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WO2023237677A1 - Combinaisons comprenant de la vitamine c et bifidobacterium animalis ssp. lactis - Google Patents

Combinaisons comprenant de la vitamine c et bifidobacterium animalis ssp. lactis Download PDF

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Publication number
WO2023237677A1
WO2023237677A1 PCT/EP2023/065388 EP2023065388W WO2023237677A1 WO 2023237677 A1 WO2023237677 A1 WO 2023237677A1 EP 2023065388 W EP2023065388 W EP 2023065388W WO 2023237677 A1 WO2023237677 A1 WO 2023237677A1
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WO
WIPO (PCT)
Prior art keywords
combination
vitamin
lactis
bifidobacterium animalis
animalis ssp
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Ceased
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PCT/EP2023/065388
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English (en)
Inventor
Thanh-Van PHAM
Wilbert SYBESMA
Robert STEINERT
Ateequr Rehman
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DSM IP Assets BV
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DSM IP Assets BV
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Priority to KR1020257000744A priority Critical patent/KR20250022799A/ko
Priority to JP2024571228A priority patent/JP2025521181A/ja
Priority to EP23732030.4A priority patent/EP4536213A1/fr
Publication of WO2023237677A1 publication Critical patent/WO2023237677A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/314—Foods, ingredients or supplements having a functional effect on health having an effect on lung or respiratory system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/32—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the digestive tract
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/70—Vitamins
    • A23V2250/708—Vitamin C
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/51—Bifidobacterium
    • A23V2400/515—Animalis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to combinations comprising vitamin C and Bifidobacterium animalis ssp. lactis, and uses thereof for improving gut health in animals and humans. It was found that a combination of vitamin C and Bifidobacterium animalis ssp. lactis, when delivered to the large intestine, increases the abundance of beneficial bacteria in the intestinal tract.
  • Bifidobacteria are one of the major genera of bacteria that make up the micorobiota in the intestinal tract of mammals; some are used as probiotics. As a resident within the human gut, bifidobacteria create a bacteria-host, symbiotic-like relationship, providing the human host with many health benefits, include but not limited to: re-establishing normal intestinal microflora, improving intestinal and immune functioning, preventing the loss of nutrients, preventing constipation, preventing the initiation of colon cancer, treating liver damage, and lowering cholesterol levels in the blood. Bifidobacteria also have antibiotic activity and have been found to aid in antitumor activity in the host.
  • Bifidobacterium bifidum shows promise in treating the following conditions: infection by Helicobacter pylori (H. pylori), irritable bowel syndrome (IBS), depletion of intestinal bacteria after chemotherapy, constipation, lung infections, ulcerative colitis, certain kinds of diarrhea, necrotizing enterocolitis, a type of infection in the intestinal lining caused by harmful bacteria, pouchitis, a complication of surgery for ulcerative colitis, and eczema (Guglielmetti S.
  • W02020/043797 discloses that vitamins can be useful to increase the growth of certain beneficial bacteria in the intestine. However, W02020/043797 does not describe that vitamins can be used in combination with probiotics to increase the abundance of other beneficial bacteria.
  • the human gut is home to hundreds of different microbes, and it would be desirable to be able to boost specific beneficial bacteria. In particular, it would be desirable to increase the abundance of Bifidobacterium bifidum in the intestine to enhance wellness, improve health, and support the immune system.
  • the present invention relates to the following items:
  • H. pylori Helicobacter pylori
  • IBS irritable bowel syndrome
  • Combination comprising vitamin C and Bifidobacterium animalis ssp. lactis for use in increasing the abundance of Bifidobacterium bifidum in the large intestine of an animal, preferably a human, wherein said use comprises administering or delivering the vitamin C and the Bifidobacterium animalis ssp. lactis to the large intestine.
  • Combination comprising vitamin C and Bifidobacterium animalis ssp. lactis for the use according to item 10, wherein the vitamin C and the Bifidobacterium animalis ssp. lactis are administered or delivered to the large intestine by a delayed-release formulation.
  • Combination comprising vitamin C and Bifidobacterium animalis ssp. lactis for the use according to item 10 or item 11 , wherein said use comprises administering or delivering the vitamin C and the Bifidobacterium animalis ssp. lactis simultaneously and/or sequentially to the animal, preferably a human.
  • Combination comprising vitamin C and Bifidobacterium animalis ssp. lactis for the use according to any one of item 10-12, wherein the animal, including a human, is experiencing one or more condition(s) selected from: Helicobacter pylori (H. pylori) infection, irritable bowel syndrome (IBS), depletion of intestinal bacteria after chemotherapy, constipation, lung infection, ulcerative colitis, diarrhea, necrotizing enterocolitis, pouchitis, and eczema.
  • H. pylori Helicobacter pylori
  • IBS irritable bowel syndrome
  • Combination comprising vitamin C and Bifidobacterium animalis ssp. lactis for the use according to any one of item 10-13, wherein the Bifidobacterium animalis ssp. lactis is Bifidobacterium animalis ssp. lactis BB-12, preferably Bifidobacterium animalis ssp. lactis DSM 32269.
  • Bifidobacterium bifidum is a bacterial species known for its beneficial effects on human health.
  • the present inventors have found that vitamin C in combination with Bifidobacterium animalis ssp. lactis can boost the growth of Bifidobacterium bifidum bacteria in the large intestine, leading to an increase of Bifidobacterium bifidum levels in the gut.
  • the present invention relates to combinations comprising vitamin C and Bifidobacterium animalis ssp. lactis.
  • the Bifidobacterium animalis ssp. lactis is a Bifidobacterium animalis ssp. lactis BB-12 strain; more preferably it is Lactobacillus rhamnosus DSM 32550.
  • the combination is for simultaneous and/or sequential administration.
  • Patent claims relating to a “combination” are product claims.
  • the product of the present invention comprises two active ingredients: a vitamin (vitamin C) and a probiotic (Bifidobacterium animalis ssp. lactis).
  • a vitamin vitamin C
  • a probiotic Bacillus subtilis ssp. lactis
  • Vitamin C also known as L-ascorbic acid, is a water-soluble vitamin that is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters. Vitamin C is also involved in protein metabolism. Further, vitamin C is an important physiological antioxidant. Vitamin C plays an important role in immune function and improves nutrient absorption. Vitamin C can be purchased from DSM GmbH. Alternative suppliers are, for example, TER Chemicals Distribution Group, BIOCHEM Bernburg GmbH, DVA International GmbH, Falken Trade GmbH, and Neupert Ingredients GmbH.
  • Bifidobacterium animalis ssp. lactis strain is Bifidobacterium animalis ssp. lactis BB-12. It can be purchased, for example, from Chr. Hansen as BB-12®.
  • Bifidobacterium animalis ssp. lactis DSM 32269 Biocare Copenhagen
  • Bifidobacterium animalis ssp. lactis DSM 32269 Biocare Copenhagen
  • B. animalis ssp. lactis DSM 32269 is identical or equivalent to B. animalis ssp. lactis BB-12® for practical purposes. Therefore, Bifidobacterium animalis ssp. lactis DSM 32269 (Biocare Copenhagen) will herein be referred to as a Bifidobacterium animalis ssp. lactis BB-12 strain.
  • Bifidobacterium animalis ssp. lactis strains are, for example, Bifidobacterium lactis Bi- 07® (Howaru; Danisco/ IFF/DuPont), Bifidobacterium lactis BI-04® (Howaru; Danisco/ IFF/ DuPont), and Bifidobacterium lactis HN019 (Howaru; IFF/DuPont).
  • Bifidobacterium animalis ssp. lactis DSM 32269 (Biocare Copenhagen) is a preferred strain according to the present invention. Bifidobacterium animalis ssp.
  • lactis DSM 32269 has been deposited at Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, D-38124 Braunschweig, Germany, according to the Budapest Treaty on 26. February 2016. The accession number given by the International Depository Authority is DSM 32269.
  • the combination of the present invention is for simultaneous administration.
  • the combination for simultaneous administration is a fixed combination.
  • a free combination can also be used.
  • the combination is for sequential administration.
  • the combination for sequential administration is a free combination.
  • the combination is an oral dosage form; more preferably, it is a solid oral dosage form.
  • the combination of the present invention can be, for example, a pharmaceutical combination or composition, a dietary supplement, or a food supplement.
  • the present invention relates to vitamin C and Bifidobacterium animalis ssp. lactis (i.e., a combination of vitamin C and Bifidobacterium animalis ssp. lactis) for use as a medicament.
  • the combinations of the invention are for use in the treatment of a patient that is in need of increasing the abundance of Bifidobacterium bifidum in the large intestine.
  • said patient is suffering from one or more of the following conditions: infection by Helicobacter pylori (H. pylori), irritable bowel syndrome (IBS), depletion of intestinal bacteria after chemotherapy, constipation, lung infection, ulcerative colitis, diarrhea, necrotizing enterocolitis (a type of infection in the intestinal lining caused by harmful bacteria), pouchitis (a complication of surgery for ulcerative colitis), and eczema.
  • the present invention relates to vitamin C and Bifidobacterium animalis ssp. lactis (i.e., a combination of vitamin C and Bifidobacterium animalis ssp. lactis) for use in improving gut health in an animal.
  • Said improvement comprises or consists of increasing the abundance of Bifidobacterium bifidum in the large intestine of said animal.
  • lactis is for use in increasing the abundance of Bifidobacterium bifidum in the large intestine (colon) of an animal, wherein said use preferably comprises delivering the vitamin C and Bifidobacterium animalis ssp. lactis to the large intestine.
  • the animal is a human.
  • the vitamin C and Bifidobacterium animalis ssp. lactis is preferably directly delivered to the large intestine. That is, the vitamin is delivered/ administered in a manner such that the vitamin is not absorbed in the stomach and/or small intestine; rather the vitamin and the probiotic is delivered/ administered to the distal intestinal tract, preferably the large intestine (colon). This is preferably done by delivering/ administering the vitamin C and Bifidobacterium animalis ssp. lactis in a delayed-release formulation. Oral administration is preferred.
  • the animal is experiencing one or more condition(s) selected from the group consisting of: infection by Helicobacter pylori (H. pylori), irritable bowel syndrome (IBS), depletion of intestinal bacteria after chemotherapy, constipation, lung infection, ulcerative colitis, diarrhea, necrotizing enterocolitis (a type of infection in the intestinal lining caused by harmful bacteria), pouchitis (a complication of surgery for ulcerative colitis), and eczema.
  • H. pylori Helicobacter pylori
  • IBS irritable bowel syndrome
  • the Bifidobacterium animalis ssp. lactis used is Bifidobacterium animalis ssp. lactis BB-12. Bifidobacterium animalis ssp. lactis DSM 32269 is particularly preferred.
  • the present invention relates to a method of increasing the abundance of Bifidobacterium bifidum in the intestine, preferably the large intestine, comprising administering to the animal an effective dose of vitamin C and Bifidobacterium animalis ssp. lactis (preferably, Bifidobacterium animalis ssp. lactis BB-12; in particular Bifidobacterium animalis ssp. lactis DSM 32269).
  • the method is for improving intestinal health in an animal, including a human, wherein said improvement comprises increasing the abundance of Bifidobacterium bifidum in the large intestine.
  • the animal is a human.
  • the vitamin C and the Bifidobacterium animalis ssp. lactis is delivered directly to the large intestine. Delivery to the large intestine can be achieved by administering the vitamin C and the Bifidobacterium animalis ssp. lactis as a delayed-release formulation.
  • the methods of the invention can be used to treat, prevent, and/or lessen the symptoms of infection by Helicobacter pylori (H.
  • IBS irritable bowel syndrome
  • depletion of intestinal bacteria after chemotherapy constipation, lung infection, ulcerative colitis, diarrhea, necrotizing enterocolitis (a type of infection in the intestinal lining caused by harmful bacteria), pouchitis (a complication of surgery for ulcerative colitis), and eczema in an animal, including a human, in need thereof.
  • the present invention relates to the use of vitamin C and Bifidobacterium animalis ssp. lactis (i.e. , a combination of vitamin C and Bifidobacterium animalis ssp. lactis) for increasing the abundance of Bifidobacterium bifidum in the large intestine of an animal, preferably a human, wherein said use comprises delivering the vitamin C and the Bifidobacterium animalis ssp. lactis to the large intestine.
  • the use comprises delivering the vitamin C and Bifidobacterium animalis ssp. lactis to the large intestine by a delayed-release formulation.
  • the animal including a human, is experiencing one or more condition(s) selected from the group consisting of: infection by Helicobacter pylori (H. pylori), irritable bowel syndrome (IBS), depletion of intestinal bacteria after chemotherapy, constipation, lung infection, ulcerative colitis, diarrhea, necrotizing enterocolitis (a type of infection in the intestinal lining caused by harmful bacteria), pouchitis (a complication of surgery for ulcerative colitis), and eczema.
  • H. pylori Helicobacter pylori
  • IBS irritable bowel syndrome
  • the vitamin C (ascorbic acid) dose is up to 2000 mg/day, preferably 100-2000 mg/day; more preferably 200-1000 mg/day.
  • vitamin C is dosed/ administered in an amount such that its local concentration in the colon is at least 0.05 g/L, preferably at least 0.1 g/L, most preferably at least 0.33 g/L.
  • Preferred local concentrations in the colon range from about 0.05 g/L to about 1 .5 g/L, more preferably from about 0.1 g/L to about 1 g/L, most preferably from about 0.2 g/L to about 0.5 g/L.
  • the dosage of the Bifidobacterium animalis ssp. lactis can be up to 5E+10 cfu/day. Preferably, the dosage range is from 1 E+08 to 1 E+10 cfu/day, more preferably from 1 E+09 to 5E+10 cfu/day.
  • the Bifidobacterium animalis ssp. lactis is a Bifidobacterium animalis ssp. lactis BB- 12. Bifidobacterium animalis ssp. lactis DSM 32269 is particularly preferred.
  • Patent claims relating to a “combination” or “pharmaceutical combination” are product claims.
  • the product of the present invention comprises two active ingredients: a vitamin (vitamin C) and a probiotic (Bifidobacterium animalis ssp. lactis).
  • a “combination for simultaneous administration” or a “combination for simultaneous consumption” is a combination that is suitable for simultaneous administration or consumption, respectively.
  • the vitamin can be administered/consumed in one pill or tablet, while the probiotic is administered/consumed in another pill or tablet, wherein both pills/tablets are administered/consumed within 24 hours.
  • the vitamin and the probiotic are formulated in the same composition and are administered/consumed at exactly the same time.
  • a “combination for sequential administration or consumption” is a combination that is suitable for sequential administration or consumption, respectively.
  • sequential administration or “sequential consumption”, it is meant that during a period of two or more days of continuous treatment, only one of the vitamin and the probiotic is administered/consumed on any given day.
  • the vitamin can be administered/consumed on day one, and the probiotic is administered/consumed only the next day (i.e., after more than 24 hours), or even later.
  • the active ingredients can be administered/consumed in any order.
  • a “fixed combination” is a combination that delivers both actives (i.e., the vitamin and the probiotic) at the same time to a patient.
  • a solid oral dosage form e.g., a tablet or capsule
  • a liquid oral dosage form e.g., oral drops
  • a fixed combination is another example of a fixed combination.
  • a “free combination” is a combination that allows to administer/consume both actives (i.e., the vitamin and the probiotic) separately, i.e. one at a time.
  • Treatment regimens in which the vitamin and the probiotic are not administered/consumed by the same route and/or are not administered/consumed at the same time require free combinations.
  • Simultaneous administration/consumption can be done both by using a fixed combination and a free combination. Sequential administration/consumption requires a free combination; fixed combinations are not suitable for sequential administration/consumption.
  • free combinations are more versatile: they are suitable for sequential administration/consumption and - if both actives are administered/consumed on the same day - also for simultaneous administration/consumption.
  • separate administration/consumption it is meant that the vitamin and the probiotic are administered/consumed one at a time.
  • separate administration/consumption can refer to both sequential administration/consumption and - when referring to the administration/ consumption of both actives on the same day but one at a time - also to simultaneous administration/consumption.
  • administering means to give or to deliver an active to a human or animal; likewise, the human or animal can take (consume) the active.
  • vitamin C which can be used interchangeably with “ascorbic acid” also includes pharmaceutically acceptable salts thereof (e.g., sodium ascorbate and calcium ascorbate) and pharmaceutically acceptable esters thereof (in particular ascorbyl palmitate) and other pharmaceutically acceptable forms.
  • pharmaceutically acceptable salts thereof e.g., sodium ascorbate and calcium ascorbate
  • pharmaceutically acceptable esters thereof in particular ascorbyl palmitate
  • Bifidobacterium bifidum means to increase the level (or the amount, or number, or the population size) of Bifidobacterium bifidum compared to the respective control (i.e., the level/ amount/ number/ population size of Bifidobacterium bifidum when the combination of vitamin C and Bifidobacterium animalis ssp. lactis has not been added).
  • intestine refers to the portion of the gastrointestinal tract consisting of the small intestine and the large intestine.
  • the “large intestine” (intestinum crassum) is the lower part of the gastrointestinal tract and is also referred to herein as “colon”.
  • "Direct delivery” or “directly delivered” means that the vitamin is formulated in a manner such that the vitamin is not absorbed in the stomach and/or small intestine; rather the vitamin is made available in the distal intestinal tract, preferably the large intestine (colon), where it is available to the microbiome.
  • the vitamin is not part of a person's usual daily nutritional requirements (generally obtained through diet and conventional vitamin supplementation), and is administered in excess thereof.
  • the preferred method according to the present invention is through a form which delays release until the large intestinal tract (colon) is reached.
  • a large enough dose can be administered, so that only a portion of the administered vitamin is absorbed in the proximal small intestine, and the remainder, which is an effective dose, is available to the large intestinal tract; although not preferred, the latter method of delivery can be used for humans as well.
  • "direct delivery” or “directly delivered” means that the probiotic is formulated in a manner such that it is not released in the stomach and/or small intestine but rather it is made available in the distal intestinal tract, preferably the large intestine (colon).
  • delayed release refers to the release of the vitamin and/or the probiotic at a time later than immediately after administration.
  • “delayed release” means delivery of the vitamin (and/or probiotic), upon oral administration, to the large intestine (colon) in a delayed manner relative to an immediate release formulation.
  • An “enteric layer” or “enteric coating” is a layer surrounding a core, wherein the core comprises the active agent and the layer confers resistance to gastric juice.
  • Prevent can include lessening the risk of an adverse condition occurring, lessening the symptoms of an adverse condition, lessening the severity of an adverse condition, and prolonging the time for occurrence of an adverse condition.
  • Oral formulation means that the vitamin and/or probiotic is formulated for oral administration/ consumption.
  • Co-administering or “co-administration” means that the vitamin and/or the probiotic is delivered/ administered/ consumed simultaneously (i.e. , together), or separately but within a time frame of 24 hours.
  • the vitamin can be delivered/ administered/ consumed first.
  • the probiotic can be delivered/ administered/ consumed first.
  • vitamin C is administered in an amount such that its local concentration in the colon is at least 0.05 g/L, preferably at least 0.1 g/L, most preferably at least 0.33 g/L.
  • Preferred local concentrations in the colon range from about 0.05 g/L to about 1.5 g/L, more preferably from about 0.1 g/L to about 1 g/L, most preferably from about 0.2 g/L to about 0.5 g/L.
  • Specific dosages per day can range up to 2000 mg/day, preferably 100-2000 mg/day; more preferably 200-1000 mg/day.
  • the dosage of the probiotic can be up to 5E+10 cfu/day.
  • the dosage range of the probiotic is from 1 E+08 to 1 E+10 cfu/day, more preferably from 1 E+09 to 5E+10 cfu/day.
  • the vitamin (vitamin C ) and/or the probiotic (Bifidobacterium animalis ssp. lactis), preferably both, is (are) preferably present in a formulation which allows the vitamin (and/or probiotic) to be available predominantly in the large intestine.
  • Oral formulations are preferred.
  • Other formulations include non-oral routes, such as via suppositories or injections.
  • a preferred delivery includes a method of administering a large enough dose so that only a portion of the vitamin and/or probiotic delivered is absorbed in the stomach, and the remainder, which is an effective dose, is available to the intestinal tract; although not preferred, this method of delivery can be used for humans as well.
  • Delayed-release formulations are known in the art.
  • the delayed-release formulations have an enteric coating (also referred to as enteric layer).
  • the vitamin and/or probiotic is in a formulation comprising an enteric capsule, filled with a composition comprising the vitamin and/or probiotic.
  • the enteric capsule confers resistance against the acidic environment of the stomach.
  • soft gel formulations may deliver the active agent in solution and yet offer advantages of solid dosage forms.
  • the formulation is a tablet comprising (i) a core comprising the vitamin and/or the probiotic, and (ii) a delayed-release coating such as an enteric coating.
  • a core comprising the vitamin and/or the probiotic
  • a delayed-release coating such as an enteric coating.
  • This may be a hard gel capsule.
  • a matrix-based delivery system can be used for direct colon delivery.
  • Matrix based systems have no discrete layer of coating material, but the active agent (i.e., the vitamin and/or the probiotic) is more or less homogenously distributed within the matrix.
  • colonrelease systems that embed the active agent in e.g. in a fiber matrix (enzyme-triggered) and an enteric coating on top.
  • the release of the vitamin and/or probiotic may be delayed until the small intestine. In another embodiment, the release is delayed until the distal small intestine. In yet another, preferred embodiment, the release of the vitamin and/or probiotic is delayed until the colon (large intestine).
  • the vitamin and/or probiotic is formulated in a solid dosage form for oral administration.
  • the formulation may be in the form of a capsule, pellet, bead, sphere, mini spheres, tablet, mini tablet, or granule, optionally coated with a delayed release coating that prevents the release of the active agent before the small intestine, preferably before the colon.
  • Coating, or matrix materials for the delayed release of the vitamin and/or probiotic, in particular for targeted release in the ileum or the large intestine upon oral administration are known in the art. They can be subdivided into coating materials that disintegrate above a specific pH, coating materials that disintegrate after a specific residence time in the gastrointestinal tract and coating materials that disintegrate due enzymatic triggers specific to the microflora of a specific region of the intestines. Coating materials from different categories are commonly used in combinations. Coating materials of the different categories for targeting to the large intestine have been reviewed for example in Bansal et al. (Polim. Med. 2014, 44, 2,109-118).
  • the delayed-release coating comprises at least one component selected from coating materials that disintegrate pH-dependently, coating materials that disintegrate time-dependently, coating materials that disintegrate due to enzymatic triggers in the intestinal environment (e.g., in the intestinal environment of the ileum and the large intestine), and combinations thereof.
  • Coating materials that disintegrate pH-dependently include polyvinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate HP-50, HP-55 or HP-55S, cellulose acetate phthalate, shellac, hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(methacrylic acid, ethyl acrylate) 1 :1 (Eudragit® L100-55, Eudragit® L30D-55), poly(methacrylic acid, methyl methacrylate) 1 :1 (Eudragit® L-100, Eudragit® L12.5), poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit® S-100, Eudragit® S12,5, and Eudragit® FS30D).
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • Coating materials that disintegrate time-dependently include Eudragit® RL, Eudragit®RS, and ethylcellulose.
  • Coating materials that disintegrate due to enzymatic triggers in the large intestinal environment include chondroitin sulfate, pectin, guar gum, chitosan, inulin, lactulose, raffinose, stachyose, alginate, dextran, xanthan gum, locust bean gum, arabinogalactan, cyclodextrin, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, amylose, resistant starch, and azo compounds being degraded by azo bonds splitting bacteria.
  • the aim of this study was to investigate the effect of a combination of vitamin C and Bifidobacterium animalis ssp. lactis on the composition of the gut microbiota in a long-term continuous fermentation experiment.
  • Stabilization period After inoculation of the colon reactors with an appropriate fecal sample, a two-week stabilization period allowed the microbial community to differentiate in the different reactors depending on the local environmental conditions. During this period the basic nutritional matrix was provided to the SHIME to support the maximum diversity of the gut microbiota originally present in the faecal inoculum.
  • Control period During this two-week reference period, the standard SHIME nutrient matrix was further dosed to the model for a period of 14 days. Analysis of samples in this period allowed to determine the baseline microbial community composition and activity in the different reactors, which is used as a reference for results obtained during the treatment.
  • the probiotic strain used in this experiment was the Bifidobacterium animalis ssp. lactis BB-12 equivalent Bifidobacterium animalis ssp. lactis DSM 32269 (Biocare Copenhagen).
  • Samples for quantitative 16S-targeted Illumina sequencing were collected 3x/week during the last week of the control and treatment period.
  • Next-generation 16S rRNA gene amplicon sequencing of the V3-V4 region was performed by LGC Genomics GmbH (Berlin, Germany) on samples from the medium-term SHIME experiment. Library preparation and sequencing were performed on an Illumina MiSeq platform with v3 chemistry.
  • the 341 F (50-CCTACGGGNGGCWGCAG-30) and 785R (50- GACTACHVGGGTATCTAAKCC-30) primers were used as described by De Paepe et al. (2017) with the reverse primer being adapted to increase coverage.

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Abstract

La présente invention concerne une combinaison comprenant de la vitamine C et Bifidobacterium animalis ssp. Lactis et son utilisation pour améliorer la santé intestinale chez les animaux et les êtres humains. Il a été découvert qu'une combinaison de vitamine C et de Bifidobacterium animalis ssp. lactis, lorsqu'elle est administrée au gros intestin, augmente l'abondance de bactéries Bifidobacterium bifidum dans le tractus intestinal.
PCT/EP2023/065388 2022-06-10 2023-06-08 Combinaisons comprenant de la vitamine c et bifidobacterium animalis ssp. lactis Ceased WO2023237677A1 (fr)

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