WO2018062354A1 - Intestinal microbiota improving agent and intestinal microbiota improving composition that include eggshell membrane–containing powder - Google Patents

Intestinal microbiota improving agent and intestinal microbiota improving composition that include eggshell membrane–containing powder Download PDF

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Publication number
WO2018062354A1
WO2018062354A1 PCT/JP2017/035121 JP2017035121W WO2018062354A1 WO 2018062354 A1 WO2018062354 A1 WO 2018062354A1 JP 2017035121 W JP2017035121 W JP 2017035121W WO 2018062354 A1 WO2018062354 A1 WO 2018062354A1
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Prior art keywords
eggshell membrane
intestinal flora
powder
composition
improving
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PCT/JP2017/035121
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French (fr)
Japanese (ja)
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長谷部　由紀夫
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株式会社 アルマード
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Priority claimed from JP2016190536A external-priority patent/JP7086517B2/en
Priority claimed from JP2016190537A external-priority patent/JP2018052855A/en
Application filed by 株式会社 アルマード filed Critical 株式会社 アルマード
Publication of WO2018062354A1 publication Critical patent/WO2018062354A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • 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
    • A61K35/56—Materials from animals other than mammals
    • A61K35/57—Birds; Materials from birds, e.g. eggs, feathers, egg white, egg yolk or endothelium corneum gigeriae galli
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/148—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an intestinal flora improving agent and a composition for improving intestinal flora containing eggshell membrane-containing powder or fine powder as an active ingredient. Further, the present invention relates to a composition for improving intestinal flora and promoting the formation of type III collagen, which comprises eggshell membrane-containing powder or fine powder and a hydrolyzed eggshell membrane component.
  • the eggshell membrane is a membrane inside the eggshell of avian egg such as a chicken egg and consists of 2 sheets inside and outside, the outer shell membrane is in close contact with the inner surface of the eggshell, and the inner shell is wrapped in egg white and has antibacterial properties , Protecting developing embryos from infection.
  • Eggshell membrane has a network-like structure composed of type I, type V and type X collagen, glucosamine, desmosine and tough fibrous proteins mainly composed of hyaluronic acid, and these proteins contain cysteine Are relatively stable to acids, alkalis, and proteases, and insoluble in water.
  • eggshell membrane powder is pulverized using a jet mill so that the volume average particle size is 6 ⁇ m or less or the volume maximum particle size is 20 ⁇ m (800 mesh) or less. It has been proposed to powderize (patent document 1).
  • hydrolyzing hydrolyzed eggshell membrane obtained by hydrolyzing protein is dried and powdered for improvement of handling property and storage stability (Patent Document 2), and alkalinity It has been proposed to increase the storage stability and safety by setting the pH of the hydrolyzed eggshell membrane powder to 3 to 6 (Patent Document 3).
  • the present invention is highly safe, can be used daily as a food additive, food and drink, supplement, medicine as a simple and convenient method, and intestinal flora that can improve or maintain the living body in a good condition with a single material.
  • An object of the present invention is to provide a remedy or a composition for improving intestinal flora.
  • it has a function to promote the formation of type III collagen, and provides a composition capable of improving and / or maintaining the living body in a better state by the synergistic effect of both functions. To be an issue.
  • Eggshell membrane or hydrolysed eggshell membrane is not only for skin softening, skin regeneration, hair growth promotion, hair loss prevention, etc., but also for daily health promotion and health maintenance such as elimination of stiff shoulder, enhancement of appetite, fatigue recovery, etc. It is considered to be effective.
  • eggshell membrane-containing fine powder Patent Document 1
  • hydrolyzed eggshell membrane powder Patent Documents 2 and 3
  • Eggshell membrane-containing fine powder (patent document 1) and hydrolyzed eggshell membrane powder are known to have a function of promoting the formation of type III collagen in the body when digested and absorbed in the body There is.
  • the hydrolyzed eggshell membrane is almost 100% digested and absorbed in the blood, the eggshell membrane-containing powder and fine powder remain in the intestine without digestion and absorption of about 54%.
  • the remaining components prevent the growth of bad bacteria among enteric bacteria and improve the enteric flora, and have completed the present invention.
  • a hydrolyzed eggshell membrane component having a function of further promoting the formation of type III collagen and an eggshell membrane-containing powder or fine powder, than an eggshell membrane-containing powder or fine powder which is only about 46% digested and absorbed
  • the function to improve the internal flora and the function to promote the formation of type III collagen act synergistically to improve the immune function by improving the intestinal flora, and to prevent the development of adult diseases such as cancer, as well as to promote the generation of type III collagen
  • the strengthening of blood vessel, lung, liver and skin tissues has resulted in the completion of a composition that has an enhanced anti-aging effect and can further improve and / or maintain good health.
  • the present invention is summarized as an intestinal flora improving agent containing an eggshell membrane-containing powder as an active ingredient.
  • the present invention also provides a composition for improving intestinal flora, which comprises an eggshell membrane-containing powder as an active ingredient.
  • mice challenged with colitis with DSS after ingestion of eggshell membrane-containing fine powder supplementation prevalence of enterobacteria The result after 17 days by the oral intake experiment of the hydrolysis eggshell membrane powder supplement using a mouse. The expression level in skin of a type III collagen gene by real time PCR is shown.
  • enteric bacteria Hundreds of enteric bacteria are inhabited in a balanced manner in human intestine in a balance of about 100 trillion or more.
  • useful bacteria such as lactic acid bacteria and bifidobacteria (good bacteria) such as E. coli and clostridial bacteria Harmful bacteria (bad bacteria) and opportunistic bacteria form a kind of ecosystem (gut flora) while maintaining balance with each other in the intestine.
  • the enteric flora improvement agent which can be ingested easily and routinely can be provided in various uses, such as a food additive, food-drinks, a supplement, and a pharmaceutical.
  • the intestinal flora improving agent of the present invention is nonirritating, can be used in various forms in combination with various components, and can be easily tableted. It can also be used in combination with nutritional and cosmetic ingredients to obtain further systemic effects.
  • the intestinal flora improving function of the eggshell membrane-containing powder or fine powder and the function of promoting the formation of type III collagen and the hydrolyzed eggshell membrane component acts synergistically to enhance the skin-beautifying effect and anti-aging effect by promoting the formation of type III collagen in blood vessels, lungs, liver, skin etc. and improving intestinal flora. Health condition can be improved and / or well maintained.
  • This composition can be used in various forms as food additives, food and drink, supplements, edible cosmetic agents and medicines, and when hydrolyzed eggshell membrane powder is used as the hydrolyzed eggshell membrane component, tableting is easy. Can be done.
  • the intestinal flora improving agent or composition for improving intestinal flora according to the present invention contains eggshell membrane-containing powder as an active ingredient, and in experiments using rats, 46% of ingested eggshell membrane-containing fine powder is digested Absorbed, the rest remained in the intestine without absorption. It is demonstrated in Example 1 that this remaining component can increase intestinal bacterial diversity and reduce the number of pathogenic bacteria such as E. coli.
  • any membrane can be used as long as it is inside the eggshells of all terrestrial egg live animals, particularly avian eggs.
  • eggshell membranes of hen eggs are preferable in terms of availability and cost.
  • the eggshell membrane-containing powder used in the present invention is not particularly limited as long as it is a powder containing at least an eggshell membrane, and the powder refers to any powder regardless of the particle size.
  • the raw material in a state in which the eggshell membrane is attached to the exfoliated eggshell membrane or eggshell may be powdered by any known method. Alternatively, a commercially available eggshell membrane-containing powder may be used.
  • the eggshell membrane-containing fine powder to be used in the present invention refers to powder having a volume maximum particle size and / or a volume average particle size smaller than about 100 ⁇ m.
  • “volume average particle diameter” and “volume maximum particle diameter” of powder or fine powder mean values measured using a laser diffraction type particle size distribution analyzer (manufactured by Seishin Co., Ltd., LMS-30). Do. When measuring the particle size, a measurement sample in which eggshell membrane-containing fine powder is dispersed in water using a surfactant is used.
  • volume average particle diameter means the particle diameter in 50% of the cumulative value from the small particle diameter side in particle size distribution.
  • eggshell membrane-containing fine powder to be used in the present invention one having a volume average particle size of 6 ⁇ m or less, or a volume maximum particle size of 20 ⁇ m or less is particularly preferable from the viewpoint of digestive and absorption efficiency. It is preferable to manufacture eggshell membrane containing raw materials, such as a commercially available eggshell membrane containing powder, by a pulverization process using a jet mill in which they collide with each other in gas.
  • the hydrolyzed eggshell membrane component used in the present invention is a solution having a protein degrading action such as an aqueous acid solution, an alkaline aqueous solution, an alkaline organic solvent solution, and a proteinase-containing solution, as the eggshell membrane or the aforementioned eggshell membrane-containing powder It is obtained by hydrolysis in vacuo. Although it can also be used as an aqueous solution or an extract, it is preferably in the form of a powder obtained by a drying means such as spray drying or lyophilization for handling and storage stability. As the hydrolyzed eggshell membrane powder, a powder having a pH of 3 to 6 is particularly preferable in view of storage stability and safety.
  • the human skin is composed of an epithelial layer on the surface and a connective tissue-like dermal layer below it, and the protein constituting the dermal layer is mainly collagen, and is also composed of elastin, albumin, globulin and mucin.
  • Collagen constituting the dermal layer is mainly ⁇ 1 (I) collagen and ⁇ 1 (III) collagen (hereinafter referred to as "type III collagen"), type I collagen mainly maintains the skin structure, type III collagen It plays different functions mainly from the application of skin softness.
  • type III collagen is also called fetal collagen, it is most abundant in the case of the fetus and more in the case of fetal skin with type III collagen, but begins to decrease from the 10s and continues to decrease, so type III collagen in the skin If you can increase the rate of aging, you can stop the aging of the skin with age and make the skin smooth and moist.
  • type III collagen is contained in connective tissues such as blood vessels, lungs and liver.
  • the eggshell membrane-containing fine powder not only promotes the formation of type III collagen in the skin but also promotes the generation of type III collagen in blood vessels by the amino acid component that is absorbed and absorbed and absorbed into the blood by about 46%.
  • the elasticity of the whole blood vessel can be increased, and fibrosis can be suppressed even in the liver.
  • About 46% of the eggshell membrane-containing fine powder is digested and absorbed, and about 100% of the hydrolyzed eggshell membrane component is digested and absorbed, and the eggshell membrane component taken up into the blood only promotes the formation of type III collagen in the skin
  • the blood vessels can promote the formation of type III collagen to increase the elasticity of the whole blood vessels, but also can suppress fibrosis in the liver.
  • Both the eggshell membrane component-containing powder and the hydrolyzed eggshell membrane component used in the present invention have a function to promote the formation of type III collagen when digested and absorbed, but the hydrolyzed eggshell membrane component is almost 100% digested and absorbed. Was found to be more effective.
  • the combined use of the eggshell membrane component-containing powder and the hydrolyzed eggshell membrane component not only enhances the formation promoting effect of type III collagen, but also combines with the improvement effect of intestinal flora to synergistically make the skin beautify and prevent aging
  • the composition preferably contains 10 to 90% by weight of eggshell membrane-containing fine powder and 90 to 10% by weight of hydrolyzed eggshell membrane powder.
  • the composition of the present invention can be an oral composition such as tablets, powders, granules, capsules, solutions and the like.
  • oral compositions such as tablets, powders, granules, capsules, solutions and the like.
  • various components and production methods for producing oral compositions of various dosage forms are appropriately selected from components known in the field of production of supplements, pharmaceuticals, etc. be able to.
  • the content of the eggshell membrane-containing powder contained in the tablet of the present invention is not particularly limited, but the total of the eggshell membrane-containing powder and the hydrolyzed eggshell membrane powder contained in the tablet of the present invention
  • the content of.) Is not particularly limited, but the granulation and tableting to particles can be smoothly performed, and the intestinal flora improving effect and the type III collagen formation promoting effect are further enhanced when the tablet is ingested, etc.
  • excipient a binder, a disintegrant, a lubricant, other nutrients, etc. can be added to the tablet of this embodiment as various additives for forming a tablet.
  • excipient known excipients can be appropriately used, but at least one of modified starch and lactose may be used in an amount of 0.3 to 3 times the weight of the eggshell membrane component from the viewpoint of formability. Preferably, it is more preferably 1 to 2.5 times.
  • modified starch one or more kinds of dextrin such as roasted dextrin, oxidized starch, low viscosity modified starch and the like can be used.
  • the use ratio is preferably 1: 5 to 5: 1.
  • known binders can be suitably used, and examples thereof include starch paste, gum arabic paste, hydroxypropyl cellulose and the like.
  • disintegrant known disintegrants can be suitably used, and for example, celluloses can be used.
  • lubricant known lubricants can be appropriately used, and examples thereof include magnesium stearate, sucrose fatty acid ester, waxes, talc, vitamin C and the like.
  • the tablet of the present embodiment preferably contains eggshell calcium as a hardness improver in order to increase the hardness of the tablet to prevent deformation and damage and to improve the handleability.
  • Eggshell calcium is a fine powder obtained by crushing and drying eggshells of birds such as chicken eggs, and the content of eggshell calcium contained in the tablet is preferably 0.1 to 20% by weight, more preferably 0.5 to It is 15% by weight.
  • a well-known coating film can be used suitably for a coating film, For example, brand name "sealac" (made by Gifu shellac KK) can be used.
  • the tablet of the present embodiment may be coated with a sugar coating, may be colored, and may be subjected to polishing after coloring.
  • the size of the tablet of the present embodiment is not particularly limited, but in general, it is preferable from the viewpoint of handleability and ease of administration that the tablet has a circular or oval shape with a diameter of about 7 to 10 mm.
  • the weight of one tablet is about 350 to 600 mg, and the eggshell membrane component is preferably contained in about 10 to 240 mg, more preferably about 20 to 150 mg. If the eggshell membrane component is contained in an amount of about 10 to 240 mg, the adult can take 1 to 200 tablets per day (10 to 48,000 mg of eggshell membrane component per day).
  • the tablet of this embodiment can be manufactured by a known tablet manufacturing method using a raw material for tableting containing at least eggshell membrane-containing fine powder and hydrolyzed eggshell membrane powder. For example, through a tableting process of forming raw tablets by tableting to form a plain tablet, if necessary, a granulation process, a protective coating process, a sugar coating process, etc. are performed, and further coloring and polishing are performed. It is also good.
  • the effective dose of the pharmaceutical preparation as the intestinal flora improving agent of the present invention, the effective dosage of the pharmaceutical as the composition for intestinal flora improvement of the present invention, the degree of symptoms to be treated or prevented, administration It varies according to the condition (including age and gender) and dosage form of the subject.
  • the oral dose of such a medicament to a human is preferably 1 to 100,000 mg per day, in terms of eggshell membrane components.
  • the effective dose can be a total of 10 to 48,000 mg of eggshell membrane components per day, preferably, 20 to 3,500 mg. Since the eggshell membrane-containing component of the present invention is highly safe and there is no concern about side effects, there is no problem if the amount taken or applied exceeds the above range, as long as other components are appropriately selected.
  • composition of the present invention can be a food additive such as confectionery, beverage, health food, preserved food, processed food and the like.
  • the subjects of “pharmaceutical” and “food and drink” are not limited to humans, but also include pharmaceuticals and feeds for mammals such as pets and livestock.
  • the concept of "food and drink” includes enteral nutrition food, nutritive function food, functional display food, food for specified health use, etc. in addition to ordinary food and drink.
  • the volume maximum particle size is 19.6 ⁇ m
  • the volume average particle size is 5.8 ⁇ m (hereinafter referred to as It is called "800 mesh fine powder”.
  • mice Normal control mice (CON group) were fed with AIN-93G basal regular diet and normal drinking water throughout the course of the experiment. 8% eggshell membrane 800 mesh fine powder fortified feed was adjusted with corn starch and casein to maintain calories and protein balance.
  • the disease activity index (DAI) was monitored daily from the day of receiving DSS water, using three scores of mouse weight, stool firmness and blood stool.
  • mice in the DSS group had the lowest bacterial species abundance among the three groups ( Figure 2). This result was as expected, as the bacterial species in the gut is reduced, correlating with disease states including inflammatory bowel disease in humans and DSS-induced colitis in mice, but surprisingly, the eggshell membrane The intake restored the bacterial species abundance to the same extent as the CON group.
  • Enterobacteriaceae which is a marker of enteritis and a marker of oxidative stress in human inflammatory bowel disease and mouse colitis, are more susceptible to the inflammatory DSS group (Proteobacteri all bacteria) compared to the CON group. 39% of the) were detected very frequently. In contrast, Enterobacteriaceae was detected very rarely in the D-ESM 8 group (about 6%). Similarly, DSS administration increased the number of Enterococcaceae but was lowered to near normal levels by eggshell membrane fine powder supplementation.
  • SCFA short-chain fatty acids
  • Quantitative real-time PCR analysis was performed as follows. Back skin and liver samples were taken from each mouse and ground in liquid nitrogen. After homogenization of whole skin tissue or whole liver tissue, total RNA was isolated and cDNA synthesis was performed using a trade name "Takara PrimeScript RT reagent kit”. The real time PCR method was performed using a brand name "SYBR Premix Ex Taq II (Takara) on Thermal Cycler Dice Real Time System” (Takara). As a primer, a primer designed for amplification of a gene encoding Col3a1 (collagen type III) was used.
  • the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was similarly amplified.
  • the PCR cycle was 30 cycles of initial denaturation at 95 ° C. for 30 cycles (denaturation at 95 ° C. for 5 seconds, annealing and elongation at 60 ° C. for 1 minute).
  • a sugar coating paste A (70 parts by weight of granulated sugar, 3 parts by weight of gum arabic, 4 parts by weight of gelatin, 3 parts by weight of eggshell calcium, and the like on a surface of the sufficiently dried protected coated tablet)
  • the paste was mixed with 65 parts by weight of water and then dried at a temperature of 40 ° C. for about 4 hours. Thereafter, a sugar coating paste B obtained by diluting sugar coating paste A with water was coated using a sugar coating apparatus, and then dried at a temperature of 40 ° C. for 4 hours to obtain sugar coating coated tablets.
  • a coloring agent containing the trade name "SR Red K3" (manufactured by San-Ei Gen Co., Ltd.) is applied to the surface of a sugar-coated tablet and dried at 40 to 50 ° C to produce a red-colored tablet. Glossing was performed using carnauba wax. The weight of one tablet thus obtained was 400 mg and contained about 80 mg of eggshell membrane component per tablet. The glazed tablets were screened to remove any defects, weighed after product inspection, and packaged in a double bag enclosed with a desiccant. The tablets had sufficient hardness and shape retention, and did not deform or disintegrate during sorting, inspection or packaging, and were excellent in handleability.
  • the present invention is (1) an intestinal flora improving agent containing an eggshell membrane-containing powder as an active ingredient, (9) a composition for improving intestinal flora, which comprises an eggshell membrane-containing powder as an active ingredient.
  • An improvement composition can be provided.
  • the intestinal flora improving agent and the composition for improving intestinal flora according to the present invention are non-irritating, can be used in various forms in combination with various components, and have nutritional and cosmetic components in order to obtain further systemic effects.
  • the effect is that it can be used in combination with
  • the intestinal flora improving function of the eggshell membrane-containing powder or fine powder and the function of promoting the formation of type III collagen and the hydrolysis eggshell membrane component have III
  • the synergistic effect with the type-collagen formation promoting function promotes the production of type III collagen in blood vessels, lungs, liver, skin, etc., and the improvement of intestinal flora to enhance the beautifying effect and anti-aging effect, and health
  • the condition can be improved and / or well maintained.
  • This composition can be used in various forms as food additives, food and drink, supplements, edible cosmetic agents and medicines, and when hydrolyzed eggshell membrane powder is used as the hydrolyzed eggshell membrane component, tableting is easy.
  • the enteral flora improving agent according to any one of (1) to (3) which is a preparation to be administered orally.
  • the intestinal flora improving agent according to any one of (1) to (4) which is a food additive, food and drink, a supplement or a medicine.
  • the intestinal flora improving agent according to (4) wherein the preparation is a tablet.
  • Intestinal flora improvement is due to the component remaining in the intestine without being absorbed in the intestine increasing the diversity of intestinal bacteria and decreasing the number of pathogenic bacteria, (1) to The intestinal flora improvement agent in any one of (7).
  • the component which is not absorbed and remains in the intestine in the intestine increases the diversity of intestinal bacteria and decreases the number of pathogenic bacteria, (9) to The composition for intestinal flora improvement in any one of (18).
  • an intestinal flora improving agent containing an eggshell membrane-containing powder or a fine powder which is nonirritating and can be used in various forms and in combination with various components.
  • This preparation can be used in various applications and forms such as food additives, food and drink, supplements, medicines, etc., and can be easily taken on a daily basis.
  • a composition for improving intestinal flora containing eggshell membrane-containing powder or fine powder which is nonirritating and can be used in various forms and in combination with various components.
  • the intestinal flora improving function possessed by the eggshell membrane-containing fine powder, the function promoting formation of type III collagen, and the function promoting formation of type III collagen possessed by the hydrolyzed eggshell membrane component It acts synergistically to promote the formation of type III collagen in blood vessels, lungs, liver, skin, etc. and to improve intestinal flora, thereby enhancing skin-beautifying effects and anti-aging effects, improving health and / or Or it becomes a composition which can be maintained well.
  • This composition can be used in various applications and forms such as food additives, food and drink, supplements, edible cosmetic agents, medicines and the like, and can be easily ingested on a daily basis.

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Abstract

[Problem] To provide an intestinal microbiota improving agent which includes a powder or fine powder that contains eggshell membrane. Also to provide a composition for improving intestinal microbiota and for promoting type III collagen growth which utilizes both the intestinal microbiota improving agent and a hydrolyzed eggshell membrane component. [Solution] An eggshell membrane–containing powder, in particular, an eggshell membrane–containing fine powder having a volume-average particle size of no larger than 6 μm or a volume-based maximum particle size of no larger than 20 μm is effective as an intestinal microbiota improving agent. A preparation which includes this intestinal microbiota improving agent can be used for a variety of purposes and in a variety of forms, for example as a food additive, a food or beverage product, a dietary supplement, or a pharmaceutical. Furthermore, a composition which includes a hydrolyzed eggshell membrane component enhances type III collagen growth promoting capabilities, functions synergistically with intestinal microbiota improving effects, and is excellent for improving skin and preventing the appearance of aging.

Description

卵殻膜含有粉末を含む腸内フローラ改善剤および腸内フローラ改善用組成物An intestinal flora improving agent and a composition for improving intestinal flora comprising eggshell membrane-containing powder
　本発明は、卵殻膜含有粉末もしくは微粉末を有効成分として含有する腸内フローラ改善剤および腸内フローラ改善用組成物に関する。さらに、卵殻膜含有粉末もしくは微粉末と加水分解卵殻膜成分を含む、腸内フローラを改善し、III型コラーゲンの生成を促進するための組成物に関する。 The present invention relates to an intestinal flora improving agent and a composition for improving intestinal flora containing eggshell membrane-containing powder or fine powder as an active ingredient. Further, the present invention relates to a composition for improving intestinal flora and promoting the formation of type III collagen, which comprises eggshell membrane-containing powder or fine powder and a hydrolyzed eggshell membrane component.
　卵殻膜は、鶏卵などの鳥類の卵の卵殻の内側にある膜で、内外２枚からなり、外卵殻膜は卵殻内面に密着し、内卵殻膜は卵白を包んでおり、抗菌性を有し、発生中の胚を感染から保護している。卵殻膜は、Ｉ型、Ｖ型およびＸ型コラーゲン、グルコサミン、デスモシンおよびヒアルロン酸を主成分とした強靭な繊維性のタンパク質等からなる網目状の構造を有し、これらのタンパク質はシステインを含むものが多く、酸、アルカリ、プロテアーゼに対して比較的安定で、水に不溶性である。以前は食品産業の廃棄物として利用されていなかったが、皮膚の再生を促進する効果や、特に胎児性コラーゲンと呼ばれるIII型コラーゲンの生成を促進する効果が発見されてから、化粧品や栄養剤としての開発が進められ、実用化されている。 The eggshell membrane is a membrane inside the eggshell of avian egg such as a chicken egg and consists of 2 sheets inside and outside, the outer shell membrane is in close contact with the inner surface of the eggshell, and the inner shell is wrapped in egg white and has antibacterial properties , Protecting developing embryos from infection. Eggshell membrane has a network-like structure composed of type I, type V and type X collagen, glucosamine, desmosine and tough fibrous proteins mainly composed of hyaluronic acid, and these proteins contain cysteine Are relatively stable to acids, alkalis, and proteases, and insoluble in water. It has not been used as a waste in the food industry before, but it has been found to be effective as a cosmetic and a nutrient after its effect to promote skin regeneration and especially to promote the formation of type III collagen called fetal collagen. Development has been advanced and put to practical use.
　たとえば、卵殻膜成分の消化吸収効率を高めるために、体積平均粒子径が６μｍ以下または体積最大粒子径が２０μｍ（８００メッシュ）以下となるように、卵殻膜粉末をジェットミルを用いて粉砕し微粉末化する（特許文献１）ことが提案された。また、不溶性の卵殻膜を水に可溶性にするため、タンパク質を加水分解した加水分解卵殻膜を、取扱性、保存安定性の向上のために乾燥粉末化すること（特許文献２）、さらに、アルカリ性である加水分解卵殻膜粉末をｐＨ３～６にして、保存安定性、安全性を高めること（特許文献３）が提案されている。 For example, in order to increase the efficiency of digestion and absorption of eggshell membrane components, eggshell membrane powder is pulverized using a jet mill so that the volume average particle size is 6 μm or less or the volume maximum particle size is 20 μm (800 mesh) or less. It has been proposed to powderize (patent document 1). In addition, in order to make insoluble eggshell membrane soluble in water, hydrolyzing hydrolyzed eggshell membrane obtained by hydrolyzing protein is dried and powdered for improvement of handling property and storage stability (Patent Document 2), and alkalinity It has been proposed to increase the storage stability and safety by setting the pH of the hydrolyzed eggshell membrane powder to 3 to 6 (Patent Document 3).
特開２０１３－２１６６５２号公報JP, 2013-216652, A 特許第５１７９８４７号明細書Patent No. 5179847 specification 特開２０１６－９８２０６号公報JP, 2016-98206, A
　本発明は、安全性が高く、食品添加剤、飲食品、サプリメント、医薬品として日常的に簡便な方法で利用することのでき、単一素材で生体を良好な状態に改善または維持できる腸内フローラ改善剤または腸内フローラ改善用組成物を提供することを課題とする。
　さらに、腸内フローラの改善機能に加えて、III型コラーゲンの生成促進機能を有し、両機能の相乗効果により生体をさらに良好な状態に改善および／または維持することのできる組成物を提供することを課題とする。 INDUSTRIAL APPLICABILITY The present invention is highly safe, can be used daily as a food additive, food and drink, supplement, medicine as a simple and convenient method, and intestinal flora that can improve or maintain the living body in a good condition with a single material. An object of the present invention is to provide a remedy or a composition for improving intestinal flora.
Furthermore, in addition to the improvement function of intestinal flora, it has a function to promote the formation of type III collagen, and provides a composition capable of improving and / or maintaining the living body in a better state by the synergistic effect of both functions. To be an issue.
　卵殻膜または加水分解卵殻膜は、美肌化、皮膚再生、育毛発毛促進、脱毛防止などの作用の他に、肩凝りの解消、食欲増進、疲労回復等の日常的な健康増進、健康維持に有効であるとされている。また、体内で消化吸収されやすくするために、卵殻膜含有微粉末（特許文献１）及び加水分解卵殻膜粉末（特許文献２、３）とすることが知られている。卵殻膜含有微粉末（特許文献１）及び加水分解卵殻膜粉末（特許文献２、３）は、体内で消化吸収されると体内のIII型コラーゲンの生成を促進する機能を有することが知られている。 Eggshell membrane or hydrolysed eggshell membrane is not only for skin softening, skin regeneration, hair growth promotion, hair loss prevention, etc., but also for daily health promotion and health maintenance such as elimination of stiff shoulder, enhancement of appetite, fatigue recovery, etc. It is considered to be effective. In addition, in order to facilitate digestion and absorption in the body, it is known to use eggshell membrane-containing fine powder (Patent Document 1) and hydrolyzed eggshell membrane powder (Patent Documents 2 and 3). Eggshell membrane-containing fine powder (patent document 1) and hydrolyzed eggshell membrane powder (patent documents 2 and 3) are known to have a function of promoting the formation of type III collagen in the body when digested and absorbed in the body There is.
　本発明者らは、加水分解卵殻膜がほぼ１００％消化され、血液中に吸収されるのに対して、卵殻膜含有粉末、微粉末は、約５４％が消化吸収されずに腸内に残り、その残った成分が腸内細菌のうちの悪玉菌の増殖を防止し、腸内フローラを改善することを初めて見出し、本発明を完成させるに至った。 While the hydrolyzed eggshell membrane is almost 100% digested and absorbed in the blood, the eggshell membrane-containing powder and fine powder remain in the intestine without digestion and absorption of about 54%. For the first time, it has been found that the remaining components prevent the growth of bad bacteria among enteric bacteria and improve the enteric flora, and have completed the present invention.
　さらに、約４６％しか消化吸収されない卵殻膜含有粉末または微粉末より、III型コラーゲンの生成をより促進する機能を有する加水分解卵殻膜成分と卵殻膜含有粉末または微粉末を併用することにより、腸内フローラ改善機能とIII型コラーゲンの生成促進機能とが相乗的に作用して、腸内フローラの改善による免疫機能の向上、癌等の成人病の予防に加えて、III型コラーゲンの生成促進による血管、肺、肝臓、皮膚の組織の強化により、老化防止効果が増強され、健康状態もさらに改善および／または良好に維持できる組成物を完成するに至った。 Furthermore, the combined use of a hydrolyzed eggshell membrane component having a function of further promoting the formation of type III collagen and an eggshell membrane-containing powder or fine powder, than an eggshell membrane-containing powder or fine powder which is only about 46% digested and absorbed, The function to improve the internal flora and the function to promote the formation of type III collagen act synergistically to improve the immune function by improving the intestinal flora, and to prevent the development of adult diseases such as cancer, as well as to promote the generation of type III collagen The strengthening of blood vessel, lung, liver and skin tissues has resulted in the completion of a composition that has an enhanced anti-aging effect and can further improve and / or maintain good health.
　本発明は、卵殻膜含有粉末を有効成分とする腸内フローラ改善剤を要旨とする。
また、本発明は、腸内フローラ改善用組成物であって、卵殻膜含有粉末を有効成分として含むことを特徴とする組成物を要旨とする。 The present invention is summarized as an intestinal flora improving agent containing an eggshell membrane-containing powder as an active ingredient.
The present invention also provides a composition for improving intestinal flora, which comprises an eggshell membrane-containing powder as an active ingredient.
ＤＳＳで大腸炎を誘発したマウスに、卵殻膜含有微粉末サプリメントを摂取させた後の細菌メタゲノム解析の結果：腸内細菌プロファイルResults of Bacterial Metagenomics Analysis after Ingesting Eggshell Membrane-Containing Fine Powdered Supplements to DSS-Induced Colitis Mice: Enteric Bacterial Profile ＤＳＳで大腸炎を誘発したマウスに、卵殻膜含有微粉末サプリメントを摂取させた後の細菌メタゲノム解析の結果：腸内細菌種の豊富さResults of Bacterial Metagenomics Analysis After Ingesting Eggshell Membrane-Containing Fine Powdered Supplements to DSS-Induced Colitis Mice: Abundance of Enteric Bacterial Species ＤＳＳで大腸炎を誘発したマウスに、卵殻膜含有微粉末サプリメントを摂取させた後の細菌メタゲノム解析の結果：腸内細菌の存在比Results of bacterial metagenomic analysis of mice challenged with colitis with DSS after ingestion of eggshell membrane-containing fine powder supplementation: prevalence of enterobacteria マウスを用いた加水分解卵殻膜粉末サプリメントの経口摂取実験による１７日後の結果。リアルタイムＰＣＲによるIII型コラーゲン遺伝子の皮膚における発現量を示す。The result after 17 days by the oral intake experiment of the hydrolysis eggshell membrane powder supplement using a mouse. The expression level in skin of a type III collagen gene by real time PCR is shown.
　ヒトの腸内には、数百種の腸内細菌が約１００兆個以上バランスよく生息しており、例えば乳酸菌、ビフィズス菌のような有用菌（善玉菌）、例えば大腸菌、クロストリジウム菌のような有害菌（悪玉菌）、および日和見菌が腸内において互いにバランスを保ちながら、一種の生態系（腸内フローラ）を形成している。この腸内フローラのバランスが、老化、ストレス、疾病、環境変化、食生活の変化により崩れると、悪玉菌の増加等により腸内に有害な物質が蓄積されて、便秘、下痢症状、免疫機能の低下のみならず、血液中に吸収された有害物質により、心臓、肝臓および腎臓に負担を与え、老化を促進したり、癌の原因にもなることがあることが知られている。 Hundreds of enteric bacteria are inhabited in a balanced manner in human intestine in a balance of about 100 trillion or more. For example, useful bacteria such as lactic acid bacteria and bifidobacteria (good bacteria) such as E. coli and clostridial bacteria Harmful bacteria (bad bacteria) and opportunistic bacteria form a kind of ecosystem (gut flora) while maintaining balance with each other in the intestine. If the balance of the intestinal flora breaks down due to aging, stress, diseases, environmental changes, or changes in the diet, harmful substances are accumulated in the intestine due to an increase in bad bacteria etc., resulting in constipation, diarrhea, immune function Not only it is known that harmful substances absorbed in the blood can burden the heart, liver and kidneys, accelerate aging, and cause cancer as well as lowering.
　卵殻膜含有微粉末は、ラットを用いた実験で約５４％が消化吸収されずに腸内に残り、その残った成分が腸内細菌のうちの悪玉菌の増殖を防止し、腸内フローラを改善することが見出された。本発明によれば、食品添加剤、飲食品、サプリメント、医薬品等のさまざまな用途で、日常的に簡単に摂取できる腸内フローラ改善剤を提供することができる。本発明の腸内フローラ改善剤は、刺激性がなく、様々な形態で種々の成分と併用することができ、錠剤化も簡単に行うことができる。さらなる全身効果を得るために、栄養、美容成分と併用することもできる。
　また、卵殻膜含有微粉末は、約４６％が消化吸収され、加水分解卵殻膜成分はほぼ１００％が消化吸収され、血液中に取り込まれた卵殻膜成分により、皮膚におけるIII型コラーゲンの生成を促進するだけでなく、血管でもIII型コラーゲンの生成を促進して血管全体の弾性を増すことができる。したがって、卵殻膜含有粉末または微粉末と加水分解卵殻膜成分を併用すれば、卵殻膜含有粉末または微粉末の有する腸内フローラ改善機能およびIII型コラーゲンの生成促進機能と、加水分解卵殻膜成分の有するIII型コラーゲンの生成促進機能とが相乗的に作用して、血管、肺、肝臓、皮膚等におけるIII型コラーゲンの生成の促進と、腸内フローラの改善により美肌効果や老化防止効果が増強され、健康状態を改善および／または良好に維持することができる。この組成物は、食品添加剤、飲食品、サプリメント、可食性美容剤、医薬品として様々な形態で利用することができ、加水分解卵殻膜成分として加水分解卵殻膜粉末を用いれば、錠剤化も簡単に行うことができる。本発明の腸内フローラ改善剤または腸内フローラ改善用組成物は、卵殻膜含有粉末を有効成分とするものであり、ラットを用いた実験では、摂取した卵殻膜含有微粉末の４６％が消化吸収され、残りは吸収されずに腸内に残った。この残った成分が腸内細菌の多様性を増加させ、かつ大腸菌のような病原性細菌の数を減少させ、腸内フローラを改善できることを、実施例１で示す。 The eggshell membrane-containing fine powder remains in the intestine without digestion and absorption for about 54% in the experiment using rats, and the remaining components prevent the growth of the bad bacteria of the enteric bacteria, and the enteric flora It was found to improve. ADVANTAGE OF THE INVENTION According to this invention, the enteric flora improvement agent which can be ingested easily and routinely can be provided in various uses, such as a food additive, food-drinks, a supplement, and a pharmaceutical. The intestinal flora improving agent of the present invention is nonirritating, can be used in various forms in combination with various components, and can be easily tableted. It can also be used in combination with nutritional and cosmetic ingredients to obtain further systemic effects.
In addition, about 46% of the eggshell membrane-containing fine powder is digested and absorbed, and about 100% of the hydrolyzed eggshell membrane component is digested and absorbed, and the eggshell membrane component taken up into the blood produces type III collagen in the skin. As well as promoting, even blood vessels can promote the formation of type III collagen to increase the elasticity of the whole blood vessel. Therefore, when the eggshell membrane-containing powder or fine powder and the hydrolyzed eggshell membrane component are used in combination, the intestinal flora improving function of the eggshell membrane-containing powder or fine powder and the function of promoting the formation of type III collagen and the hydrolyzed eggshell membrane component The effect of promoting the production of type III collagen acts synergistically to enhance the skin-beautifying effect and anti-aging effect by promoting the formation of type III collagen in blood vessels, lungs, liver, skin etc. and improving intestinal flora. Health condition can be improved and / or well maintained. This composition can be used in various forms as food additives, food and drink, supplements, edible cosmetic agents and medicines, and when hydrolyzed eggshell membrane powder is used as the hydrolyzed eggshell membrane component, tableting is easy. Can be done. The intestinal flora improving agent or composition for improving intestinal flora according to the present invention contains eggshell membrane-containing powder as an active ingredient, and in experiments using rats, 46% of ingested eggshell membrane-containing fine powder is digested Absorbed, the rest remained in the intestine without absorption. It is demonstrated in Example 1 that this remaining component can increase intestinal bacterial diversity and reduce the number of pathogenic bacteria such as E. coli.
　本発明で使用される卵殻膜は、陸生の卵生動物すべての卵、特に鳥類の卵の卵殻の内側にある膜であればいずれも使用できる。特に鶏卵の卵殻膜が、入手の容易性、コストの点から好ましい。 As the eggshell membrane used in the present invention, any membrane can be used as long as it is inside the eggshells of all terrestrial egg live animals, particularly avian eggs. In particular, eggshell membranes of hen eggs are preferable in terms of availability and cost.
　本発明で使用される卵殻膜含有粉末は、少なくとも卵殻膜を含む粉末であれば特に制限はなく、粉末とは粒子サイズにかかわらず、あらゆる粉体をいう。剥離された卵殻膜または卵殻に卵殻膜が付着した状態の原料を使用して、公知のいずれの方法で粉末化してもよい。また、市販の卵殻膜含有粉末を用いてもよい。 The eggshell membrane-containing powder used in the present invention is not particularly limited as long as it is a powder containing at least an eggshell membrane, and the powder refers to any powder regardless of the particle size. The raw material in a state in which the eggshell membrane is attached to the exfoliated eggshell membrane or eggshell may be powdered by any known method. Alternatively, a commercially available eggshell membrane-containing powder may be used.
　本発明で使用される卵殻膜含有微粉末は、粉末のうち、体積最大粒子径および／または体積平均粒子径が概ね１００μｍより小さいものをいう。本願明細書において、粉末または微粉末の「体積平均粒子径」、「体積最大粒子径」は、レーザー回折式粒度分布測定機（株式会社セイシン製、ＬＭＳ－３０）を用いて測定した値を意味する。粒子径の測定に際しては、卵殻膜含有微粉末を界面活性剤を用いて水に分散させた測定試料を用いる。また、「体積平均粒子径」とは、粒度分布における小粒径側からの累積値が５０％における粒子径を意味する。 The eggshell membrane-containing fine powder to be used in the present invention refers to powder having a volume maximum particle size and / or a volume average particle size smaller than about 100 μm. In the present specification, “volume average particle diameter” and “volume maximum particle diameter” of powder or fine powder mean values measured using a laser diffraction type particle size distribution analyzer (manufactured by Seishin Co., Ltd., LMS-30). Do. When measuring the particle size, a measurement sample in which eggshell membrane-containing fine powder is dispersed in water using a surfactant is used. Moreover, "volume average particle diameter" means the particle diameter in 50% of the cumulative value from the small particle diameter side in particle size distribution.
　本発明で使用される卵殻膜含有微粉末として、特に体積平均粒子径が６μｍ以下、または体積最大粒子径が２０μｍ以下のものが、消化吸収効率の点から好ましい。市販の卵殻膜含有粉末等の卵殻膜含有原料を、ガス中で相互に衝突させるジェットミルを用いる微粉砕工程により製造することが好ましい。 As the eggshell membrane-containing fine powder to be used in the present invention, one having a volume average particle size of 6 μm or less, or a volume maximum particle size of 20 μm or less is particularly preferable from the viewpoint of digestive and absorption efficiency. It is preferable to manufacture eggshell membrane containing raw materials, such as a commercially available eggshell membrane containing powder, by a pulverization process using a jet mill in which they collide with each other in gas.
　本発明で使用される加水分解卵殻膜成分は、卵殻膜あるいは前述した卵殻膜含有粉末を、酸水溶液、アルカリ水溶液、アルカリ性有機溶媒溶液、およびタンパク質分解酵素含有液などのタンパク質の分解作用を有する液中で加水分解することによって得られる。水溶液、エキスとしても使用できるが、取扱性や保存安定性のため、噴霧乾燥、凍結乾燥等の乾燥手段により得られる粉末形態のものが好ましい。加水分解卵殻膜粉末としては、特にｐＨが３～６である粉末が保存安定性、安全性の点から好ましい。 The hydrolyzed eggshell membrane component used in the present invention is a solution having a protein degrading action such as an aqueous acid solution, an alkaline aqueous solution, an alkaline organic solvent solution, and a proteinase-containing solution, as the eggshell membrane or the aforementioned eggshell membrane-containing powder It is obtained by hydrolysis in vacuo. Although it can also be used as an aqueous solution or an extract, it is preferably in the form of a powder obtained by a drying means such as spray drying or lyophilization for handling and storage stability. As the hydrolyzed eggshell membrane powder, a powder having a pH of 3 to 6 is particularly preferable in view of storage stability and safety.
　ヒトの皮膚は表面にある上皮層とその下の結合組織性の真皮層からなっており、真皮層を構成するタンパク質は主としてコラーゲンであり、他にエラスチン、アルブミン、グロブリン、ムチンよりなっている。真皮層を構成するコラーゲンは、主としてα１（Ｉ）型コラーゲンおよびα１(III）型コラーゲン（以下、「III型コラーゲン」という。）であり、Ｉ型コラーゲンは主として皮膚の構造維持、III型コラーゲンは主として皮膚の柔軟性の付与とそれぞれ異なる機能を果たしている。 The human skin is composed of an epithelial layer on the surface and a connective tissue-like dermal layer below it, and the protein constituting the dermal layer is mainly collagen, and is also composed of elastin, albumin, globulin and mucin. Collagen constituting the dermal layer is mainly α1 (I) collagen and α1 (III) collagen (hereinafter referred to as "type III collagen"), type I collagen mainly maintains the skin structure, type III collagen It plays different functions mainly from the application of skin softness.
　皮膚におけるI型コラーゲンとIII型コラーゲンの割合は、加齢に伴って変化する。III型コラーゲンは胎児性コラーゲンとも呼ばれるように、胎児のときに最も多く、胎児の皮膚ではIII型コラーゲンの方が多いが、１０代から減りはじめ、そのまま減少していくので、皮膚におけるIII型コラーゲンの割合を増加することができれば、加齢による皮膚の老化を止め、皮膚をなめらかでしっとりさせることができる。また、III型コラーゲンは皮膚以外にも、血管、肺、肝臓等の結合組織中に含まれている。 The proportion of type I collagen and type III collagen in the skin changes with age. As type III collagen is also called fetal collagen, it is most abundant in the case of the fetus and more in the case of fetal skin with type III collagen, but begins to decrease from the 10s and continues to decrease, so type III collagen in the skin If you can increase the rate of aging, you can stop the aging of the skin with age and make the skin smooth and moist. In addition to skin, type III collagen is contained in connective tissues such as blood vessels, lungs and liver.
　卵殻膜含有微粉末は、約４６％が消化吸収され、吸収され血液中に取り込まれたアミノ酸成分により、皮膚におけるIII型コラーゲンの生成を促進するだけでなく、血管でもIII型コラーゲンの生成を促進して血管全体の弾性を増すことができ、肝臓でも線維化を抑制することができる。
　卵殻膜含有微粉末は約４６％が消化吸収され、加水分解卵殻膜成分はほぼ１００％が消化吸収され、血液中に取り込まれた卵殻膜成分により、皮膚におけるIII型コラーゲンの生成を促進するだけでなく、血管でもIII型コラーゲンの生成を促進して血管全体の弾性を増すことができ、肝臓でも線維化を抑制することができる。本発明で使用する卵殻膜成分含有粉末と加水分解卵殻膜成分のいずれも消化吸収されると、III型コラーゲンの生成を促進する機能を有するが、ほぼ１００％消化吸収される加水分解卵殻膜成分の方がその促進効果が高いことがわかった。 The eggshell membrane-containing fine powder not only promotes the formation of type III collagen in the skin but also promotes the generation of type III collagen in blood vessels by the amino acid component that is absorbed and absorbed and absorbed into the blood by about 46%. Thus, the elasticity of the whole blood vessel can be increased, and fibrosis can be suppressed even in the liver.
About 46% of the eggshell membrane-containing fine powder is digested and absorbed, and about 100% of the hydrolyzed eggshell membrane component is digested and absorbed, and the eggshell membrane component taken up into the blood only promotes the formation of type III collagen in the skin Not only the blood vessels can promote the formation of type III collagen to increase the elasticity of the whole blood vessels, but also can suppress fibrosis in the liver. Both the eggshell membrane component-containing powder and the hydrolyzed eggshell membrane component used in the present invention have a function to promote the formation of type III collagen when digested and absorbed, but the hydrolyzed eggshell membrane component is almost 100% digested and absorbed. Was found to be more effective.
　そのため、卵殻膜成分含有粉末と加水分解卵殻膜成分を併用すると、III型コラーゲンの生成促進効果がさらに高められるだけでなく、腸内フローラの改善効果と相まって、相乗的に美肌化、老化防止効果が高められ、健康状態を改善および／または良好に維持できる組成物が提供できた。その組成物は、卵殻膜含有微粉末を１０～９０重量％、加水分解卵殻膜粉末を９０～１０重量％含有することが好ましい。 Therefore, the combined use of the eggshell membrane component-containing powder and the hydrolyzed eggshell membrane component not only enhances the formation promoting effect of type III collagen, but also combines with the improvement effect of intestinal flora to synergistically make the skin beautify and prevent aging Can be provided to provide a composition that can improve health and / or maintain well. The composition preferably contains 10 to 90% by weight of eggshell membrane-containing fine powder and 90 to 10% by weight of hydrolyzed eggshell membrane powder.
　本発明の製剤は、本発明の組成物は、錠剤、散剤、顆粒剤、カプセル剤、液剤などの経口用組成物とすることができる。刺激性がないために剤型に特に制限はなく、種々の剤型の経口用組成物を製造するための各種成分および製造法は、サプリメント、医薬品等の製造分野で公知な成分から適宜選択することができる。特に、保存、流通に適し、服用時に変形、崩壊が生じず、経口で簡単に服用できる観点から、錠剤に用いることが好ましい。 In the preparation of the present invention, the composition of the present invention can be an oral composition such as tablets, powders, granules, capsules, solutions and the like. There is no particular limitation on the dosage form because it is not irritative, and various components and production methods for producing oral compositions of various dosage forms are appropriately selected from components known in the field of production of supplements, pharmaceuticals, etc. be able to. In particular, it is preferable to use it for tablets, from the viewpoint of being suitable for storage and distribution, causing no deformation or disintegration at the time of taking, and easily taking orally.
　本発明の錠剤に含まれる卵殻膜含有粉末の含有量は、特に制限されないが、本発明の錠剤に含まれる卵殻膜含有粉末と加水分解卵殻膜粉末の合計（以下、「卵殻膜成分」ともいう。）の含有量は、特に制限されないが、粒子への造粒と打錠が円滑に行え、かつ錠剤を摂取した際の腸内フローラ改善効果とIII型コラーゲン生成促進効果がより増強されるなどの観点から、錠剤の全重量に対して５～４５重量％の割合、より好ましくは１０～４０重量％の割合で含有するのが好ましい。含有量を５重量％以上とすることにより、多量の錠剤を摂取する必要がなくなり、一方、４５重量％以下とすることにより造粒および打錠が容易となり、錠剤を製造しやすくなる。 The content of the eggshell membrane-containing powder contained in the tablet of the present invention is not particularly limited, but the total of the eggshell membrane-containing powder and the hydrolyzed eggshell membrane powder contained in the tablet of the present invention The content of.) Is not particularly limited, but the granulation and tableting to particles can be smoothly performed, and the intestinal flora improving effect and the type III collagen formation promoting effect are further enhanced when the tablet is ingested, etc. From the viewpoint of the above, it is preferable to contain 5 to 45% by weight, more preferably 10 to 40% by weight, with respect to the total weight of the tablet. By setting the content to 5% by weight or more, it is not necessary to ingest a large amount of tablets, and by setting the content to 45% by weight or less, granulation and tableting become easy, and tablets can be easily produced.
　本実施形態の錠剤には、錠剤を形成するための各種の添加剤として、賦形剤、結合剤、崩壊剤、滑沢剤、その他の栄養素等を添加することができる。
　賦形剤としては、公知の賦形剤が適宜使用できるが、化工澱粉および乳糖の少なくとも１種を、賦形性の観点から卵殻膜成分の重量に対して０．３～３倍用いることが好ましく、１～２．５倍であることがより好ましい。化工澱粉としては、焙焼デキストリンなどのデキストリン、酸化澱粉、低粘性変性澱粉などの１種または２種以上を用いることができる。賦形剤として化工澱粉と乳糖を併用する場合は、使用割合（重量比）が、１：５～５：１であることが好ましい。
　結合剤としては、公知の結合剤が適宜使用できるが、たとえば、デンプン糊、アラビアゴム糊、ヒドロキシプロピルセルロースなどが挙げられる。
　崩壊剤としては、公知の崩壊剤が適宜使用できるが、たとえば、セルロース類などを用いることができる。
　滑沢剤としては、公知の滑沢剤が適宜使用できるが、たとえば、ステアリン酸マグネシウム、ショ糖脂肪酸エステル、ワックス類、タルク、ビタミンＣなどが挙げられる。 An excipient, a binder, a disintegrant, a lubricant, other nutrients, etc. can be added to the tablet of this embodiment as various additives for forming a tablet.
As the excipient, known excipients can be appropriately used, but at least one of modified starch and lactose may be used in an amount of 0.3 to 3 times the weight of the eggshell membrane component from the viewpoint of formability. Preferably, it is more preferably 1 to 2.5 times. As the modified starch, one or more kinds of dextrin such as roasted dextrin, oxidized starch, low viscosity modified starch and the like can be used. When the modified starch and lactose are used in combination as an excipient, the use ratio (weight ratio) is preferably 1: 5 to 5: 1.
As the binder, known binders can be suitably used, and examples thereof include starch paste, gum arabic paste, hydroxypropyl cellulose and the like.
As the disintegrant, known disintegrants can be suitably used, and for example, celluloses can be used.
As the lubricant, known lubricants can be appropriately used, and examples thereof include magnesium stearate, sucrose fatty acid ester, waxes, talc, vitamin C and the like.
　また、本実施形態の錠剤は、錠剤の硬度を高くして、変形や傷つきを防止し、取扱性を向上させるため、硬度向上剤として卵殻カルシウムを含有することが好ましい。卵殻カルシウムは、鶏卵などの鳥類の卵の殻を粉砕・乾燥した微粉末であり、錠剤に含まれる卵殻カルシウムの含有量は、好ましくは０．１～２０重量％、より好ましくは０．５～１５重量％である。
　さらに、本実施形態の錠剤は、錠剤中に含まれる成分の変質や分解を防止し、かつ、錠剤表面の耐傷つき性を向上させるため、コーティング皮膜で覆うことが好ましい。コーティング皮膜は、公知のコーティング皮膜が適宜使用できるが、たとえば、商品名「セラック」（岐阜セラック株式会社製）を用いることができる。本実施形態の錠剤は、糖衣で覆われていてもよく、着色してもよく、着色後に艶出し処理を施してもよい。 In addition, the tablet of the present embodiment preferably contains eggshell calcium as a hardness improver in order to increase the hardness of the tablet to prevent deformation and damage and to improve the handleability. Eggshell calcium is a fine powder obtained by crushing and drying eggshells of birds such as chicken eggs, and the content of eggshell calcium contained in the tablet is preferably 0.1 to 20% by weight, more preferably 0.5 to It is 15% by weight.
Furthermore, it is preferable to cover the tablet of the present embodiment with a coating film in order to prevent deterioration or degradation of components contained in the tablet and to improve scratch resistance of the tablet surface. A well-known coating film can be used suitably for a coating film, For example, brand name "sealac" (made by Gifu shellac KK) can be used. The tablet of the present embodiment may be coated with a sugar coating, may be colored, and may be subjected to polishing after coloring.
　本実施形態の錠剤の大きさは特に制限されないが、一般には直径が約７～１０ｍｍ程度の円形や楕円形とするのが、取扱性、服用のし易さから好ましい。錠剤の１個の重さは、約３５０～６００ｍｇ程度であり、卵殻膜成分が好ましくは約１０～２４０ｍｇ、より好ましは約２０～１５０ｍｇ含まれるようにする。卵殻膜成分が約１０～２４０ｍｇの量で含有されるとすれば、成人では当錠剤を１日当たり１～２００個（１日当たりの卵殻膜成分で１０～４８，０００ｍｇ）摂取することができる。 The size of the tablet of the present embodiment is not particularly limited, but in general, it is preferable from the viewpoint of handleability and ease of administration that the tablet has a circular or oval shape with a diameter of about 7 to 10 mm. The weight of one tablet is about 350 to 600 mg, and the eggshell membrane component is preferably contained in about 10 to 240 mg, more preferably about 20 to 150 mg. If the eggshell membrane component is contained in an amount of about 10 to 240 mg, the adult can take 1 to 200 tablets per day (10 to 48,000 mg of eggshell membrane component per day).
　本実施形態の錠剤は、卵殻膜含有微粉末と加水分解卵殻膜粉末とを少なくとも含む打錠用原料を用いて、公知の錠剤製造方法により製造することができる。たとえば、打錠用原料を打錠して裸錠を形成する打錠工程を経て、必要に応じて、造粒工程、保護コーティング工程、糖衣コーティング工程等を行い、さらに着色、艶出しを行ってもよい。 The tablet of this embodiment can be manufactured by a known tablet manufacturing method using a raw material for tableting containing at least eggshell membrane-containing fine powder and hydrolyzed eggshell membrane powder. For example, through a tableting process of forming raw tablets by tableting to form a plain tablet, if necessary, a granulation process, a protective coating process, a sugar coating process, etc. are performed, and further coloring and polishing are performed. It is also good.
　また、本発明の腸内フローラ改善剤としての医薬品の有効投与量は、また、本発明の腸内フローラ改善用組成物としての医薬品の有効投与量は、治療もしくは予防すべき症状の程度、投与対象の状態（年齢、性別を含む）、剤型などによって異なる。このような医薬品のヒト（体重６０ｋｇの成人）に対する経口投与量は、卵殻膜成分に換算して、好ましくは１日当たり１～１００，０００ｍｇである。たとえば、有効投与量は、１日当たり卵殻膜成分を合計で１０～４８，０００ｍｇとすることができ、好ましくは、２０～３，５００ｍｇとすることができる。本発明の卵殻膜含有成分は、安全性が高く副作用の心配がないので、他の成分を適切に選択する限りにおいて、摂取量または適用量が上記の範囲を超えても問題はない。 In addition, the effective dose of the pharmaceutical preparation as the intestinal flora improving agent of the present invention, the effective dosage of the pharmaceutical as the composition for intestinal flora improvement of the present invention, the degree of symptoms to be treated or prevented, administration It varies according to the condition (including age and gender) and dosage form of the subject. The oral dose of such a medicament to a human (adult with a body weight of 60 kg) is preferably 1 to 100,000 mg per day, in terms of eggshell membrane components. For example, the effective dose can be a total of 10 to 48,000 mg of eggshell membrane components per day, preferably, 20 to 3,500 mg. Since the eggshell membrane-containing component of the present invention is highly safe and there is no concern about side effects, there is no problem if the amount taken or applied exceeds the above range, as long as other components are appropriately selected.
　さらに、本発明の組成物は、菓子類、飲料、健康食品、保存食品、加工食品などの食品添加剤とすることができる。ここで、「医薬品」および「飲食品」の対象はヒトに限定されるのもではなく、ペットや家畜のような哺乳動物用の医薬品および飼料も包含する。また、「飲食品」の概念には、通常の飲食品の他、経腸栄養食品、栄養機能食品、機能性表示食品、特定保健用食品などが包含される。 Furthermore, the composition of the present invention can be a food additive such as confectionery, beverage, health food, preserved food, processed food and the like. Here, the subjects of "pharmaceutical" and "food and drink" are not limited to humans, but also include pharmaceuticals and feeds for mammals such as pets and livestock. Moreover, the concept of "food and drink" includes enteral nutrition food, nutritive function food, functional display food, food for specified health use, etc. in addition to ordinary food and drink.
　以下に、本発明を実施例に基づいて詳細に説明するが、本発明はこれらの実施例により限定されるものではない。 Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited by these examples.
[卵殻膜含有微粉末の腸内フローラ改善機能および腸炎改善機能]
（１）卵殻膜含有微粉末の製造
　卵殻膜含有粉末サンプルとして、商品名「ＥＭパウダー３００」（キユーピー株式会社製）をジェットミルで微粉砕したものを用いた。ジェットミルとしては、シングルトラックジェットミル（株式会社セイシン製、ＦＳ－４）を用いて、風量：１．２ｍ３／ｍｉｎ、動力：１１ｋｗにて、体積最大粒子径が８００メッシュ（目開きで約２０μｍ）程度となるまで粉砕を実施した。レーザー回折式粒度分布測定機（株式会社セイシン製、ＬＭＳ－３０）を用いて粉砕後の粒径を測定したところ、体積最大粒子径は１９．６μｍ、体積平均粒子径は５．８μｍ（以下、「８００メッシュ微粉末」という。）であった。 [Intestinal flora improvement function and enteritis improvement function of eggshell membrane-containing fine powder]
(1) Production of eggshell membrane-containing fine powder As an eggshell membrane-containing powder sample, one obtained by finely pulverizing product name “EM powder 300” (manufactured by Kewpie Corporation) using a jet mill was used. As a jet mill, a single track jet mill (manufactured by Seishin Co., Ltd., FS-4) is used, and the air volume is 1.2 m 3 / min, the power is 11 kw, and the maximum particle diameter is 800 mesh (about an opening) The grinding was carried out to about 20 μm). When the particle size after grinding is measured using a laser diffraction type particle size distribution analyzer (manufactured by Seishin Co., Ltd., LMS-30), the volume maximum particle size is 19.6 μm, and the volume average particle size is 5.8 μm (hereinafter referred to as It is called "800 mesh fine powder".
（２）実験動物
　７週齢のオスC57BL6/Jマウスを購入し３日間順応させた後、平均体重が等しくなるように３つの群（ｎ＝８）に分けた。７日間、対照AIN-93G基礎常用飼料（ＤＳＳ群）または８％の卵殻膜８００メッシュ微粉末を補強した飼料（Ｄ－ＥＳＭ８群）のどちらかを給餌した。その後９日間、両群に以前と同じ実験用飼料を与えながら、1.5％（W/V）のデキストラン硫酸ナトリウム（ＤＳＳ）（分子量40KDa；MP Biomedicals,Irvine,CA）を含む飲料水を与えて、大腸炎を誘発させた。通常の対照マウス（ＣＯＮ群）には、実験の全過程において、AIN-93G基礎常用飼料と通常の飲料水を与えた。
　８％の卵殻膜８００メッシュ微粉末補強飼料は、カロリーとタンパク質バランスを維持するために、コーンスターチとカゼインで調節した。病気活性指数（disease activity index:DAI）は、マウスの体重、便の硬さ、血便の３つのスコアを用いて、ＤＳＳ水を与えた日以降毎日モニターした。 (2) Experimental animals 7-week-old male C57BL6 / J mice were purchased and acclimated for 3 days, and then divided into three groups (n = 8) so that the average body weights would be equal. For 7 days, either control AIN-93G basal regular diet (DSS group) or diet supplemented with 8% eggshell membrane 800 mesh fine powder (D-ESM group 8) was fed. Then, drinking water containing 1.5% (W / V) dextran sodium sulfate (DSS) (molecular weight 40 KDa; MP Biomedicals, Irvine, CA) was given for 9 days while both groups were fed the same experimental diet as before. It caused colitis. Normal control mice (CON group) were fed with AIN-93G basal regular diet and normal drinking water throughout the course of the experiment.
8% eggshell membrane 800 mesh fine powder fortified feed was adjusted with corn starch and casein to maintain calories and protein balance. The disease activity index (DAI) was monitored daily from the day of receiving DSS water, using three scores of mouse weight, stool firmness and blood stool.
（３）盲腸の細菌メタゲノム解析
　メタゲノムＤＮＡを、QIAamp Stool Minキット(Qiagen,Hilden,Germany)を用いて、マウスの盲腸の内容物から抽出した。16S　rRNA遺伝子の可変領域３と４を増幅するために、（５’－ＣＣＴＡＣＧＧＧＮＧＧＣＷＧＣＡＧ－３’）と（５’－ＣＡＧＧＡＣＴＡＣＨＶＧＧＧＴＡＴＣＴＡＡＴＣＣ－３’）のプライマーを用いて増幅した。増幅物の長さが２５０bp以上で平均qualityスコアが３０以上のＤＮＡ配列について配列決定した。
　代表的な配列をGreengenes OTUデータベースにしたがって、Ribosomal Database Project(RDP)分類を用いて分類した。
　セグメント細菌と数種の病原性細菌の変化を検出するために、定量的リアルタイムＰＣＲを行った。 (3) Bacterial metagenomic analysis of the cecum Metagenomic DNA was extracted from the contents of the mouse cecum using the QIAamp Stool Min kit (Qiagen, Hilden, Germany). In order to amplify variable regions 3 and 4 of the 16S rRNA gene, primers of (5′-CCTACGGGNGGCWGCAG-3 ′) and (5′-CAGGACTACHVGGGTATCTAATCC-3 ′) were used for amplification. Sequences were performed on DNA sequences having a length of 250 bp or more and an average quality score of 30 or more.
Representative sequences were classified according to the Greengenes OTU database using Ribosomal Database Project (RDP) classification.
Quantitative real-time PCR was performed to detect changes in segment bacteria and several pathogenic bacteria.
（４）細菌メタゲノム解析の結果
　細菌門レベルの解析によれば、３つの実験群（Ｄ－ＥＳＭ８、ＤＳＳ、ＣＯＮ）の間で、最も広く行き渡っている３つの細菌門の相対量が著しく異なっていた。図１に示すように、Bacteriodetesは、ＣＯＮ群での６７．０％から、ＤＳＳ群では３４．６％に減少し、Ｄ－ＥＳＭ８群では５５．２％に回復した。 Firmicutesは、ＣＯＮ群での２６．５％から、ＤＳＳ群では１３．７％に減少し、Ｄ－ＥＳＭ８群では１８．６％に回復した。 Proteobacteriaは、ＣＯＮ群での０．９％から、ＤＳＳ群では４０．２％に増加し、Ｄ－ＥＳＭ８群では８．０％に回復した。
　次に、α多様性、β多様性の２つの分類を評価した。α多様性解析により、ＤＳＳ群のマウスは３つの群のうちで細菌種の豊富さが最も低かった（図２）。
ヒトにおける炎症性腸疾患やマウスにおけるＤＳＳ誘発大腸炎を含む疾病状態に相関して、腸内の細菌種が減少することから、この結果は予想どおりであったが、意外なことに、卵殻膜摂取により細菌種の豊富さはＣＯＮ群と同程度にまで回復した。 (4) Results of bacterial metagenome analysis According to bacterial level analysis, the relative amounts of the three most widely distributed bacteria are significantly different among the three experimental groups (D-ESM8, DSS, CON) The As shown in FIG. 1, the Bacteriodetes decreased from 67.0% in the CON group to 34.6% in the DSS group and recovered to 55.2% in the D-ESM 8 group. Firmicutes decreased from 26.5% in the CON group to 13.7% in the DSS group and recovered to 18.6% in the D-ESM 8 group. Proteobacteria increased from 0.9% in the CON group to 40.2% in the DSS group and recovered to 8.0% in the D-ESM 8 group.
Next, two classes of alpha diversity and beta diversity were evaluated. By alpha diversity analysis, mice in the DSS group had the lowest bacterial species abundance among the three groups (Figure 2).
This result was as expected, as the bacterial species in the gut is reduced, correlating with disease states including inflammatory bowel disease in humans and DSS-induced colitis in mice, but surprisingly, the eggshell membrane The intake restored the bacterial species abundance to the same extent as the CON group.
　図３の上段に示すように、腸炎のマーカーおよびヒト炎症性腸疾患とマウス大腸炎の酸化ストレスのマーカーである増加したEnterobacteriaceaeは、ＣＯＮ群と比べて炎症性のＤＳＳ群（Proteobacteria門が全細菌の３９％）で極めて頻繁に検出された。反対に、Enterobacteriaceaeは、Ｄ－ＥＳＭ８群（約６％）では極めてまれに検出された。同様に、ＤＳＳ投与によりEnterococcaceaeの数が増加したが、卵殻膜微粉末の補給によってほぼ通常レベルまで下げられた。
　短鎖脂肪酸（ＳＣＦＡ）のような腸内細菌の代謝産物は大腸細胞の第一エネルギー源であり、宿主の遺伝子発現に直接影響を及ぼすことが考えられるので、ＳＣＦＡ産生菌の存在を評価した（図３の下段）。炎症性腸疾患で減少することが分かっているRuminococcaceae科やPorphyromonadaceae科などのＳＣＦＡ産生菌がＤＳＳ群では減少していたが、卵殻膜摂取により、これらは改善した。 As shown in the upper row of FIG. 3, Enterobacteriaceae, which is a marker of enteritis and a marker of oxidative stress in human inflammatory bowel disease and mouse colitis, are more susceptible to the inflammatory DSS group (Proteobacteri all bacteria) compared to the CON group. 39% of the) were detected very frequently. In contrast, Enterobacteriaceae was detected very rarely in the D-ESM 8 group (about 6%). Similarly, DSS administration increased the number of Enterococcaceae but was lowered to near normal levels by eggshell membrane fine powder supplementation.
Metabolites of enteric bacteria such as short-chain fatty acids (SCFA) are the primary energy source of colonic cells and are thought to directly affect host gene expression, so the presence of SCFA-producing bacteria was assessed ( Bottom of FIG. 3). Although SCFA-producing bacteria such as Ruminococcaceae and Porphyromomonadaceae, which have been known to decrease in inflammatory bowel disease, were reduced in the DSS group, eggshell membrane intake improved them.
（５）まとめ
　上記（４）の結果から、卵殻膜成分含有微粉末の摂取により、腸内細菌の多様性を増加させるだけでなく、大腸菌のような病原性細菌の絶対数を減少させ、セグメント化された糸状菌の異常繁殖を抑制することが示された。
　このように、卵殻膜含有微粉末の摂取により、腸内菌共生バランス失調症、腸内毒素症を改善し、腸内フローラを改善することが示された。 (5) Summary From the results of the above (4), intake of eggshell membrane component-containing fine powder not only increases the diversity of intestinal bacteria but also reduces the absolute number of pathogenic bacteria such as E. coli It has been shown to suppress the overgrowth of transformed filamentous fungi.
Thus, it was shown that intake of eggshell membrane-containing fine powder improves intestinal bacterial symbiotic balance disorder, enterotoxicosis and intestinal flora.
[卵殻膜含有微粉末および加水分解卵殻膜粉末のIII型コラーゲン生成促進機能]
　卵殻膜８００メッシュ微粉末と加水分解卵殻膜粉末のそれぞれを、１日１回、１７日間マウスに経口摂取させて、サプリメント経口摂取実験を行った。加水分解卵殻膜粉末としてｐＨが３～６である加水分解卵殻膜粉末（特許文献３）を用いた。 [Type III collagen formation promoting function of eggshell membrane-containing fine powder and hydrolyzed eggshell membrane powder]
Eggshell membrane 800 mesh fine powder and hydrolysed eggshell membrane powder were orally ingested to mice once a day for 17 days, and a supplement oral intake experiment was conducted. A hydrolyzed eggshell membrane powder having a pH of 3 to 6 (Patent Document 3) was used as the hydrolyzed eggshell membrane powder.
　８週齢のヘアレスマウスに対して、加水分解卵殻膜粉末をMediGelに混合し、サプリメントとして１日１回、１７日間、動物の活動期に自主的に摂取させた。ヒト１日摂取量の１／２、１倍、２倍換算の量を与え（各々ｎ＝６）、また、卵殻膜８００メッシュ微粉末をヒト１日摂取量の１倍換算の量として同様に摂取させた（ｎ＝６）。対照として、サプリメントを与えないヘアレスマウスを用いた。１７日後のそれぞれのマウスの皮膚と肝臓におけるIII型コラーゲン遺伝子発現を定量的リアルタイムＰＣＲで調べた。 For 8-week-old hairless mice, hydrolyzed eggshell membrane powder was mixed with MediGel, and it was voluntarily consumed once daily for 17 days as a supplement in the active phase of the animal as a supplement. The amount equivalent to 1/2, 1 and 2 times the daily human intake is given (each n = 6), and the eggshell membrane 800 mesh fine powder is similarly used as the amount equivalent to 1-fold human daily intake It was ingested (n = 6). A hairless mouse without a supplement was used as a control. The type III collagen gene expression in skin and liver of each mouse after 17 days was examined by quantitative real time PCR.
　定量的リアルタイムＰＣＲ解析は、以下のように行った。
　各マウスから背部皮膚および肝臓サンプルを採取し、液体窒素中で粉砕した。全皮膚組織または全肝臓組織のホモジナイス後、総ＲＮＡを単離し、商品名「Takara PrimeScript RT reagent kit」を用いてｃＤＮＡ合成を行った。リアルタイムＰＣＲ法は商品名「SYBR Premix Ex TaqTM II(Takara) on Thermal Cycler Dice Real Time System」(Takara)を用いて行った。プライマーとしてＣｏｌ３ａ１（III型コラーゲン）をコードする遺伝子の増幅用に設計されたプライマーを用いた。内部標準として、ハウスキーピング遺伝子であるグリセルアルデヒド－３－ホスフェートデヒドロゲナーゼ（ＧＡＰＤＨ）ｍＲＮＡを同様に増幅した。ＰＣＲサイクルは、最初の変性を９５℃で３０秒、４０サイクル（９５℃で５秒の変性、６０℃で１分のアニーリングおよび伸長反応）行った。 Quantitative real-time PCR analysis was performed as follows.
Back skin and liver samples were taken from each mouse and ground in liquid nitrogen. After homogenization of whole skin tissue or whole liver tissue, total RNA was isolated and cDNA synthesis was performed using a trade name "Takara PrimeScript RT reagent kit". The real time PCR method was performed using a brand name "SYBR Premix Ex Taq II (Takara) on Thermal Cycler Dice Real Time System" (Takara). As a primer, a primer designed for amplification of a gene encoding Col3a1 (collagen type III) was used. As an internal standard, the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was similarly amplified. The PCR cycle was 30 cycles of initial denaturation at 95 ° C. for 30 cycles (denaturation at 95 ° C. for 5 seconds, annealing and elongation at 60 ° C. for 1 minute).
　皮膚におけるIII型コラーゲン遺伝子の発現量を図４に示す。
　経口で加水分解卵殻膜粉末を摂取したマウスの背部皮膚において、III型コラーゲンをコードする遺伝子の発現が量依存的に上昇する（ｐ＝０．０８）ことが示された。経口で卵殻膜８００メッシュ微粉末を摂取したマウスよりも効果的に、III型コラーゲンをコードする遺伝子の発現を上昇させた。 The expression level of type III collagen gene in skin is shown in FIG.
It has been shown that expression of the gene encoding type III collagen is increased in a dose-dependent manner (p = 0.08) in the back skin of mice orally ingested with hydrolyzed eggshell membrane powder. The expression of the gene encoding type III collagen was increased more effectively than the mice orally given eggshell membrane 800 mesh fine powder.
　肝臓における、加水分解卵殻膜粉末を摂取したマウスのIII型コラーゲン遺伝子の発現量については、サプリメントとしてヒトが摂取する１倍換算の量を与えたマウスでは、対照群と変化がなかったが、２倍換算量を与えた場合に、III型コラーゲン遺伝子の発現が有意（ｐ＝０．００７）に上昇した。肝臓におけるIII型コラーゲン遺伝子の発現の上昇により、肝臓線維化抑制および血管の環境改善効果が期待される。 With regard to the expression level of type III collagen gene in mice that ingested hydrolyzed eggshell membrane powder in the liver, there was no change from the control group in mice given 1-fold equivalent amount to be ingested by humans as a supplement, The expression of the type III collagen gene was significantly increased (p = 0.007) when a doubled amount was given. The increase in expression of type III collagen gene in the liver is expected to suppress liver fibrosis and improve the environment of blood vessels.
[錠剤の製造]
　実施例２で使用した卵殻膜８００メッシュ微粉末と加水分解卵殻膜粉末を、それぞれ２０．０重量部、商品名「ワキシａ」（日食株式会社製）１０．０重量部、商品名「パインファイバー」（松谷化学株式会社製）２０．０重量部、乳糖（メグレ社製）２５．９重量部、卵殻カルシウム　商品名「カルホープ」（キユーピー株式会社製）１０．０重量部、β－カロチン５．０重量部、ビタミンＢ２　０．０５重量部、ビタミンＥ０．０５重量部、およびナイアシン２．０重量部を、Ｖ型混合機を用いて混合することにより、原料混合物を調製した。この原料混合物９３重量部に対して、エチルアルコール１５重量部を混合し、得られた混合物を湿式造粒装置を用いて造粒してから、温度５０℃で約１６時間乾燥して、打錠用の顆粒を製造した。 [Manufacture of tablets]
20.0 parts by weight of eggshell membrane 800 mesh fine powder and hydrolyzed eggshell membrane powder used in Example 2; 10.0 parts by weight under the trade name "waxi a" (manufactured by Eclipse Corp.); trade name "Pine "Fiber" (made by Matsutani Chemical Co., Ltd.) 20.0 parts by weight, Lactose (made by Megret Co., Ltd.) 25.9 parts by weight, eggshell calcium product name "Calhope" (made by Kewpie Co., Ltd.) 10.0 parts by weight, β-carotene 5 A raw material mixture was prepared by mixing .0 parts by weight, 0.05 parts by weight of vitamin B2, 0.05 parts by weight of vitamin E, and 2.0 parts by weight of niacin using a V-type mixer. 15 parts by weight of ethyl alcohol is mixed with 93 parts by weight of this raw material mixture, and the resulting mixture is granulated using a wet granulator and then dried at a temperature of 50 ° C. for about 16 hours for tableting. Granules were produced.
　打錠用の顆粒１００重量部に対して、ビタミンＣを９重量部およびショ糖脂肪酸エステルを１重量部の割合で混合し、得られた混合物を打錠装置を使用して、１粒が２００ｍｇの裸錠を製造した。裸錠の表面に、コーティング装置を使用して商品名「セラック」（岐阜セラック株式会社製）の水溶液を塗布し、温度４０℃で２時間乾燥して保護コーティングされた錠剤を得た。十分に乾燥させた保護コーティングされた錠剤の表面に、糖衣被覆装置を使用して、糖衣用ペーストＡ（グラニュー糖７０重量部、アラビアガム３重量部、ゼラチン４重量部、卵殻カルシウム３重量部および水６５重量部を混合したペースト）を被覆した後、温度４０℃で約４時間乾燥した。その後、糖衣用ペーストＡを水で希釈した糖衣用ペーストＢを糖衣被覆装置を使用して被覆した後、温度４０℃で４時間乾燥し、糖衣コーティング錠を得た。 9 parts by weight of vitamin C and 1 part by weight of sucrose fatty acid ester are mixed with 100 parts by weight of granules for tableting, and the obtained mixture is used in a tableting apparatus to 200 mg per tablet. Produced a bare tablet. An aqueous solution of trade name "Serac" (manufactured by Gifu Shellac Co., Ltd.) was applied to the surface of the plain tablet using a coating apparatus, and dried at a temperature of 40 ° C for 2 hours to obtain a protectively coated tablet. A sugar coating paste A (70 parts by weight of granulated sugar, 3 parts by weight of gum arabic, 4 parts by weight of gelatin, 3 parts by weight of eggshell calcium, and the like on a surface of the sufficiently dried protected coated tablet) The paste was mixed with 65 parts by weight of water and then dried at a temperature of 40 ° C. for about 4 hours. Thereafter, a sugar coating paste B obtained by diluting sugar coating paste A with water was coated using a sugar coating apparatus, and then dried at a temperature of 40 ° C. for 4 hours to obtain sugar coating coated tablets.
　糖衣コーティング錠の表面に、商品名「ＳＲレッドＫ３」（三栄源社製）を含む着色料を塗布した後、４０～５０℃で乾燥して、赤色に着色した錠剤を製造し、その表面にカルナウバロウを用いて艶出しを行った。これにより得られた錠剤１個の重量は４００ｍｇであり、錠剤１個当たり卵殻膜成分を約８０ｍｇの割合で含有していた。艶出し処理を行った錠剤を選別して不良品を除き、製品検査後に計量し、乾燥剤を同封した二重袋で包装した。錠剤は十分な硬度および形状保形性を有しており、選別、検査、包装時に変形したり、崩壊するとはなく、取扱性に優れていた。 A coloring agent containing the trade name "SR Red K3" (manufactured by San-Ei Gen Co., Ltd.) is applied to the surface of a sugar-coated tablet and dried at 40 to 50 ° C to produce a red-colored tablet. Glossing was performed using carnauba wax. The weight of one tablet thus obtained was 400 mg and contained about 80 mg of eggshell membrane component per tablet. The glazed tablets were screened to remove any defects, weighed after product inspection, and packaged in a double bag enclosed with a desiccant. The tablets had sufficient hardness and shape retention, and did not deform or disintegrate during sorting, inspection or packaging, and were excellent in handleability.
　［本発明のまとめ］
　以上まとめる。本発明は、（１）卵殻膜含有粉末を有効成分とする腸内フローラ改善剤、（９）腸内フローラ改善用組成物であって、卵殻膜含有粉末を有効成分として含むことを特徴とする組成物であり、食品添加剤、飲食品、サプリメント、可食性美容剤、医薬品等のさまざまな用途で、日常的に簡単に摂取できる腸内フローラ改善剤および日常的に簡単に摂取できる腸内フローラ改善用組成物を提供することができる。本発明の腸内フローラ改善剤、および腸内フローラ改善用組成物は、刺激性がなく、様々な形態で種々の成分と併用することができ、さらなる全身効果を得るために、栄養、美容成分と併用することもできるという効果を奏する。卵殻膜含有粉末または微粉末と加水分解卵殻膜成分を併用すれば、卵殻膜含有粉末または微粉末の有する腸内フローラ改善機能およびIII型コラーゲンの生成促進機能と、加水分解卵殻膜成分の有するIII型コラーゲンの生成促進機能とが相乗的に作用して、血管、肺、肝臓、皮膚等におけるIII型コラーゲンの生成の促進と、腸内フローラの改善により美肌効果や老化防止効果が増強され、健康状態を改善および／または良好に維持することができる。この組成物は、食品添加剤、飲食品、サプリメント、可食性美容剤、医薬品として様々な形態で利用することができ、加水分解卵殻膜成分として加水分解卵殻膜粉末を用いれば、錠剤化も簡単に行うことができるという効果を奏するとともに、以下の（２）ないし（８）の態様、および（１０）ないし（１９）の態様を包含する。
（２）卵殻膜含有粉末が、体積最大粒子径および／または体積平均粒子径が１００μｍより小さい卵殻膜含有微粉末である、（１）に記載の腸内フローラ改善剤。
（３）体積平均粒子径が６μｍ以下、または体積最大粒子径が２０μｍ以下の卵殻膜含有微粉末である、（１）または（２）に記載の腸内フローラ改善剤。
（４）経口投与される製剤である、（１）ないし（３）のいずれかに記載の腸内フローラ改善剤。
（５）食品添加剤、飲食品、サプリメントまたは医薬品である、（１）ないし（４）のいずれかに記載の腸内フローラ改善剤。
（６）製剤が錠剤である、（４）に記載の腸内フローラ改善剤。
（７） 卵殻膜含有粉末の一日摂取量が１０～４８，０００ｍｇである、（１）ないし（６）のいずれかに記載の腸内フローラ改善剤。
（８）腸内フローラ改善が、腸内において、吸収されずに腸内に残った成分が腸内細菌の多様性を増加させ、かつ病原性細菌の数を減少させることによる、（１）ないし（７）のいずれかに記載の腸内フローラ改善剤。
（１０）卵殻膜含有粉末が、体積平均粒子径が６μｍ以下、または体積最大粒子径が２０μｍ以下の卵殻膜含有微粉末である、（９）に記載の腸内フローラ改善用組成物。
（１１）さらに加水分解卵殻膜成分を含む、（９）または（１０）に記載の腸内フローラ改善用組成物。
（１２）加水分解卵殻膜成分が加水分解卵殻膜粉末である、（１１）に記載の腸内フローラ改善用組成物。
（１３）卵殻膜含有微粉末１０～９０重量％および加水分解卵殻膜粉末９０～１０重量％を含んでなる、（１２）に記載の腸内フローラ改善用組成物。
（１４）III型コラーゲン生成促進のための組成物でもある、（１１）ないし（１３）のいずれかに記載の腸内フローラ改善用組成物。
（１５）経口投与される製剤である、（９）ないし（１４）のいずれかに記載の腸内フローラ改善用組成物。
（１６）食品添加剤、飲食品、サプリメント、可食性美容剤、または医薬品である、（９）ないし（１５）のいずれかに記載の腸内フローラ改善用組成物。
（１７）製剤が錠剤である、（１５）または（１６）に記載の腸内フローラ改善用組成物。
（１８）卵殻膜含有粉末と加水分解卵殻膜粉末の合計の一日摂取量が１０～４８，０００ｍｇである、（１１）ないし（１７）のいずれかに記載の腸内フローラ改善用組成物。
（１９） 腸内フローラ改善が、腸内において、吸収されずに腸内に残った成分が腸内細菌の多様性を増加させ、かつ病原性細菌の数を減少させることによる、（９）ないし（１８）のいずれかに記載の腸内フローラ改善用組成物。 Summary of the Invention
Summarize the above. The present invention is (1) an intestinal flora improving agent containing an eggshell membrane-containing powder as an active ingredient, (9) a composition for improving intestinal flora, which comprises an eggshell membrane-containing powder as an active ingredient. A composition for improving intestinal flora that can be easily taken on a daily basis and an enteric flora that can be taken easily on a daily basis in various applications such as food additives, food and drink, supplements, edible beauty agents, medicines, etc. An improvement composition can be provided. The intestinal flora improving agent and the composition for improving intestinal flora according to the present invention are non-irritating, can be used in various forms in combination with various components, and have nutritional and cosmetic components in order to obtain further systemic effects. The effect is that it can be used in combination with When the eggshell membrane-containing powder or fine powder and the hydrolyzed eggshell membrane component are used in combination, the intestinal flora improving function of the eggshell membrane-containing powder or fine powder and the function of promoting the formation of type III collagen and the hydrolysis eggshell membrane component have III The synergistic effect with the type-collagen formation promoting function promotes the production of type III collagen in blood vessels, lungs, liver, skin, etc., and the improvement of intestinal flora to enhance the beautifying effect and anti-aging effect, and health The condition can be improved and / or well maintained. This composition can be used in various forms as food additives, food and drink, supplements, edible cosmetic agents and medicines, and when hydrolyzed eggshell membrane powder is used as the hydrolyzed eggshell membrane component, tableting is easy. And the embodiments of (2) to (8) below and the embodiments of (10) to (19).
(2) The intestinal flora improving agent according to (1), wherein the eggshell membrane-containing powder is an eggshell membrane-containing fine powder having a volume maximum particle size and / or a volume average particle size of less than 100 μm.
(3) The intestinal flora improving agent according to (1) or (2), which is an eggshell membrane-containing fine powder having a volume average particle size of 6 μm or less, or a volume maximum particle size of 20 μm or less.
(4) The enteral flora improving agent according to any one of (1) to (3), which is a preparation to be administered orally.
(5) The intestinal flora improving agent according to any one of (1) to (4), which is a food additive, food and drink, a supplement or a medicine.
(6) The intestinal flora improving agent according to (4), wherein the preparation is a tablet.
(7) The intestinal flora improving agent according to any one of (1) to (6), wherein the daily intake of the eggshell membrane-containing powder is 10 to 48,000 mg.
(8) Intestinal flora improvement is due to the component remaining in the intestine without being absorbed in the intestine increasing the diversity of intestinal bacteria and decreasing the number of pathogenic bacteria, (1) to The intestinal flora improvement agent in any one of (7).
(10) The composition for improving intestinal flora according to (9), wherein the eggshell membrane-containing powder is an eggshell membrane-containing fine powder having a volume average particle diameter of 6 μm or less, or a volume maximum particle diameter of 20 μm or less.
(11) The composition for improving intestinal flora according to (9) or (10), further comprising a hydrolyzed eggshell membrane component.
(12) The composition for improving intestinal flora according to (11), wherein the hydrolyzed eggshell membrane component is a hydrolyzed eggshell membrane powder.
(13) The composition for improving intestinal flora according to (12), comprising 10 to 90% by weight of eggshell membrane-containing fine powder and 90 to 10% by weight of hydrolyzed eggshell membrane powder.
(14) The composition for improving intestinal flora according to any one of (11) to (13), which is also a composition for promoting type III collagen formation.
(15) The composition for improving intestinal flora according to any one of (9) to (14), which is a preparation to be administered orally.
(16) The composition for improving intestinal flora according to any one of (9) to (15), which is a food additive, food and drink, a supplement, an edible cosmetic agent, or a medicine.
(17) The composition for improving intestinal flora according to (15) or (16), wherein the preparation is a tablet.
(18) The composition for improving intestinal flora according to any one of (11) to (17), wherein the total daily intake of the eggshell membrane-containing powder and the hydrolyzed eggshell membrane powder is 10 to 48,000 mg.
(19) In the intestinal flora improvement, the component which is not absorbed and remains in the intestine in the intestine increases the diversity of intestinal bacteria and decreases the number of pathogenic bacteria, (9) to The composition for intestinal flora improvement in any one of (18).
　本発明によれば、刺激性がなく、様々な形態で種々の成分と併用することができる、卵殻膜含有粉末または微粉末を含む腸内フローラ改善剤を提供することができる。この製剤は、食品添加物、飲食品、サプリメント、医薬品等の様々な用途、形態で利用することができ、日常的に簡単に摂取することができる。
本発明によれば、刺激性がなく、様々な形態で種々の成分と併用することができる、卵殻膜含有粉末または微粉末を含む腸内フローラ改善用組成物を提供することができる。
　そして、加水分解卵殻膜成分と併用すれば、卵殻膜含有微粉末の有する腸内フローラ改善機能およびIII型コラーゲンの生成促進機能と、加水分解卵殻膜成分の有するIII型コラーゲンの生成促進機能とが相乗的に作用して、血管、肺、肝臓、皮膚等におけるIII型コラーゲンの生成の促進と、腸内フローラの改善が図られ、美肌効果や老化防止効果が増強され、健康状態を改善および／または良好に維持することができる組成物となる。この組成物は、食品添加剤、飲食品、サプリメント、可食性美容剤、医薬品等の様々な用途、形態で利用することができ、日常的に簡単に摂取することができる。 According to the present invention, it is possible to provide an intestinal flora improving agent containing an eggshell membrane-containing powder or a fine powder which is nonirritating and can be used in various forms and in combination with various components. This preparation can be used in various applications and forms such as food additives, food and drink, supplements, medicines, etc., and can be easily taken on a daily basis.
According to the present invention, it is possible to provide a composition for improving intestinal flora containing eggshell membrane-containing powder or fine powder which is nonirritating and can be used in various forms and in combination with various components.
And, when used in combination with the hydrolyzed eggshell membrane component, the intestinal flora improving function possessed by the eggshell membrane-containing fine powder, the function promoting formation of type III collagen, and the function promoting formation of type III collagen possessed by the hydrolyzed eggshell membrane component It acts synergistically to promote the formation of type III collagen in blood vessels, lungs, liver, skin, etc. and to improve intestinal flora, thereby enhancing skin-beautifying effects and anti-aging effects, improving health and / or Or it becomes a composition which can be maintained well. This composition can be used in various applications and forms such as food additives, food and drink, supplements, edible cosmetic agents, medicines and the like, and can be easily ingested on a daily basis.

Claims (19)

  1. 　卵殻膜含有粉末を有効成分とする腸内フローラ改善剤。 An intestinal flora improving agent comprising an eggshell membrane-containing powder as an active ingredient.
  2. 　卵殻膜含有粉末が、体積最大粒子径および／または体積平均粒子径が１００μｍより小さい卵殻膜含有微粉末である、請求項１に記載の腸内フローラ改善剤。 The intestinal flora improving agent according to claim 1, wherein the eggshell membrane-containing powder is an eggshell membrane-containing fine powder having a volume maximum particle size and / or a volume average particle size of less than 100 μm.
  3. 　卵殻膜含有粉末が、体積平均粒子径が６μｍ以下、または体積最大粒子径が２０μｍ以下の卵殻膜含有微粉末である、請求項１または２に記載の腸内フローラ改善剤。 The intestinal flora improving agent according to claim 1 or 2, wherein the eggshell membrane-containing powder is an eggshell membrane-containing fine powder having a volume average particle size of 6 μm or less, or a volume maximum particle size of 20 μm or less.
  4. 　経口投与される製剤である、請求項１ないし３のいずれかに記載の腸内フローラ改善剤。 The enteral flora improving agent according to any one of claims 1 to 3, which is an orally administered preparation.
  5. 　食品添加剤、飲食品、サプリメントまたは医薬品である、請求項１ないし４のいずれかに記載の腸内フローラ改善剤。 The intestinal flora improving agent according to any one of claims 1 to 4, which is a food additive, food and drink, a supplement or a medicine.
  6. 　製剤が錠剤である、請求項４に記載の腸内フローラ改善剤。 The enteric flora improving agent according to claim 4, wherein the preparation is a tablet.
  7. 卵殻膜含有粉末の一日摂取量が１０～４８，０００ｍｇである、請求項１ないし６のいずれかに記載の腸内フローラ改善剤。 The intestinal flora improving agent according to any one of claims 1 to 6, wherein the daily intake of the eggshell membrane-containing powder is 10 to 48,000 mg.
  8. 　腸内フローラ改善が、腸内において、吸収されずに腸内に残った成分が腸内細菌の多様性を増加させ、かつ病原性細菌の数を減少させることによる、請求項１ないし７のいずれかに記載の腸内フローラ改善剤。 The method according to any one of claims 1 to 7, wherein the improvement of intestinal flora is caused by the fact that in the intestine, components which are not absorbed and remain in the intestine increase the diversity of intestinal bacteria and decrease the number of pathogenic bacteria. Intestinal flora improving agent described in.
  9. 　腸内フローラ改善用組成物であって、卵殻膜含有粉末を有効成分として含むことを特徴とする組成物。 A composition for improving intestinal flora, which comprises an eggshell membrane-containing powder as an active ingredient.
  10. 　卵殻膜含有粉末が、体積平均粒子径が６μｍ以下、または体積最大粒子径が２０μｍ以下の卵殻膜含有微粉末である、請求項９に記載の腸内フローラ改善用組成物。 The composition for intestinal flora improvement according to claim 9, wherein the eggshell membrane-containing powder is an eggshell membrane-containing fine powder having a volume average particle size of 6 μm or less, or a volume maximum particle size of 20 μm or less.
  11. 　さらに加水分解卵殻膜成分を含む、請求項９または１０に記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to claim 9 or 10, further comprising a hydrolyzed eggshell membrane component.
  12. 　加水分解卵殻膜成分が加水分解卵殻膜粉末である、請求項１１に記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to claim 11, wherein the hydrolyzed eggshell membrane component is a hydrolyzed eggshell membrane powder.
  13. 　卵殻膜含有微粉末１０～９０重量％および加水分解卵殻膜粉末９０～１０重量％を含んでなる、請求項１２に記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to claim 12, comprising 10 to 90% by weight of eggshell membrane-containing fine powder and 90 to 10% by weight of hydrolyzed eggshell membrane powder.
  14. 　III型コラーゲン生成促進のための組成物でもある、請求項１１ないし１３のいずれかに記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to any one of claims 11 to 13, which is also a composition for promoting type III collagen formation.
  15. 　経口投与される製剤である、請求項９ないし１４のいずれかに記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to any one of claims 9 to 14, which is an orally administered preparation.
  16. 　食品添加剤、飲食品、サプリメント、可食性美容剤、または医薬品である、請求項９ないし１５のいずれかに記載の腸内フローラ改善用組成物。 The composition for intestinal flora improvement according to any one of claims 9 to 15, which is a food additive, food and drink, supplement, edible cosmetic agent, or medicine.
  17. 　製剤が錠剤である、請求項１５または１６に記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to claim 15 or 16, wherein the preparation is a tablet.
  18. 　卵殻膜含有粉末と加水分解卵殻膜粉末の合計の一日摂取量が１０～４８，０００ｍｇである、請求項１１ないし１７のいずれかに記載の腸内フローラ改善用組成物。 The composition for improving intestinal flora according to any one of claims 11 to 17, wherein the total daily intake of the eggshell membrane-containing powder and the hydrolyzed eggshell membrane powder is 10 to 48,000 mg.
  19. 　腸内フローラ改善が、腸内において、吸収されずに腸内に残った成分が腸内細菌の多様性を増加させ、かつ病原性細菌の数を減少させることによる、請求項９ないし１９のいずれかに記載の腸内フローラ改善用組成物。
     
     
     
     
     
     
     
          20. The method according to any one of claims 9 to 19, wherein the improvement of intestinal flora is that in the intestine, components which are not absorbed but remain in the intestine increase the diversity of intestinal bacteria and decrease the number of pathogenic bacteria. A composition for improving intestinal flora according to any one of the preceding claims.







PCT/JP2017/035121 2016-09-29 2017-09-28 Intestinal microbiota improving agent and intestinal microbiota improving composition that include eggshell membrane–containing powder WO2018062354A1 (en)

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