiotic bacteria, such as for example, lactobacillus and bifidobacterium.
  • the present invention overcomes the need in the art by providing a probiotic composition that includes one or more agents and/or excipients that maximize the stability of the probiotics under storage conditions.
  • composition comprising at least one probiotic species in a carrier comprised of least two sugar alcohols selected from the group consisting of erythritol, lactitol, maltitol, mannitol, sorbitol, and xylitol.
  • a method of enhancing stability of a probiotic composition comprising combining at least one probiotic species with a carrier comprised of least two sugar alcohols selected from the group consisting of erythritol, lactitol, maltitol, mannitol, sorbitol, and xylitol.
  • the carrier may further comprise a disintegrant, a glidant, and/or a lubricant.
  • the disintegrant may be any suitable disintegrant such as for example, a disintegrant selected from the group consisting of sodium croscarmellose, crospovidone, gellan gum, hydroxypropyl cellulose, starch, and sodium starch glycolate.
  • the glidant may be any suitable glidant such as for example, a glidant selected from the group consisting of silicon dioxide, colloidal silicon dioxide, and talc.
  • the lubricant may be any suitable lubricant such as for example, a lubricant selected from the group consisting of calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumerate, and vegetable based fatty acids.
  • the carrier is present in the composition in a range of approximately 30% w/w to approximately 98% w/w; this weight percentage is a cumulative weight percentage taking into consideration all ingredients present in the carrier.
  • the probiotic may be any probiotic species such as for example, a probiotic selected from the group consisting of Lactobacillus acidophilus, L. bulgaricus, L. casei, L. paracasei, L. fermentum, L. plantarum, L. rhamnosus, L. salivarius, Bifidobacterium bifidum, B. infantis, B. animalis subsp. lactis, B.
  • a probiotic selected from the group consisting of Lactobacillus acidophilus, L. bulgaricus, L. casei, L. paracasei, L. fermentum, L. plantarum, L. rhamnosus, L. salivarius, Bifidobacterium bifidum, B. infantis, B. animalis subsp. lactis, B.
  • the probiotic is Streptococcus salivarius.
  • Combinations of probiotic species are also contemplated under the composition and method of the present invention such as for example, a combination of L. acidophilus and B. animalis subsp. lactis.
  • the concentration of probiotics contemplated under the composition and method of the present invention is in a range of approximately 10 6 to approximately 10 10 colonies per dosage form; this concentration is an individual concentration range for each probiotic present in the composition.
  • the composition may further include a phytonutrient, such as for example, a phytonutrient is selected from catechins, polyphenols, and oligomeric proanthocyanidins (OPCs). Where the phytonutrient is OPC, it may be obtained from grape seed or pine bark and incorporated into the composition in a range of approximately 0.5% w/w to approximately 10% w/w.
  • a phytonutrient such as for example, a phytonutrient is selected from catechins, polyphenols, and oligomeric proanthocyanidins (OPCs). Where the phytonutrient is OPC, it may be obtained from grape seed or pine bark and incorporated into the composition in a range of approximately 0.5% w/w to approximately 10% w/w.
  • OPCs oligomeric proanthocyanidins
  • the composition may further include a vitamin, a dietary mineral, and/or a trace mineral.
  • the vitamin may be selected from the group consisting of vitamin A (retinol), vitamin B 1 (thiamine), vitamin B 2 (riboflavin), vitamin B 3 (niacin), vitamin B 5 (pantothenic acid), vitamin B 6 (pyridoxine), vitamin B 7 (biotin), vitamin B 9 (folic acid), vitamin B 12 (cyanocobalamin), vitamin C (ascorbic acid), vitamin D 1 (lamisterol), vitamin D 2 (ergocalciferol), vitamin D 3 (dihyrotachysterol), vitamin D 4 (7-dehydrositosterol), vitamin E (tocopherol), and vitamin K (naphthoquinone).
  • the dietary mineral may be selected from the group consisting of calcium, chloride, magnesium, phosphorous, potassium, sodium, and sulfur.
  • the trace mineral may be selected from the group consisting of chromium, cobalt, copper, fluorine, iodine, iron, manganese, molybdenum, selenium, and zinc.
  • the composition of the present invention may be an oral dosage form, a powder that is mixed into a liquid, or a chewing gum.
  • the oral dosage form may be selected from the group consisting of tablets, caplets, and capsules, wherein the tablets and caplets may be solid or chewable.
  • the composition is a powder, it may be mixed into a liquid that is selected from the group consisting of water, milk, juice, and yogurt.
  • the gum may be solf gum or hard chewing gum tablets.
  • probiotic species such as mannitol, sorbitol, alone or together with the additional sugar alcohol lactitol and/or a phytonutrient, such as OPC
  • sugar alcohols such as mannitol, sorbitol
  • a phytonutrient such as OPC
  • Figure 1 is a bar graph showing the results of the L. acidophilus stability tests described in Examples 11 and 12 (Tables 32 and 34).
  • organ refers to both animal and human species. While the term “animal” as used herein will typically be used to refer mammals, the term is not exclusive to mammals and where appropriate may include both mammals and non-mammals.
  • excipient refers to an inert substance that is typically used as a diluent or vehicle for a drug or dietary supplement.
  • probiotic refers to bacterial genera that have a beneficial effect in animal organs, such as the human GI and vaginal tracts.
  • the bacterial genera used most often as probiotics are lactobacilli and bifidobacteria; however, other beneficial bacterial species, such as S. thermophilis are also probiotics.
  • S. thermophilis beneficial bacterial species
  • the probiotic species that may be used in the compositions of the present invention may be any known probiotic, such as, for example, L. acidophilus, L. bulgaricus, L. casei, L. paracasei, L. fermentum, L. plantarum, L. rhamnosus, L. salivarius, B. bifidum, B. infantis, B. animalis subsp. lactis, B. longum, S.
  • thermophilis E.faecalis, E.faecium, Bifidobacterium breve, Lactobacillus brevis, Lactococcus lactis, Pediococcus acidilactici, Lactobacillus helveticus, Bacillus coagulans and Streptococcus salivarius.
  • the probiotic species is Streptococcus salivarius. It is to be understood that the foregoing list is intended only to be illustrative and not a limiting representation of the probiotics that may be included in the probiotic compositions of the present invention. In this respect, any additional probiotic species may also be used in the compositions of the present invention, such as, for example, any additional known and/or available lactobacillus or bifidobacterium species.
  • prebiotic refers a nondigestible food ingredient that beneficially affects the host by selectively stimulating growth and/or activity of one or more probiotic species in the colon, such as for example, lactobacilli and/or bifidobacteria. Because prebiotics have a chemical structure that resists digestion through the alimentary tract, they reach the colon as intact molecules where they are able to elicit systemic physiological functions and act as fermentable substrates for colonic microflora.
  • prebiotics include fructooligosaccharides, such as inulin, which is extracted from chicory, artichokes, asparagus, dandelions, dahlias, endive, garlic, leeks, lettuce, and onions; trans- galactosyloligosaccharides; glactosyllactose; isomaltooligosaccharides; raffinose; lactulose; lactitol (a sugar alcohol); and partially hydrolyzed guar gum.
  • inulin is extracted from chicory, artichokes, asparagus, dandelions, dahlias, endive, garlic, leeks, lettuce, and onions
  • trans- galactosyloligosaccharides glactosyllactose
  • isomaltooligosaccharides raffinose
  • lactulose lactitol (a sugar alcohol); and partially hydrolyzed guar gum.
  • lactitol a sugar alcohol
  • An example of a prebiotic that may be used with the probiotic compositions of the present invention is the sugar alcohol lactitol, which is currently commercially used as a replacement sweetener for low calorie foods. Lactitol has two calories (9 kilojoules) per gram and approximately 40% of the sweetness of sugar.
  • the United States Food and Drug Administration (“FDA”) classifies lactitol, along with other sugar alcohols, which may or may not be prebiotics, i.e., erythritol, maltitol, mannitol, sorbitol, and xylitol, as "generally recognized as safe" (“GRAS").
  • the choice of the prebiotic to be combined with a particular probiotic will be determined according to which prebiotic provides the most suitable substrate for a particular probiotic.
  • synergy between one or more prebiotics and/or synergy between one or more prebiotics and other ingredients should always be considered. Synergy between the prebiotics lactitol and OPC with the sugar alcohols mannitol and sorbitol is illustrated in the experiment set forth in Example 10.
  • Example 10 the mannitol and sorbitol sugar alcohols described in the carbohydrate carrier system disclosed in U.S. Patent Publication No. 2003/0118642 Al to Norman et al., which is incorporated by reference herein, were combined with L. acidophilus to form two probiotic batches (Table 27), which were tested for stability (Table 28).
  • the PHARMABURST ® product SPI Polyols, New Castle, DE
  • PHARMABURST ® includes the sugar alcohols mannitol and sorbitol.
  • L. acidophilus probiotics that are formulated to include at least the sugar alcohols mannitol and sorbitol in combination with lactitol and/or OPC results in probiotic compositions that have a long shelf-live.
  • acidophilus probiotic tablets were prepared as set forth in Table 33 (Example 12), one batch with L. acidophilus and lactitol (Batch I), a second with L. acidophilus and PHARMABURST ® (Batch J), and a third with L. acidophilus, lactitol, and PHARMABURST ® (Batch K).
  • Table 34 (Example 12) show that under the harsh conditions of 40°C/75%RH, lactitol alone was not effective in maintaining the stability of L. acidophilus whereas PHARMABURST ® alone and the combination of a relatively low weight percent of PHARMABURST ® in combination with lactitol showed some viable colonies of L. acidophilus after two weeks.
  • a log graph comparing the stability test results of Batch E (Table 32) with Batches I, J, and K (Table 34) is shown in Figure 1.
  • 100% lactitol failed to stabilize L. acidophilus; 100% PHARMABURST ® showed limited viability of L. acidophilus; a combination of 10% PHARMABURST ® and 90% lactitol showed limited viability of L. acidophilus; and a combination of 87% PHARMABURST ® and 13% lactitol showed significant viability of L. acidophilus .
  • the results of the stability tests as shown in Figure 1 indicate that at an optimal ratio, a synergistic effect occurs between the PHARMABURST ® ingredients and lactitol.
  • phytonutrient refers to a nutrient derived from a plant source that has a beneficial effect on the health of the organism, i.e., the animal or human, taking the phytonutrient.
  • Phytonutrients differ from nutrients in that they are not required for normal metabolism of the organism.
  • Many phytonutrients are antioxidants that impart bright colors to fruits and vegetables. For example, lutein makes corn yellow, lycopene makes tomatoes red, carotene makes carrots orange, and anthocyanin makes blueberries blue. Both the bright colors and the antioxidant properties of phytonutrients are due to alternating single-bonded and double-bonded carbons.
  • Phytonutrients that may be included in the probiotic formulations of the present invention include without limitation catechins, which are found in tea; polyphenols, which are found in fruit skins such as grape skin, apple skin, and orange skin; and oligomeric proanthocyanidins ("OPCs") which are found in fruits, vegetables, nuts, seeds, flowers, and bark, but which are generally extracted from grape seeds and/or pine bark.
  • OPCs oligomeric proanthocyanidins
  • OPCs may be added to the probiotic compositions in a wide range, such as for example, from approximately 0.05% w/w to approximately 25% w/w; generally; however, a range of approximately 0.5% w/w to approximately 10% w/w should be sufficient for the OPC to show effect.
  • the present invention also includes the addition of at least one probiotic species in combination with at least one prebiotic and at least one OPC.
  • the addition of the prebiotic lactitol and the phytonutrient OPC to the L. acidophilus and B. animalis subsp. lactis probiotic composition described therein resulted in the highest stability count for the probiotic composition at 6 months under the storage conditions of 25°C/60%RH with a desiccant.
  • Batch I of Tables 31 and 32 of Example 11 demonstrate that the addition of the prebiotic lactitol and the phytonutrient OPC to the L. acidophilus probiotic composition described therein maintained the stability count of the L.
  • acidophilus probiotic composition at a very high level for two weeks under the harsh storage conditions of 40°C/75%RH without a desiccant.
  • Additional ingredients that may be included with the probiotic combinations described above include vitamins, dietary minerals, trace minerals, and other phytonutrients. See Example 8, Tables 20-22.
  • Vitamins that may be included in the probiotic composition of the present invention include without limitation, vitamins such as vitamin A (retinol), vitamin B 1 (thiamine), vitamin B 2 (riboflavin), vitamin B 3 (niacin), vitamin B 5 (pantothenic acid), vitamin B 6 (pyridoxine), vitamin B 7 (biotin), vitamin Bp (folic acid), vitamin B 12 (cyanocobalamin), vitamin C (ascorbic acid), vitamin D 1 (lamisterol), vitamin D 2 (ergocalciferol), vitamin D 3 (dihyrotachysterol), vitamin D 4 (7-dehydrositosterol), vitamin E (tocopherol), and vitamin K (naphthoquinone).
  • vitamins such as vitamin A (retinol), vitamin B 1 (thiamine), vitamin B 2 (riboflavin), vitamin B 3 (niacin), vitamin B 5 (pantothenic acid), vitamin B 6 (pyridoxine), vitamin B 7 (biotin), vitamin Bp (folic acid), vitamin B
  • vitamin salts such as for example, retinol acetate, retinol palmitate, and thiamine mononitrate.
  • Dietary minerals that may be included in the probiotic compositions of the present invention include without limitation, calcium, chloride, magnesium, phosphorous, potassium, sodium, and sulfur.
  • Trace minerals that may be included in the probiotic compositions of the present invention include without limitation, chromium, cobalt, copper, fluorine, iodine, iron, manganese, molybdenum, selenium, and zinc.
  • compositions of the present invention may be manufactured into various formulations, such as for example, oral dosage forms, such as tablets, caplets, or capsules; chewing gum; or powders to be dissolved in a liquid.
  • the probiotic compositions of the present invention may be formulated into oral dosage forms, such as tablets, caplets, or capsules.
  • the probiotic tablets and caplets of the present invention may be formulated for swallowing or for chewing. In the latter case, the tablets and caplets should be prepared with flavoring.
  • the flavored chewable tablets and caplets may include a sweetener, which may be an artificial or natural sweetener or both.
  • the probiotic capsules of the present invention will be manufactured primarily for swallowing.
  • Procedures for preparing tablets, caplets, and capsules are known to those of ordinary skill in the art and include without limitation wet granulation, dry granulation, and direct compression (for tablets and caplets).
  • a chilsonation is used to manufacture the powder for the dosage forms.
  • a chilsonator houses grooved, rotating rollers that are pressed tightly against one another by hydraulic pressure.
  • Raw materials are placed into the hopper of the chilsonator and are fed by a system of horizontal and vertical screws into the rollers.
  • the sheets are milled into a fine granular powder using a Fitz mill and then passed through a screen to produce a uniform free flowing granule.
  • the chilsonation process results in a finished powder that is two to four times denser than the starting material, a feature that permits the ingredients to be fashioned into the desired dosage form.
  • the powder With dry granulation, the powder may be incorporated into a gelatin capsule or it may be mixed with gelatin to form a tablet or caplet. With wet granulation, the powder is moistened thus creating large "chunks" of material that are subsequently dried and milled to convert the chunks to particles of a desired size for the manufacturing process. Once the particles of a desired size are obtained, the particles are incorporated into a gelatin capsule or mixed with gelatin to form a tablet or caplet.
  • Most direct compression formulations consist of three types of ingredients: an inert carrier that provides volume to the final dosage form; a lubricant that aids in the compression process; and the active ingredients.
  • Carriers may be present in dosage forms in many ranges, from 0.5% w/w to 95% w/w. Within the context of the present invention, carriers used to formulate the probiotic compositions of the present invention will generally be in the range of approximately 30% w/w to approximately 98% w/w.
  • the carrier used in the Examples is a PHARMABURST ® carrier (SPI Polyols, New Castle, DE).
  • the ingredients are mixed in a batch blender, such as a twin-shell or V-blender, and discharged into a bin (usually portable), which then feeds a chute to the tableting process.
  • a batch blender such as a twin-shell or V-blender
  • in-bin blending is also used.
  • in-bin blending the unmixed material is placed in a portable bin, which may contain internal baffles, and is tumbled; in-bin blending avoids the need to transfer the material from the blender to the portable container.
  • direct compression formulations there is a wide particle-size distribution with the active agent usually being at the fine end of the range. To avoid segregation of the particles, reliable flow must be maintained in the bins at all time. To ensure that all tablets are of the highest quality, tablets must be sampled at regular intervals during production for active ingredient concentration, tablet hardness, and dissolution rates.
  • Direct compression may be used to make tablets and caplets for swallowing and also chewable tablets and caplets.
  • the hardness of the tablets and caplets will need to be reduced and the ingredients of the tablets and caplets will need to be adjusted to ensure that the tablets and caplets have a pleasant taste and pleasant mouth-feel.
  • the taste of the chewable tablets and caplets may be adjusted through the use of various flavorings and sweeteners and the mouth- feel of the chewable tablets and caplets may be adjusted though the use of varying prebiotics, such as inulin, lactitol, mannitol, etc.
  • the mouth feel of the chewable tablets must be adjusted to ensure that the when the tablet or caplet body is crushed, it folds into the flavored matrix; if the body is too brittle, it may fracture causing an uncomfortable sensation in the user's mouth.
  • the product should also have a pleasant odor when the bulk package is opened.
  • Each of the features of the chewable tablet may be attained by adjusting the excipients until the desired properties are achieved.
  • two different direct compression machines may be used to manufacture the dosage forms. Single punch presses typically exhibit low compression speeds while rotary presses exhibit high compression speeds. The Examples describe the use of both a single punch press (Examples 1 and 2) and rotary presses (also called rotary machines; Examples 2-4 and 7-10).
  • the probiotic compositions of the present invention may also be incorporated into chewing gum.
  • the chewing gum preferably includes a flavor and may be hard chewing gum or soft chewing gum.
  • the flavored hard or soft chewing gum may include a sweetener, which may be an artificial or natural sweetener or both. Procedures for manufacturing gum are known to those of ordinary skill in the art.
  • Gum is traditionally made using four ingredients: a gum base, such as a resin obtained from pine trees; a natural sweetener, such as sugar, or an artificial sweetener; a softener, such as glycerin; and flavoring.
  • a gum base such as a resin obtained from pine trees
  • a natural sweetener such as sugar, or an artificial sweetener
  • a softener such as glycerin
  • flavoring The raw materials for the gum are mixed with a mixer while kept at a constant temperature during the prescribed processing time.
  • Mixed gum materials are then sent to a hopper and extruded by twin screws to make a gum sheet.
  • the inside and outside of the gum sheets are powdered to prevent sticking to the matching during rolling and packaging.
  • the gum sheet thickness is controlled with a roller. After extrusion, the gum sheet is scored and cut for proper sizing, passed through a cooling tunnel, and stacked on trays for packaging.
  • the gum is coated between the cutting and cooling steps.
  • Specially designed machines are available for each of the steps; thus, gum can be made using a mixing machine, an extruding machine, a forming machine, a cooling machine, and a stacking machine.
  • Gum may also be prepared using the direct compression procedure described in U.S. Patent Publication No. 2004/0013767 to Norman and Amin, which is incorporated by reference herein. Under this procedure, a gum base, granulating agent, processing aid, and one or more lubricants are mixed and subjected to direct compression on a traditional tabletting machine. Sweeteners, colorings, and flavorings may also be added to the mixture.
  • a commercially available mixture of polyol(s) and/or sugars in a gum base is sold commercially as PHARMAGUM ® (SPI Polyols, Inc., New Castle, Delaware). The direct compression procedure is particularly useful for preparing chewing gum tablets.
  • the probiotic is added during the initial mixing stage prior to extrusion or direct compression.
  • the probiotic compositions of the present invention may be prepared as a powder that is intended to be dissolved in a liquid, such as water, milk, juice, and yogurt. It is understood that the individual liquids may be mixed together where appropriate.
  • the probiotic formulation may be combined with fruit juice and yogurt or milk and yogurt to make probiotic yogurt shakes.
  • the probiotic formulation may also be combined with milk and ice cream to make probiotic milk shakes. Flavorings for the probiotic liquid formulations contemplated under the invention are known to those of ordinary skill in the art.
  • excipients that may be used to formulate appropriate dosage forms include binders, disintegrants, lubricants, coatings, plasticizers, compression agents, wet granulation agents, and sweeteners, all of which are known to those of ordinary skill in the art to which the invention pertains. All of the following examples are provided by way of illustration and not limitation. Binders are used where appropriate to help the dosage form ingredients still together. Examples of binders include carbopol, povidone, and xanthan gum. Lubricants are generally always used in the manufacture of dosage forms by direct compression in order to prevent the compacted powder mass from sticking to the equipment during the tabletting or encapsulation process.
  • lubricants examples include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumerate, and vegetable based fatty acids.
  • Disintegrants aid in the break up of the compacted mass when placed in a fluid environment.
  • disintegrants include sodium croscarmellose, crospovidone, gellan gum, hydroxypropyl cellulose, starch, and sodium starch glycolate.
  • Coatings are used to control the solubility of the drug.
  • coatings include carrageenan, cellulose acetate phthalate, ethylcelluloseose, gellan gum, matodextrin, methacrylates, methylcellulose, microcrystalline cellulose, and shellac.
  • Plasticizers are used to control the release rate of the drug from the dosage form.
  • plasticizers include citrate esters, dibutyl sebacate, diethyl phthalate, polyvinylacetate phthalate, and triacetin.
  • Compression agents include calcium carbonate, dextrose, fructose, guar gum, honey, lactose, maltodextrin, maltose, mannitol, microcrystalline cellulose, molasses, sorbitol, starch, and sucrose.
  • Wet granulation agents include calcium carbonate, lactose, maltodextrin, mannitol, microcrystalline cellulose, povidone, and starch.
  • Sweeteners include aspartame, dextrose, fructose, honey, lactose, maltodextrin, maltose, mannitol, molasses, monoammonium glycyrrhizinate, sorbitol, sucralose, and sucrose.
  • Excipients that are generally used in the manufacture of chewable tablets include by way of illustration and not limitation, dextrose, fructose, guar gum, lactose, maltodextrin, maltose, mannitol, microcrystalline cellulose, and sorbitol. As is evident from the foregoing list, many of the same ingredients may be used for various different purposes in various different dosage forms.
  • the probiotic should be present in a range of approximately 10 6 colonies per dosage unit to approximately 10 10 colonies per dosage unit, although higher counts are also acceptable.
  • the probiotic composition is to be administered to an adult human being, i.e., a human being over the age of 16, the probiotic is preferably in the range of at least 10 9 , more preferably 10 10 or even higher.
  • the probiotic composition is to be administered to a child, i.e., a human being under the age of 16, the probiotic is preferably in the range of approximately 10 6 to approximately 10 .
  • the Examples set forth various studies to determine the conditions at which the probiotic compositions of the present invention have the longest duration.
  • the storage conditions play a significant difference in the duration of the probiotic compositions, c.f., the stability of the probiotic compositions at 25°C/60%RH, 30°C/65%RH, and 40°C/75%RH (Tables 16-18, 20-22 and 24-26). Further, the presence of a desiccant in the storage package may also make a difference under certain storage conditions, although, this is not always the case; c.f., Tables 12, 13, 16-18.
  • desiccants examples include without limitation, silica gel (silicon dioxide), indicating silica gel (silica gel washed with cobalt chloride), montmorillonite clay, calcium oxide, calcium sulfate, activated alumina beads, and molecular sieve (e.g., aluminosilicate materials or synthetic compounds such as clays, porous glass, microporous charcoal, or active carbon).
  • the probiotic compositions of the present invention have widespread utility in the manufacture of various consumable commercial products that upon ingestion by a human or an animal will regulate their digestive systems by ensuring that the digestive tract is populated by live probiotic species. Because it is essential that probiotic species are viable upon ingestion, the enhanced stability of the probiotic species in the probiotic compositions of the present invention ensure that the probiotic compositions have the capability to reduce the number of pathogenic species in the colon. Examples of pathogenic bacteria that may be reduced through ingestion of the probiotic compositions of the present invention include without limitation, Campylobacter jejuni, E. coli, S.
  • probiotic formulations of the presenting invention are a pleasant-tasting product that may be consumed without water. Further, the probiotic formulations of the present invention are stable at room temperature and thus, do not need special conditions in order to improve or sustain the shelf life of the product.
  • lactis were tested as a combined assay; and six tablets per pull were tested for samples where L. acidophilus and B. animalis subsp. lactis were individually assayed from the combined product. For the stability testing, weekly, biweekly, or monthly pulls were carried out until a reduction in assay count below 1 x 10 6 was observed (exceptions to this procedure are noted in the examples).
  • L. acidophilus probiotic tablets were prepared using the ingredients set forth in
  • the orange and bubble gum flavored tablets were prepared by direct compression on a rotary machine using a 1/2" round standard concave tooling and the pineapple flavored tablets were prepared using a single punch press capsule-shaped tooling.
  • the hardness of all of the tablets was in the range of 7-9 kp and disintegration times were all approximately 22 seconds.
  • the tablets of Table 3 were stored at 25°C/60%RH for stability testing without a desiccant, with a set of three tablets of each batch set aside as reserve samples for each flavor dosage form; the reserve samples were stored at 4°C.
  • Table 4 sets forth the results of the monthly stability tests on the dosage forms of Table 3 over an 11 -month period and Table 5 sets forth the results of the stability test of the reserve samples at month 13; five tablets were selected for each stability test pull.
  • the stability of the L. acidophilus in the dosage forms was determined by measuring the presence of the gram-positive rod of L. acidophilus. TABLE 4
  • L. acidophilus in each flavor batch was less than 1 x 10 6 ; by contrast, the samples stored at 4°C showed no reduction in microbial count at 13 months.
  • the B. animalis subsp. lactis tablets were prepared by direct compression on a rotary machine using 7/16" standard concave tooling. Hardness of the tablets was in the range of 10-12 kp. The compressed tablets were put into 60 cc HDPE bottles without a desiccant and exposed to the controlled temperature of 25°C/60%RH. Five tablets per pull were subjected to microbiological stability testing at the following time intervals: 0 time, 1 month, 2 months, and 3 months. The results of the stability test are set forth in Table 7.
  • Probiotic tablets 2000 tablets per flavor batch
  • B. animalis subsp. lactis probiotic were prepared using the ingredients set forth in Table
  • the tablets were prepared by direct compression on a rotary machine using a
  • the hardness of the tablets was in the range of 8-10 kp.
  • the compressed tablets were packaged into 180 cc HDPE bottles of 100 tablets each without a desiccant and exposed to the controlled temperature of 25°C/60%RH.
  • the product was subjected to monthly microbiological stability testing over a period of 12 months or until a reduction in the assay count below 1 x 10 6 was observed.
  • Six tablets per pull were analyzed at 0 time and 1 month for both L. acidophilus and B. animalis subsp. lactis and five tablets per pull were tested for L. acidophilus and B. animalis subsp. lactis independently for the remaining time periods.
  • the results of the stability test are set forth in Tables 9 and 10, respectively.
  • Example 4 The three flavor batches of Example 4 were tested for stability in a composite packaging of 100 tablets (33 of each flavor plus one additional tablet randomly selected) without a desiccant by placing the composite packaging in a 180 cc HDPE bottle at the controlled temperature of 25°C/60%RH and testing the tablets for microbiological stability each month for a period of 12 months or until an assay count below 1 x 10 was observed.
  • Five tablets per pull (randomly selected from each flavor) were analyzed for total count of L. acidophilus and B. animalis subsp. lactis combined at 1 month and six tablets per pull (randomly selected from each flavor) were analyzed for L. acidophilus and B. animalis subsp. lactis independently for the remaining time periods (in this experiment, the typical six tablet per pull per for the combined pulled probiotic and five tablet per pull for the independently pulled probiotic was reversed).
  • the results of the stability tests are set forth in Tables 11 and 12, respectively.
  • Example 6 The three flavor batches of Example 6 were tested for stability in a composite packaging of 100 tablets (33 of each flavor plus one additional tablet randomly selected) with a desiccant by placing the composite packaging in a 180 cc HDPE bottle at the controlled temperature of 25°C/60%RH and testing the tablets for microbiological stability at 3 months, 6 months, 9 months, and 12 months, or until an assay count below 1 x 10 6 was observed.
  • the tablets were analyzed for L. acidophilus and B. animalis subsp. lactis independently. The results of the stability test are set forth in Table 13.
  • PHARMABURST ® Cl one of two lactitol prebiotics, i.e., CM 50 at 7.7% or FINLAC ® DC (Xyrof ⁇ n Oy Corp., Helsinki, Finland) at 39.7% with a corresponding decrease in PHARMABURST ® Cl, and OPC from grape seed extract.
  • the batches were used to test the following parameters: (1) the organoleptic characteristics of lactitol and OPC containing products; (2) the effect of the prebiotic lactitol on probiotic stability; and (3) the effect of OPC on probiotic stability.
  • the ingredients set forth in manufacturing the tablets for each batch are set forth in Table 14; the heading for each batch specifies the lactitol sweetener used and the number of tablets per batch.
  • Table 14 The tablets of Table 14 were made by direct compression on a rotary machine using a 1/2" round standard concave tooling. The hardness of the tables was in the range of 8-10 kp. One hundred of the compressed tablets from each batch were packaged into 180 cc HDPE bottles and stability tested at a controlled temperature until a reduction in the assay count was observed. Table 15 provides the parameters for the stability testing of Batches 1 to 4 from Table 14 and includes for each testing lot: the controlled temperature used, the time periods of testing, and whether or not a desiccant was used. All samples were also tested at 0 time in addition to the time periods specified in Table 15. TABLE 15
  • Test Lot 6 from Batch 3 (7.7% lactitol, no OPC, no desiccant) had stability readings above 1 x 10 7 , indicating that the 7.7% lactitol (i.e., CM 50) and the absence of a desiccant has a positive effect on the probiotic stability of the dosage form when compared to comparable dosage forms prepared with 39.7% lactitol (i.e., FINLAC ® ) and/or are stored with a desiccant.
  • the results for Test Lot 5 from Batch 3 and Test Lots 5 and 6 from Batch 4 were all below 1 x 10 6 .
  • Test Lot 3 of Batch 3 (7.7% lactitol, no OPC, desiccant) had a significantly higher count of viable species than did Test Lot 3 of Batch 4 (39.7% lactitol, no OPC, desiccant).
  • EXAMPLE 8 MANUFACTURE OF PROBIOTIC DOSAGE FORM WITH L. ACIDOPHILUS, B. ANIMALIS SUBSP. LACTIS,
  • a batch of 500 tablets of a mango-flavored combination probiotic dosage form containing L. acidophilus, B. animalis subsp. lactis, vitamin A, and zinc oxide was prepared with the ingredients set forth in Table 19.
  • the tablets were prepared by direct compression on a rotary machine using a
  • the mango flavored tablets were stored with a desiccant and subjected to stability testing for L. acidophilus and B. animalis subsp. lactis independently at varying time points under three different storage conditions: 40°C/75%RH (Table 20); 35°C/65%RH (Table 21); and 25°C/60%RH (Table 22).
  • Tables 21 and 22 show that the samples tested at 30°C/65%RH and
  • the tablets were prepared by direct compression on a rotary machine using a
  • Table 25 shows a high percentage of live colonies of both bacterial species at
  • Table 26 shows a very high percentage of live colonies of both bacterial species at 25°C/60%RH at 9 months, indicating that perhaps the OPC from pine bark enhances the stability of the probiotic dosage forms under the specified conditions.
  • the values of the 3 -month counts for the samples of Tables 25 and 26 are significantly higher than the values of the 3- month counts for the samples of Batch 2, Test Lot 2 (OPC from grape seed, FINLAC R lactitol, desiccant) in Tables 17 and 18.
  • Tablets were made by direct compression on a rotary machine using a 1/2" round standard concave tooling. As shown in Tablet 27, the hardness of the tablets varied dramatically due to the characteristics of mannitol and sorbitol. Table 28 shows the results of the stability assay for L. acidophilus at 40°C/75%RH without a desiccant at three time points.
  • probiotic formulations were prepared with the carriers PHARMABURST ® Cl (Batch C; SPI Polyols, New Castle, DE) and STARCH 1500 ® (Batch D; Colorcon, Inc., West Point, PA).
  • the ingredients for the control formulations are set forth in Table 29.
  • Tablets were made by direct compression on a rotary machine using a 1/2" round standard concave tooling. The hardness of the tablets varied with the characteristics of each formulation. The control batches were stored for two weeks at 40°C/75%RH without a desiccant and tested for L. acidophilus at two time periods, which are set forth in Table 30.
  • the following parallel formulations were manufactured: (1) PHARMABURST ® Cl (abbreviated as "PHRMBRST" in Tables 31 and 32) and lactitol with magnesium stearate (Batch E); (2) PHARMABURST ® Cl and lactitol with calcium stearate (Batch F); (3) PHARMABURST ® Cl and pine bark OPC with lactitol (Batch G); and (4) PHARMABURST ® Cl and pine bark OPC without lactitol (Batch H).
  • AU parallel formulations were placed on accelerated stability testing according to the formulations set forth in Table 31.
  • Tablets were made by direct compression on a rotary machine using a 1/2" round standard concave tooling. The hardness of the tablets varied with the characteristics of each formulation. All samples were stored for one month at 40°C/75%RH without a desiccant and tested for L. acidophilus at the time periods specified in Table 32.
  • PHARMABURST ® to result in increased stability of L. acidophilus
  • three additional batches of tablets (Batches I, J, and K) were formulated as set forth in Table 33; the stability results for the tablets in the three batches at 40°C/75%RH are set forth in Table 34.
  • PHARMABURST ® shown in Example 12 also occurs between xylitol, maltitol and erythritol and PHARMABURST ® to result in increased stability of L. acidophilus
  • four additional batches of tablets (Batches L, M, N, and )) were formulated as set forth in Table 35.
  • the stability results for the tablets in the four batches at 40°C/75%RH for L. acidophilus are set forth in Table 36 and the stability results for B. animalis subsp. Lactis are set forth in Table 37.

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Abstract

L'invention porte sur des compositions probiotiques qui ont une stabilité améliorée dans diverses conditions de stockage. La stabilité des compositions probiotiques est améliorée par l'addition de divers agents et excipients. Des exemples d'agents et d'excipients qui peuvent être utilisés pour améliorer la stabilité de compositions probiotiques comprennent des prébiotiques, tels que les alcools de sucre mannitol, sorbitol et lactitol et/ou des phytonutriments tels que des proanthocyanidines oligomères (OPC). Les compositions probiotiques peuvent être formulées en des formes posologiques orales telles que des comprimés, des comprimés-capsules et des capsules ou fabriquées sous forme de gomme à mâcher ou sous forme de formulation pulvérulente qui peut être dissoute dans un liquide tel que l'eau, le lait, un jus ou du yaourt.
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US10155015B2 (en) 2010-01-28 2018-12-18 Ab-Biotics S.A. Probiotic compositions for use in the treatment of bowel diseases
EP2441432A1 (fr) * 2010-10-13 2012-04-18 Nestec S.A. Dispositif d'aspiration avec dépôt externe de probiotiques
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JP2014079208A (ja) * 2012-10-17 2014-05-08 Ryozo Saito 腸内環境及び腸管バリア改善サプリメント
CN103898163A (zh) * 2012-12-25 2014-07-02 东北农业大学 一种乳酸菌单质硒产品及其生产方法
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WO2017009313A1 (fr) * 2015-07-14 2017-01-19 Ergon S.R.L. Comprimé à concentration élevée en bactéries d'acide lactique
RU2779386C2 (ru) * 2017-06-05 2022-09-06 Проби Аб Микробные композиции
US11541082B2 (en) 2017-06-05 2023-01-03 Probi Ab Microbial compositions
US12226433B2 (en) 2018-08-06 2025-02-18 The Johns Hopkins University Treatment of irritable bowel syndrome with molybdenum

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