WO2023078378A1 - 提高机体免疫力、促进胃肠道健康的含透明质酸或其盐的组合物及其应用 - Google Patents

提高机体免疫力、促进胃肠道健康的含透明质酸或其盐的组合物及其应用 Download PDF

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Publication number
WO2023078378A1
WO2023078378A1 PCT/CN2022/129773 CN2022129773W WO2023078378A1 WO 2023078378 A1 WO2023078378 A1 WO 2023078378A1 CN 2022129773 W CN2022129773 W CN 2022129773W WO 2023078378 A1 WO2023078378 A1 WO 2023078378A1
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Prior art keywords
molecular weight
hyaluronic acid
salt
parts
intestinal
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PCT/CN2022/129773
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English (en)
French (fr)
Inventor
石艳丽
刘翠华
郭学平
范圣楠
冯宁
赵连真
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华熙生物科技股份有限公司
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Publication of WO2023078378A1 publication Critical patent/WO2023078378A1/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application relates to the technical fields of food, health products or medicine, in particular to a composition of hyaluronic acid or a salt thereof for improving immunity of the body and promoting gastrointestinal tract health and its application.
  • Hyaluronic acid is an acidic mucopolysaccharide composed of repeated connections of disaccharide units of D-glucuronic acid and N-acetylglucosamine, widely present in the tissue interstitium of animals and the capsule of some bacteria middle.
  • hyaluronic acid has been widely used in cosmetics, medicine and other fields. With the in-depth research and understanding of hyaluronic acid at home and abroad, its application in the food field, especially in functional foods, has also shown extensive and unique value. .
  • Immunity is the body's own defense mechanism, which is the body's ability to recognize and eliminate any foreign matter (viruses, bacteria, etc.) . Improving immunity is the physiological response of the human body to recognize and eliminate "dissidents". It can be enhanced in certain ways. In addition to exercising, you can also eat more beneficial foods, especially functional foods that can regulate immune factors and improve resistance.
  • the gastrointestinal tract is the largest immune and detoxification organ in the human body and has a decisive impact on health. More than 70% of the immune cells in the human body are located on the gastrointestinal mucosa, which makes the intestinal tract form an immune barrier to resist bacteria and viruses and maintain the stability of the intestinal environment.
  • gastrointestinal diseases has been increasing, such as gastrointestinal inflammation, gastrointestinal stones, gastric ulcer, intestinal flora imbalance, etc., more and more people are suffering from intestinal diseases Torment. Therefore, the development of raw materials and products that promote intestinal health can prevent and alleviate intestinal inflammation, promote intestinal peristalsis, and regulate intestinal flora, which can meet the needs of the market and people, and also have considerable economic benefits.
  • HA has a certain effect on improving human immunity.
  • Chinese patent application CN1498626A Application of Hyaluronic Acid in Improving Human Immunity and Immunity Deficiency Symptoms introduces a composition with hyaluronic acid as the functional ingredient. The role of immunity, but the specific molecular weight of hyaluronic acid is not described, and the function of hyaluronic acid with different molecular weights cannot be reflected, and the reference value is low.
  • Chinese patent CN108498549B composition for improving immune function and its application introduces a mixture of hyaluronic acid and lactic acid bacteria, which is used to alleviate and treat complications induced by anti-tumor chemotherapy, reduce the side effects of chemotherapy drugs, and improve the symptoms of low immunity situation.
  • the method needs to be compounded with lactic acid bacteria to act, and the lactic acid bacteria need to be prepared into freeze-dried bacteria powder, and the composition needs to add other auxiliary materials, such as freeze-drying protective agent and forming agent.
  • the operation is complicated, and there are various types of added substances, which fail to give full play to the efficacy of hyaluronic acid with different molecular weights.
  • HA also has a certain effect in promoting gastrointestinal health.
  • University of Oklahoma Health Science Center research shows that 35kDa HA can enhance the epithelial barrier function and prevent the occurrence of necrotizing enterocolitis in mice.
  • pathogenic bacteria Listeria, Citrobacter, enteropathogenic Escherichia coli
  • treatment with 530kDa hyaluronic acid can play a protective role.
  • this application intends to provide a HA complex and its products with clear ingredients and significant effects, so as to give full play to the role of hyaluronic acid in improving immunity and protecting gastrointestinal health. effect.
  • the present application provides a composition of hyaluronic acid or its salts for improving the body's immunity and promoting gastrointestinal health.
  • the composition is composed of hyaluronic acid or its salts with different molecular
  • the molecular weight of hyaluronic acid has different functions. Through synergistic effect, it can regulate immunity, improve the ability to resist gastrointestinal inflammation, promote intestinal peristalsis and the growth of intestinal probiotics, etc.
  • composition containing hyaluronic acid or a salt thereof comprising three molecular weight hyaluronic acid or a salt thereof, wherein,
  • the molecular weight of the first molecular weight hyaluronic acid or its salt is 10k-200kDa, preferably 10k-100kDa, more preferably 30k-50kDa;
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa, preferably 200k-600kDa, more preferably 200k-400kDa;
  • the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa, preferably 1300k-1500kDa.
  • composition described in Item 1 wherein, based on the total number of parts after mixing as 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • hyaluronic acid or its salt is selected from hyaluronic acid, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate and hyaluronic acid
  • One or more than two kinds of zinc preferably sodium hyaluronate or potassium hyaluronate.
  • a food composition comprising the composition according to any one of items 1-3.
  • a health care composition comprising the composition described in any one of items 1-3.
  • a pharmaceutical composition comprising the composition described in any one of items 1-3.
  • composition as described in Item 9, wherein the pharmaceutical composition is used to improve the body's immunity, relieve intestinal inflammation, increase intestinal peristalsis and/or regulate intestinal flora.
  • a method for improving immunity, alleviating intestinal inflammation, increasing intestinal peristalsis and/or regulating intestinal flora which comprises administering the composition of any one of items 1-3 to a subject.
  • composition according to any one of items 1-3 for improving the body's immunity, alleviating intestinal inflammation, increasing intestinal peristalsis and/or regulating intestinal flora.
  • composition according to any one of Items 1-3 in the preparation of medicines for improving body immunity, alleviating intestinal inflammation, increasing intestinal peristalsis and/or regulating intestinal flora.
  • composition provided in this application has clear ingredients, simple operation, and is convenient for preparation and use.
  • composition provided by this application has significant effects on improving the body's immunity, relieving gastrointestinal inflammation, promoting intestinal peristalsis, intestinal probiotic growth and protecting gastric mucosa, etc., and can be added to food and health care as functional ingredients In food, it can also be used as an excipient and used in combination with drugs.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises hyaluronic acid or a salt thereof with three different molecular weights.
  • the molecular weight of the first molecular weight hyaluronic acid or its salt is 10k-200kDa, preferably 10k-100kDa, more preferably 30k-50kDa;
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa, preferably 200k-600kDa, more preferably 200k-400kDa;
  • the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa, preferably 1300k-1500kDa.
  • the molecular weight refers to the weight average molecular weight.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises hyaluronic acid or a salt thereof with three different molecular weights, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the hyaluronic acid of the second molecular weight is 30k-50kDa; the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-400kDa; and the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa.
  • the molecular weight of the first molecular weight hyaluronic acid or its salt can be 10kDa, 20kDa, 30kDa, 40kDa, 50kDa, 60kDa, 70kDa, 80kDa, 90kDa, 100kDa, 160kDa, 200kDa, etc.;
  • the molecular weight of the second molecular weight hyaluronic acid or its salt can be 200kDa, 280kD, 300kDa, 400kDa, 500kDa, 600kDa, 700kDa, 800kDa, 900kDa, 1000kDa, etc.;
  • the molecular weight of the third molecular weight hyaluronic acid or its salt can be 1000kDa, 1100kDa, 1200kDa, 1300kDa, 1350kDa, 1400kDa, 1500kDa, etc.
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the total number of parts after mixing is 10 parts
  • the first molecular weight hyaluronic acid or its salt can be 1 part, 2 parts, 3 parts, 4 parts, etc.;
  • the second molecular weight hyaluronic acid or its salt can be 3 parts, 4 parts, 5 parts, 6 parts, etc.;
  • the third molecular weight hyaluronic acid or its salt can be 1 part, 2 parts, 3 parts, etc.
  • 1-4 parts, preferably 2-4 parts, of the first molecular weight hyaluronic acid or its salt are weighed 3 parts, and 3-6 parts are weighed, preferably 4-6 parts 5 parts of the second molecular weight hyaluronic acid or its salt, and weigh 1-3 parts of the third molecular weight hyaluronic acid or its salt 2 parts and mix to obtain the composition containing hyaluronic acid or its salt described herein .
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises hyaluronic acid or a salt thereof with three different molecular weights, wherein the first molecular weight The molecular weight of hyaluronic acid or its salt is 10k-100kDa; the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k- 1500kDa, based on the total parts after mixing as 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 200k-1000kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises hyaluronic acid or a salt thereof with three different molecular weights, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-600kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1000k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the present application provides a composition containing hyaluronic acid or a salt thereof, which comprises three different molecular weight hyaluronic acid or a salt thereof, wherein the first molecular weight hyaluronic acid or a salt thereof
  • the molecular weight of the second molecular weight hyaluronic acid or its salt is 20k-400kDa; and the molecular weight of the third molecular weight hyaluronic acid or its salt is 1300k-1500kDa. Parts are 10 parts by weight,
  • the first molecular weight hyaluronic acid or its salt is 1-4 parts, preferably 2-4 parts;
  • the second molecular weight hyaluronic acid or its salt is 3-6 parts, preferably 4-6 parts;
  • the ratio of the third molecular weight hyaluronic acid or its salt is 1-3 parts.
  • the hyaluronic acid or its salt is selected from one or more of hyaluronic acid, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate and zinc hyaluronate, preferably Sodium hyaluronate or potassium hyaluronate.
  • the present application provides the application of the composition described above in the fields of food, health products or medicines.
  • composition By applying the above-mentioned composition to the fields of food, health products or pharmaceuticals, it can improve the immune ability of the body, relieve gastrointestinal inflammation, promote intestinal peristalsis and the growth of intestinal probiotics.
  • the present application provides a food composition, which comprises the composition described above.
  • the food composition may also include auxiliary materials, such as preservatives, food colorings, flavoring agents, emulsifiers, spices and the like.
  • the present application provides a health product composition, which comprises the above-mentioned composition.
  • the health food composition may also include auxiliary materials, such as preservatives, food colorings, flavoring agents, emulsifiers, spices and the like.
  • the present application provides a pharmaceutical composition, which comprises the composition described above.
  • the pharmaceutical composition may further include auxiliary materials, such as lubricants, adhesives, colorants, diluents, absorbents and the like.
  • the excipients refer to compositions or components of compositions which are generally non-toxic, inert and/or physiologically compatible.
  • the dosage form of the above-mentioned food composition, health product composition, and pharmaceutical composition is not limited, for example, it may be in solid form, semi-solid form or liquid form.
  • the present application provides a method for improving immunity of a body, relieving intestinal inflammation, increasing intestinal peristalsis and/or regulating intestinal flora, which comprises administering the above-mentioned composition to a subject.
  • the application does not make any limitation on the method of administration, for example, the administration may be carried out in the form of oral administration.
  • subject refers to any animal (eg mammal), including but not limited to human, non-human primate, canine, feline, rodent and the like.
  • the present application provides the use of the composition described above for improving the body's immunity, relieving intestinal inflammation, increasing intestinal peristalsis and/or regulating intestinal flora.
  • the present application provides the use of the above-mentioned composition in preparing medicines for improving the body's immunity, alleviating intestinal inflammation, increasing intestinal peristalsis and/or regulating intestinal flora.
  • % means wt%, ie weight percentage.
  • the reagents or instruments used were not indicated by the manufacturer, all of which were commercially available conventional reagent products, among which, the first molecular weight hyaluronic acid or its salt, the second molecular weight hyaluronic acid or its salt, and the third molecular weight hyaluronic acid or its salt Molecular weight hyaluronic acid or its salts were provided by Bloomage Biotechnology Co., Ltd.
  • the first molecular weight sodium hyaluronate with a molecular weight of 40kDa, the second molecular weight sodium hyaluronate with a molecular weight of 280kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa were prepared according to the mass ratio of 3:5:2 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 160kDa, the second molecular weight sodium hyaluronate with a molecular weight of 280kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa were prepared according to the mass ratio of 3:5:2 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 160kDa, the second molecular weight sodium hyaluronate with a molecular weight of 600kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa were prepared according to the mass ratio of 3:5:2 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 160kDa, the second molecular weight sodium hyaluronate with a molecular weight of 280kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1000kDa were prepared according to the mass ratio of 3:5:2 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 40kDa, the second molecular weight sodium hyaluronate with a molecular weight of 600kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1000kDa were prepared according to the mass ratio of 3:5:2 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 160kDa, the second molecular weight sodium hyaluronate with a molecular weight of 600kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1000kDa were prepared according to the mass ratio of 3:5:2 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 40kDa, the second molecular weight sodium hyaluronate with a molecular weight of 280kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa were prepared according to the mass ratio of 3:6:1 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 40kDa, the second molecular weight sodium hyaluronate with a molecular weight of 280kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa were prepared according to the mass ratio of 2:5:3 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 40kDa, the second molecular weight sodium hyaluronate with a molecular weight of 280kDa, and the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa were prepared in a mass ratio of 1:3:1 Mix, mix well and set aside.
  • the first molecular weight sodium hyaluronate with a molecular weight of 40kDa is dissolved in physiological saline according to the concentration required for each experiment, and it is ready for use after completely dissolving.
  • the third molecular weight sodium hyaluronate with a molecular weight of 1350kDa was dissolved in physiological saline according to the concentration required for each experiment, and it was completely dissolved for later use.
  • the second molecular weight sodium hyaluronate with a molecular weight of 280kDa was dissolved in physiological saline according to the concentration required for each experiment, and it was ready for use after completely dissolving.
  • Sodium hyaluronate with a molecular weight of 80kDa was dissolved in physiological saline according to the concentration required for each experiment, and it was ready for use after completely dissolving.
  • the different strains of zebrafish used in the experiment were provided by the Zebrafish Drug Screening Platform of the Institute of Biology, Shandong Academy of Sciences; the samples of hyaluronic acid were provided by Bloomage Biotechnology Co., Ltd.
  • control group 200 Dose ( ⁇ g/mL) Number of immune cells (units) control group 200 55.4 ⁇ 4.06 model group 200 29.4 ⁇ 3.68 ##
  • Example 1 200 54.2 ⁇ 6.31 ** Example 2 200 49.0 ⁇ 3.09 ** Example 3 200 46.4 ⁇ 4.76 ** Example 4 200 48.5 ⁇ 1.07 ** Example 5 200 47.3 ⁇ 2.68 ** Example 6 200 45.2 ⁇ 2.02 ** Example 7 200 45.9 ⁇ 5.18 ** Example 8 200 44.0 ⁇ 6.00 ** Example 9 200 50.2 ⁇ 1.80 ** Example 10 200 53.1 ⁇ 3.09 ** Example 11 200 51.7 ⁇ 2.24 ** Comparative example 1 200 37.6 ⁇ 1.86 Comparative example 2 200 40.5 ⁇ 3.07 * Comparative example 3 200 42.0 ⁇ 1.89 * Comparative example 4 200 36.2 ⁇ 4.03 Comparative example 5 200 41.3 ⁇ 2.97 * Comparative example 6 200 32.3 ⁇ 2.11 Comparative example 7 200 40.9 ⁇ 3.04
  • the wild AB line zebrafish with 5 dpf (day post fertilization) was used as experimental animals to study the effect of hyaluronic acid samples on intestinal peristalsis. After calcein was pre-stained to the zebrafish intestine, the mean fluorescence intensity (IOD) of the intestine was calculated.
  • intestinal IOD coefficient (mean value of intestinal IOD before sample treatment - mean value of intestinal IOD after sample treatment)
  • the average value of intestinal IOD before sample treatment was calculated to obtain the intestinal IOD coefficient of zebrafish in the sample treatment group, and statistical analysis was performed. The results are shown in Table 3.
  • Example 2 200 0.77 ⁇ 0.034 ** Example 3 200 0.76 ⁇ 0.036 ** Example 4 200 0.75 ⁇ 0.021 ** Example 5 200 0.70 ⁇ 0.022 * Example 6 200 0.65 ⁇ 0.039 * Example 7 200 0.70 ⁇ 0.060 * Example 8 200 0.62 ⁇ 0.073 * Example 9 200 0.80 ⁇ 0.053 ** Example 10 200 0.84 ⁇ 0.044 ** Example 11 200 0.82 ⁇ 0.046 ** Comparative example 1 200 0.52 ⁇ 0.013 Comparative example 2 200 0.52 ⁇ 0.032 Comparative example 3 200 0.56 ⁇ 0.017 Comparative example 4 200 0.49 ⁇ 0.042 Comparative example 5 200 0.54 ⁇ 0.032 Comparative example 6 200 0.43 ⁇ 0.016 Comparative example 7 200 0.53 ⁇ 0.022
  • Lactobacillus rhamnosus and Lactobacillus helveticus in the intestinal probiotic group Lactobacillus were selected as starting strains. Lactobacillus regular medium MRS was used as the basal medium. The hyaluronic acid or its salt sample was 0.2% (w/v) of the culture medium volume, the negative control was a sugar-free MRS medium, and the positive control was a glucose MRS medium with the same concentration as HA. The concentration of bacteria (A 600 ) at different culture times was detected, and a total of 8 strains of intestinal probiotics were selected for in vitro proliferation experiments, and the results are shown in Table 4.
  • Lactobacillus regular medium MRS was used as the basal medium.
  • the hyaluronic acid or its salt sample was 0.2% (w/v) of the culture medium volume
  • the negative control was a sugar-free MRS medium
  • the positive control was a glucose MRS medium with the same concentration as HA.
  • the test samples can effectively increase the concentration and number of viable bacteria in the intestinal tract, especially Example 1 has the best effect, followed by 10, 11, 9, and 2 , indicating that the hyaluronic acid composition has the function of promoting the growth of intestinal probiotics.
  • Fluorescent zebrafish whose immune cells developed at 3dpf were specifically labeled were used as experimental animals, and were randomly divided into blank control group, model group and different sample groups. No drugs and test substances were added to the blank control group, and trinitrobenzenesulfonic acid (TNBS) with a final concentration of 50 ⁇ g/mL was added to the model group and different sample groups at the same time, with 10 larvae in each group and 2 larvae at the same time. Repeat hole.
  • the above-mentioned groups of zebrafish were placed in a constant temperature incubator at 28.5°C and incubated continuously for 3 days in the dark.
  • the larvae of each group were cleaned, and the larvae of the blank control group and the model group were placed in new culture water, and the larvae of other groups were placed in culture water containing 100 ⁇ g/mL of different samples to be tested, and continued to culture at 28.5 °C for 3 days.
  • the number of immune cells showing red fluorescence in the zebrafish intestinal tract was counted using Imagepro-plus software, and the data were statistically analyzed using GraphPad software.
  • Example 5 100 19.2 ⁇ 1.114 * Example 6 100 18.9 ⁇ 1.174 * Example 7 100 19.9 ⁇ 0.900 * Example 8 100 20.5 ⁇ 1.062 * Example 9 100 19.9 ⁇ 0.632 * Example 10 100 17.2 ⁇ 0.791 ** Example 11 100 19.2 ⁇ 0.466 * Comparative example 1 100 24.7 ⁇ 0.800 Comparative example 2 100 24.2 ⁇ 1.012 Comparative example 3 100 23.5 ⁇ 1.061 Comparative example 4 100 22.7 ⁇ 1.067 Comparative example 5 100 22.3 ⁇ 1.078 Comparative example 6 100 25.5 ⁇ 0.614 Comparative example 7 100 23.4 ⁇ 0.723
  • using the composition described in this application can significantly improve the number of immune cells in zebrafish with immune disorders, improve immune activity, promote intestinal peristalsis, improve the survival rate of various intestinal probiotics, and improve the intestinal bacteria. group, can significantly relieve enteritis, indicating that the composition described in this application has a significant effect on improving immunity and protecting the gastrointestinal tract, and can be added to food and health food as functional ingredients, or used in combination with drugs.

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Abstract

一种提高机体免疫力、保护胃肠道健康的含透明质酸或其盐的组合物及其应用。所述的含透明质酸或其盐的组合物，其包含三种分子量透明质酸或其盐。组合物通过协同增效实现增强免疫力、缓解肠道炎症、促进肠道蠕动、调节肠道菌群的作用，可作为功效成分添加于食品及保健类食品中，也可作为辅料，与药物联合使用。

Description

提高机体免疫力、促进胃肠道健康的含透明质酸或其盐的组合物及其应用 技术领域
本申请涉及食品、保健品或医药技术领域，尤其涉及一种提高机体免疫力、促进胃肠道健康的透明质酸或其盐的组合物及其应用。
背景技术
透明质酸(HA)是一种由D-葡萄糖醛酸及N-乙酰氨基葡糖的双糖单位重复连接构成的酸性黏多糖，广泛存在于动物的组织细胞间质和某些细菌的荚膜中。目前，透明质酸已广泛应用于化妆品、医药等领域，随着国内外对透明质酸的深入研究和了解，其在食品领域，尤其是功能性食品中的应用也展现出广泛而独特的价值。
突如其来的新冠肺炎在全球蔓延，目前多数国家对疫情并未实现有效的控制。在这种情况下，加强常态化防控，提高机体自身免疫能力成为预防新冠肺炎、抵御疾病的关键。免疫力是人体自身的防御机制，是人体识别和消灭外来侵入的任何异物(病毒、细菌等)、处理损伤、衰老、死亡、变性的自身细胞以及识别和处理体内突变细胞和病毒感染细胞的能力。提高免疫力是人体识别和排除“异己”的生理反应，可以通过一定的方式来增强，除了要进行锻炼，还可多食用有益食品，尤其是具有调节免疫因子、提高抵抗力的功能性食品。
胃肠道，是人体最大的免疫和排毒器官，对健康有着举足轻重的影响。人体70％以上的免疫细胞都位于胃肠黏膜上，使肠道构成了一道免疫屏障，以抵御细菌、病毒，并维持肠道内环境的稳定。然而近年来，胃肠道疾病的发病率却越来越高，如胃肠道炎症、胃肠道结石、胃溃疡、肠道菌群失调等，越来越多的人正在饱受肠道疾病折磨之苦。因此，开发促进肠道健康的原料及产品，具有预防缓解肠道炎症、促进肠道蠕动、调节肠道菌群的作用，能够满足市场的需求、人们的需要，同时也具有可观的经济效益。
目前人们对HA的研究越来越深入，HA作为功能性原料对于提高人体 免疫力具有一定的效果。中国专利申请CN1498626A透明质酸在提高人体免疫力、改善免疫力缺乏症状方面的应用介绍了以透明质酸为功效成分的组合物，产品无毒害作用，在小鼠试验及人体实验中均具有提高免疫力的作用，但对透明质酸的具体使用分子量并未叙述，未能体现出不同分子量透明质酸的功能，参考价值较低。中国专利CN108498549B用于改善免疫功能的组合物及其应用介绍了一种透明质酸与乳酸菌的混合物，用于缓解和治疗由抗肿瘤化疗诱发的并发症，降低化疗药物副作用，改善免疫力低下的状况。该方法需要与乳酸菌复合发生作用，乳酸菌需制备成冻干菌粉，组合物还需添加其他辅料，如冻干保护剂、成型剂。操作复杂，添加物质种类繁多，未能充分发挥不同分子量透明质酸的功效。
另外，在促进胃肠道健康方面，HA也有一定的效果。俄克拉荷马大学健康科学中心研究表明35kDa的HA能增强上皮屏障功能，防止小鼠坏死性小肠结肠炎的发生。国内也有相关文献报道，在致病菌(李斯特菌、柠檬酸杆菌、肠致病性大肠杆菌)引起的小鼠肠道感染中，使用530kDa的透明质酸处理能发挥保护作用。这些实验使用单一分子量的HA，作用效果单一。
因此，为解决单一分子量HA的功效单一问题，本申请拟提供一种成分明确、作用效果显著的HA复合物及其产品，以充分发挥透明质酸在提高免疫力、保护胃肠道健康方面的作用。
发明内容
鉴于上述问题，本申请提供了一种用于提高机体免疫、促进胃肠道健康的透明质酸或其盐的组合物，该组合物以不同分子量的透明质酸或其盐为成分，根据不同分子量的透明质酸所具有的功能不同，通过协同增效实现对免疫力的调节，提高抵御胃肠道炎症的能力、促进肠道蠕动及肠道益生菌生长等。
本申请具体技术方案如下：
1、一种含有透明质酸或其盐的组合物，其包含三种分子量透明质酸或其盐，其中，
所述第一种分子量透明质酸或其盐的分子量为10k-200kDa，优选为10k-100kDa，进一步优选为30k-50kDa；
所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa，优选为 200k-600kDa，进一步优选为200k-400kDa；
所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，优选为1300k-1500kDa。
2、项1所述的组合物，其中，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
3、项1-2中任一项所述的组合物，其中，所述透明质酸或其盐选自透明质酸、透明质酸钠、透明质酸钾、透明质酸钙和透明质酸锌的一种或两种以上，优选为透明质酸钠或透明质酸钾。
4、项1-3中任一项所述的组合物在食品、保健品或药品领域中的应用。
5、一种食品组合物，其包含项1-3中任一项所述的组合物。
6、项5所述的食品组合物，其中，所述食品组合物用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群。
7、一种保健品组合物，其包含项1-3中任一项所述的组合物。
8、项7所述的食品组合物，其中，所述保健品组合物用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群。
9、一种药品组合物，其包含项1-3中任一项所述的组合物。
10、项9所述的药品组合物，其中，所述药品组合物用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群。
11.一种提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的方法，其包括向受试者施用项1-3中任一项的组合物。
12.项1-3中任一项的组合物在用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的用途。
13.项1-3中任一项的组合物在用于制备提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的药物的用途。
发明的效果
1.本申请所提供的组合物，成分明确，操作简单，便于配制及使用。
2.本申请所提供的组合物，对提高机体免疫力、缓解胃肠道炎症、促 进肠道蠕动、肠道益生菌生长及保护胃黏膜等有显著效果，可作为功效成分添加于食品及保健类食品中，也可作为辅料，与药物联合使用。
具体实施方式
下面对本申请做以详细说明。虽然显示了本申请的具体实施例，然而应当理解，可以以各种形式实现本申请而不应被这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解本申请，并且能够将本申请的范围完整的传达给本领域的技术人员。
需要说明的是，在说明书及权利要求当中使用了某些词汇来指称特定组件。本领域技术人员应可以理解，技术人员可能会用不同名词来称呼同一个组件。本说明书及权利要求并不以名词的差异作为区分组件的方式，而是以组件在功能上的差异作为区分的准则。如在通篇说明书及权利要求当中所提及的“包含”或“包括”为开放式用语，故应解释成“包含但不限定于”。说明书后续描述为实施本申请的较佳实施方式，然而所述描述乃以说明书的一般原则为目的，并非用以限定本申请的范围。本申请的保护范围当视所附权利要求所界定者为准。
本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量的透明质酸或其盐。
所述第一种分子量透明质酸或其盐的分子量为10k-200kDa，优选为10k-100kDa，进一步优选为30k-50kDa；；
所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa，优选为200k-600kDa，进一步优选为200k-400kDa；以及
所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，优选为1300k-1500kDa。
在本申请中，所述分子量指的是重均分子量。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物， 其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸 或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量 为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa。
例如，所述第一种分子量透明质酸或其盐的分子量可以为10kDa、20kDa、30kDa、40kDa、50kDa、60kDa、70kDa、80kDa、90kDa、100kDa、160kDa、200kDa等；
所述第二种分子量透明质酸或其盐的分子量可以为200kDa、280kD、300kDa、400kDa、500kDa、600kDa、700kDa、800kDa、900kDa、1000kDa等；
所述第三种分子量透明质酸或其盐的分子量可以为1000kDa、1100kDa、1200kDa、1300kDa、1350kDa、1400kDa、1500kDa等。
在一个实施方案中，其中，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
例如，以重量份计，混合后总份数为10份，
所述第一种分子量透明质酸或其盐可以为1份、2份、3份、4份等；
所述第二种分子量透明质酸或其盐可以为3份、4份、5份、6份等；
所述第三种分子量透明质酸或其盐可以为1份、2份、3份等。
在上述的具体的实施方案中，例如称取1-4份，优选为2-4份的第一种分子量透明质酸或其盐3份、称取3-6份，优选为4-6份的第二种分子量透明质酸或其盐5份，以及称取1-3份的第三种分子量透明质酸或其盐2份混合得到本文所述的含有透明质酸或其盐的组合物。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为 1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-100kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量 为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸 或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为10k-200kDa；所述第二种分子量透明质酸或其盐的分子量为200k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物， 其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-600kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，本申请提供了一种含有透明质酸或其盐的组合物，其包含三种不同分子量透明质酸或其盐，其中，所述第一种分子量透明质酸或其盐的分子量为30k-50kDa；所述第二种分子量透明质酸或其盐的分子量为20k-400kDa；以及所述第三种分子量透明质酸或其盐的分子量为1300k-1500kDa，以混合后总份数为10重量份计，
所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
所述第三种分子量透明质酸或其盐比例为1-3份。
在一个实施方案中，所述透明质酸或其盐选自透明质酸、透明质酸钠、透明质酸钾、透明质酸钙和透明质酸锌中的一种或两种以上，优选为透明质酸钠或透明质酸钾。
本申请提供了上述所述的组合物在食品、保健品或药品领域中的应用。
通过将上述所述的组合物应用到食品、保健品或药品领域中，能够提高机体的免疫能力、缓解胃肠道炎症、促进肠道蠕动及肠道益生菌生长。
本申请提供了一种食品组合物，其包含上述所述的组合物。
在一个实施方案中，所述食品组合物还可以包括辅料，所述辅料例如可以为防腐剂、食用色素、调味剂、乳化剂、香料等。
本申请提供了一种保健品组合物，其包含上述所述的组合物。
在一个实施方案中，所述保健品组合物还可以包括辅料，例如可以为防腐剂、食用色素、调味剂、乳化剂、香料等。
本申请提供了一种药品组合物，其包含上述所述的组合物。
在一个实施方案中，所述药物组合物还可以包括辅料，所述辅料例如可以为润滑剂、粘合剂、着色剂、稀释剂、吸收剂等。
在本申请中，所述辅料指的是通常无毒、惰性和/或生理学相容的组合物或组合物组分。
上述所述的食品组合物、保健品组合物、药品组合物的剂型不受限制，例如可以为固体形式、半固体形式或者液体形式等。
本申请提供了一种提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的方法，其包括向受试者施用上述所述的组合物。
在本申请中，对于施用的方法，本申请不作任何限制，例如可以为口服给药的方式进行给药。
在本申请中，对于受试者，其是指任何动物(例如哺乳动物)，包括但不限于人、非人灵长类动物、犬科动物、猫科动物、啮齿动物等。
本申请提供了上述所述的组合物在用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的用途。
本申请提供了上述所述的组合物在用于制备提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的药物的用途。
实施例
本申请对试验中所用到的材料以及试验方法进行一般性和/或具体的描述，在下面的实施例中，如果无其他特别的说明，％表示wt％，即重量百分数。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品，其中，第一种分子量透明质酸或其盐、第二种分子量透明质酸或其盐以及第三种分子量透明质酸或其盐均由华熙生物科技股份有限公司提供。
实施例1
将分子量为40kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠、以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例2
将分子量为40kDa的第一种分子量透明质酸钠、分子量为600kDa的第二种分子量透明质酸钠以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例3
将分子量为40kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠以及分子量为1000kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2混合，充分混匀待用。
实施例4
将分子量为160kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠、以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例5
将分子量为160kDa的第一种分子量透明质酸钠、分子量为600kDa的第二种分子量透明质酸钠、以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例6
将分子量为160kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠、以及分子量为1000kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例7
将分子量为40kDa的第一种分子量透明质酸钠、分子量为600kDa的第二种分子量透明质酸钠、以及分子量为1000kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例8
将分子量为160kDa的第一种分子量透明质酸钠、分子量为600kDa的第二种分子量透明质酸钠、以及分子量为1000kDa的第三种分子量透明质酸钠按质量比例为3﹕5﹕2进行混合，充分混匀待用。
实施例9
将分子量为40kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠、以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为3﹕6﹕1进行混合，充分混匀待用。
实施例10
将分子量为40kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠、以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为2﹕5﹕3进行混合，充分混匀待用。
实施例11
将分子量为40kDa的第一种分子量透明质酸钠、分子量为280kDa的第二种分子量透明质酸钠、以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为1﹕3﹕1进行混合，充分混匀待用。
对比例1
将分子量为40kDa的第一种分子量透明质酸钠按每个实验所需浓度溶 于生理盐水中，完全溶解后备用。
对比例2
将分子量为1350kDa的第三种分子量透明质酸钠按每个实验所需浓度溶于生理盐水中，完全溶解后备用。
对比例3
将分子量为40kDa的第一种分子量透明质酸钠以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为3﹕2进行混合，充分混匀待用。
对比例4
将分子量为280kDa的第二种分子量透明质酸钠按每个实验所需浓度溶于生理盐水中，完全溶解后备用。
对比例5
将分子量为280kDa的第二种分子量透明质酸钠以及分子量为1350kDa的第三种分子量透明质酸钠按质量比例为5﹕2进行混合，充分混匀待用。
对比例6
将分子量为80kDa透明质酸钠按每个实验所需浓度溶于生理盐水中，完全溶解后备用。
对比例7
将分子量为40kDa的第一种分子量透明质酸钠以及分子量为280kDa的第二种分子量透明质酸钠按质量比例为3﹕5进行混合，充分混匀待用。
表1实施例和对比例所用组分的用量表
Figure PCTCN2022129773-appb-000001
Figure PCTCN2022129773-appb-000002
实验材料
实验所用的斑马鱼不同品系均由山东省科学院生物研究所斑马鱼药物筛选平台提供；透明质酸样品由华熙生物科技股份有限公司提供。
仪器与设备
SZX16型荧光显微镜及DP2-BSW图像采集系统(日本Olympus公司)；Forma 3111型水套式CO2培养箱(美国Forma公司)；斑马鱼养殖饲养设备(北京爱生科技公司)
实验例1调节免疫力实验
以斑马鱼品系Tg(lyz：GFP)为模型，在受精卵发育48hpf(hour post fertilization)后，以免疫抑制剂氯霉素进行处理造成免疫抑制模型，并加入透明质酸样品进行处理，样品处理24h后，在荧光显微镜下观察，并拍照，统计免疫细胞的数目，使用GraphPad软件对数据进行统计分析，其结果如表2所示。
表2透明质酸组合物对斑马鱼免疫细胞的影响
组别 剂量(μg/mL) 免疫细胞数目(个)
对照组 200 55.4±4.06
模型组 200 29.4±3.68 ##
实施例1 200 54.2±6.31 **
实施例2 200 49.0±3.09 **
实施例3 200 46.4±4.76 **
实施例4 200 48.5±1.07 **
实施例5 200 47.3±2.68 **
实施例6 200 45.2±2.02 **
实施例7 200 45.9±5.18 **
实施例8 200 44.0±6.00 **
实施例9 200 50.2±1.80 **
实施例10 200 53.1±3.09 **
实施例11 200 51.7±2.24 **
对比例1 200 37.6±1.86
对比例2 200 40.5±3.07 *
对比例3 200 42.0±1.89 *
对比例4 200 36.2±4.03
对比例5 200 41.3±2.97 *
对比例6 200 32.3±2.11
对比例7 200 40.9±3.04
注：与对照组比较，#：P<0.05，有显著性；##：P<0.01，极显著性。与模型组比较，*：P<0.05，有显著性；**：P<0.01，极显著性。
从表2可以看出，与对照组相比，模型组的免疫细胞紊乱且数目显著降低，说明模型建造成功；与模型组相比，样品组斑马鱼免疫细胞数目显著增加，尤其是实施例1效果最好，10、11、9、2效果次之，说明给斑马鱼喂食透明质酸组合物会显著改善其免疫活力。
实验例2调节肠道蠕动活性实验
采用发育5dpf(day post fertilization)的野生AB系斑马鱼作为实验动物，研究透明质酸样品对肠道蠕动的影响。钙黄绿素对斑马鱼肠道预染色后，计算得到其肠道的荧光强度(IOD)均值。随后将样品与预染斑马鱼避光共孵育，并计算样品处理后斑马鱼肠道的IOD，根据公式：肠道IOD系数＝(样品处理前肠道IOD均值-样品处理后肠道IOD均值)/样品处理前肠道IOD均值，计算得到样品处理组斑马鱼的肠道IOD系数，并做统计学分析，其结果如表3所示。
表3透明质酸组合物对斑马鱼肠道蠕动的影响实验
组别 剂量(μg/mL) 肠道IOD系数
对照组 200 0.41±0.024
实施例1 200 0.87±0.015 **
实施例2 200 0.77±0.034 **
实施例3 200 0.76±0.036 **
实施例4 200 0.75±0.021 **
实施例5 200 0.70±0.022 *
实施例6 200 0.65±0.039 *
实施例7 200 0.70±0.060 *
实施例8 200 0.62±0.073 *
实施例9 200 0.80±0.053 **
实施例10 200 0.84±0.044 **
实施例11 200 0.82±0.046 **
对比例1 200 0.52±0.013
对比例2 200 0.52±0.032
对比例3 200 0.56±0.017
对比例4 200 0.49±0.042
对比例5 200 0.54±0.032
对比例6 200 0.43±0.016
对比例7 200 0.53±0.022
注：与对照组比较，*：P<0.05，有显著性；**：P<0.01，极显著性。
由表3可以看出，与空白对照组相比，样品组斑马鱼肠道内荧光染料明显降低，尤其是实施例1效果最好，10、2、9、11效果次之，说明透明质酸组合物能够促进肠道蠕动。
实验3促进肠道益生菌生长实验
选取肠道益生菌群乳杆菌属中的鼠李糖乳杆菌、瑞士乳杆菌等为出发菌株。以乳杆菌常规培养基MRS为基础培养基。透明质酸或其盐样品为培养基体积的0.2％(w/v)，阴性对照为无糖MRS培养基，阳性对照为与HA相同浓度的葡萄糖MRS培养基。检测不同培养时间的菌体浓度(A 600)，共选取了8株肠道益生菌进行体外增殖实验，其结果如表4所示。
表4透明质酸组合物对益生菌生长(OD 600)的影响
Figure PCTCN2022129773-appb-000003
Figure PCTCN2022129773-appb-000004
注：与对照组比较，*：P<0.05，有显著性；**：P<0.01，极显著性。
从表4可以看出，HA混合物对八株益生菌均有不同程度的促生长效果。以12h的数据为例，与空白对照组相比，供试样品能有效增加肠道益生菌的浓度及活菌数，尤其是实施例1效果最好，10、11、9、2效果次之，说明透明质酸组合物具有促进肠道益生菌生长的功能。
实验4缓解肠道炎症实验
以发育3dpf的免疫细胞被特异标记的荧光斑马鱼为试验动物，将其随机分成空白对照组、模型组与不同样品组。空白对照组中不添加任何药物与待测物，模型组与不同样品组中分别同时添加终浓度为50μg/mL的三硝基苯磺酸(TNBS)，每组10尾仔鱼，同时设置2个复孔。将上述各组斑马鱼均置于28.5℃的恒温培养箱中，避光连续孵育3天。结束后清洗各组仔鱼，并将空白对照组与模型组仔鱼分别置于新培养水中，其他组仔鱼置于含100μg/mL不同待测样品的培养水中，28.5℃继续培养3d。处理结束后，利用Imagepro-plus软件统计斑马鱼肠道部位显示红色荧光的免疫细胞的数量，并使用GraphPad软件对数据进行统计分析。
表5透明质酸组合物对胃肠道炎症的影响
组别 剂量(μg/mL) 免疫细胞数量
对照组 100 19.9±0.936
模型组 100 28.9±1.441 ##
实施例1 100 20.3±0.615 *
实施例2 100 18.5±1.441 **
实施例3 100 18.2±1.013 **
实施例4 100 17.7±0.775 **
实施例5 100 19.2±1.114 *
实施例6 100 18.9±1.174 *
实施例7 100 19.9±0.900 *
实施例8 100 20.5±1.062 *
实施例9 100 19.9±0.632 *
实施例10 100 17.2±0.791 **
实施例11 100 19.2±0.466 *
对比例1 100 24.7±0.800
对比例2 100 24.2±1.012
对比例3 100 23.5±1.061
对比例4 100 22.7±1.067
对比例5 100 22.3±1.078
对比例6 100 25.5±0.614
对比例7 100 23.4±0.723
注：与对照组比较，##：P<0.01，极显著性。与模型组比较，*：P<0.05，有显著性；**：P<0.01，极显著性。
由表5可以看出，与空白对照组相比，模型组斑马鱼肠道部位免疫细胞的数量明显增加，且具有显著的统计学意义；该结果说明，当斑马鱼处于肠道炎症状态下时，机体内的免疫细胞会向炎症部位迁移。当不同待测样品分别处理斑马鱼后，与模型组相比，肠道部位免疫细胞的数量均有所减少，且具有极其显著的统计学意义；该结果说明，供试品在不同程度缓解了斑马鱼肠道部位的炎症状态，因此向斑马鱼肠道部位迁移的免疫细胞数量也随之减少。
综上所述，使用本申请所述的组合物能显著改善免疫紊乱斑马鱼的免疫细胞数目，提高免疫活力，能促进肠道蠕动，提高多种肠道益生菌的存活率，改善肠道菌群，能显著缓解肠道炎，说明本申请所述的组合物对提高免疫力、保护胃肠道有显著效果，可作为功效成分添加于食品及保健类食品中，或与药物联合使用。
以上所述，仅是本申请的较佳实施例而已，并非是对本申请作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本申请技术方案内容，依据本申请的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本申请技术方案的保护范围。

Claims (13)

  1. 一种含有透明质酸或其盐的组合物，其包含三种分子量透明质酸或其盐，其中，
    所述第一种分子量透明质酸或其盐的分子量为10k-200kDa，优选为10k-100kDa，进一步优选为30k-50kDa；
    所述第二种分子量透明质酸或其盐的分子量为200k-1000kDa，优选为200k-600kDa，进一步优选为200k-400kDa；
    所述第三种分子量透明质酸或其盐的分子量为1000k-1500kDa，优选为1300k-1500kDa。
  2. 根据权利要求1所述的组合物，其中，以混合后总份数为10重量份计，
    所述第一种分子量透明质酸或其盐为1-4份，优选为2-4份；
    所述第二种分子量透明质酸或其盐为3-6份，优选为4-6份；以及
    所述第三种分子量透明质酸或其盐比例为1-3份。
  3. 根据权利要求1-2中任一项所述的组合物，其中，所述透明质酸或其盐选自透明质酸、透明质酸钠、透明质酸钾、透明质酸钙和透明质酸锌的一种或两种以上，优选为透明质酸钠或透明质酸钾。
  4. 权利要求1-3中任一项所述的组合物在食品、保健品或药品领域中的应用。
  5. 一种食品组合物，其包含权利要求1-3中任一项所述的组合物。
  6. 根据权利要求5所述的食品组合物，其中，所述食品组合物用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群。
  7. 一种保健品组合物，其包含权利要求1-3中任一项所述的组合物。
  8. 根据权利要求7所述的食品组合物，其中，所述保健品组合物用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群。
  9. 一种药品组合物，其包含权利要求1-3中任一项所述的组合物。
  10. 根据权利要求9所述的药品组合物，其中，所述药品组合物用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群。
  11. 一种提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠 道菌群的方法，其包括向受试者施用权利要求1-3中任一项所述的组合物。
  12. 权利要求1-3中任一项所述的组合物在用于提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的用途。
  13. 权利要求1-3中任一项所述的组合物在用于制备提高机体免疫能力、缓解肠道炎症、增加肠道蠕动和/或调节肠道菌群的药物的用途。
PCT/CN2022/129773 2021-11-04 2022-11-04 提高机体免疫力、促进胃肠道健康的含透明质酸或其盐的组合物及其应用 WO2023078378A1 (zh)

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