Enteric capsule preparation for improving intestinal flora, containing nicotinamide mononucleotide encapsulated therein

Abstract

[Problem] To provide a preparation which is safe for long-term intake and which can improve intestinal flora and enhance the barrier function of intestinal mucosa. [Solution] An enteric capsule preparation for improving intestinal flora, containing nicotinamide mononucleotide as an active ingredient.

Description

Technical Field

[0001] The present invention relates to an enteric-coated capsule preparation for improving intestinal flora, wherein nicotinamide mononucleotide is sealed in the enteric-coated capsule preparation. Background Art

[0002] It is known that in the human intestine, from the small intestine to the large intestine, there are about 1,000 species, 100 to 1,000 trillion intestinal bacteria, which are deeply involved in the nutritional metabolism, defense mechanism, immune mechanism, etc. of the human host. Human intestinal bacteria are roughly divided into three categories: so-called good bacteria (hereinafter referred to as good bacteria), so-called bad bacteria (hereinafter referred to as bad bacteria) and intermediate bacteria (opportunistic bacteria) that are neither good bacteria nor bad bacteria. These bacteria are closely related to each other, each maintaining a balance and choosing a comfortable place to live. Regarding the distribution of intestinal bacteria, there are few bacteria that are always present from the duodenum to the upper part of the small intestine, but toward the lower part of the small intestine, the number of bacteria increases, and from the lower part of the small intestine to the large intestine, the speed of the contents passing through is slow and there is almost no oxygen, so many bacteria (anaerobic bacteria) that prefer this environment survive. When the bacteria reach the large intestine, the number of bacteria increases rapidly and its composition becomes almost the same as the composition of the flora of the excreta. In particular, the number of obligate anaerobic bacteria such as Bacteroides, Bifidobacterium bifidum and Eubacterium increases sharply.

[0003] Among intestinal bacteria, bad bacteria proliferate in the intestines due to a Western diet consisting mainly of protein and fat, an irregular lifestyle, mental stress, constipation, and the like. If bad bacteria multiply too much, it can easily lead to rough skin, decreased immunity, and the onset of lifestyle-related diseases. In a healthy intestine, good bacteria such as Bifidobacterium bifidum and Lactobacillus are dominant, while other bacteria are at a disadvantage. When good bacteria produce short-chain fatty acids such as lactic acid and acetic acid and make the intestines acidic, they are said to inhibit the proliferation of bad bacteria and activate intestinal motility, preventing infections caused by food poisoning bacteria and pathogenic bacteria, and creating an intestinal environment that inhibits the production of carcinogenic spoilage products. Good bacteria also produce various vitamins (B1, B2, B6, B 12 , K, niacin, etc.). In addition, it has been reported that substances constituting the main body of good bacteria have the effect of improving body immunity and lowering serum cholesterol. On the other hand, when good bacteria are dominant, opportunistic bacteria contribute to the production of vitamins and hormones required for biological activities and lipid metabolism activities. On the contrary, when bad bacteria are dominant, they produce harmful substances and play roles such as weakening the barrier function and immunity of the intestine. Therefore, it is said that the golden ratio of intestinal bacteria is a balance of 10% bad bacteria, 20% good bacteria and 70% opportunistic bacteria. In the past, it was believed that the more good bacteria, the better. However, it has been found that some bacteria that are considered harmful also have beneficial effects on the body, so it is now believed that the presence of various intestinal bacteria is preferred.

[0004] There are different intestinal bacteria of various types (compositions) between people, and it is said that they are also different due to factors such as diet, climate and living environment. For example, it has been revealed that compared with the intestinal flora of the United States, France, etc., the intestinal flora of Japanese people is mainly based on, for example, Bifidobacterium bifidum and Blautia, and Archaea is less rich in the metabolic function of carbohydrates or amino acids. In addition, the balance of intestinal flora changes with age, and the types of intestinal bacteria increase as people get older. In the elderly, the number of Clostridium perfringens, Escherichia coli, Enterococcus faecalis, Lactobacillus, etc. increases, while the number of Bifidobacterium bifidum that dominates when they are young decreases. In addition, intestinal flora can change due to mental stress, drugs and diseases. For example, due to the intake of drugs such as antibiotics and proton pump inhibitors (PPI) or food poisoning, intestinal bacteria can change significantly.

[0005] In recent years, the progress of genetic analysis technology using next generation sequencers, etc. has made it possible to comprehensively analyze the genes of intestinal bacteria and their metabolites. Therefore, the profile and function of intestinal flora are becoming clear. Therefore, it has become clear that intestinal flora is closely related to diseases such as obesity, diabetes, colon cancer, arteriosclerosis and inflammatory bowel disease, and the intestinal flora of these patients is significantly different from that of healthy people. In addition, compared with the past, it is increasingly recognized that the importance of intestinal flora in maintaining human health. Therefore, disease prevention methods and treatment methods aimed at maintaining normal intestinal flora and correcting abnormal intestinal flora are being considered. When the diversity and balance of human intestinal bacteria are lost, the intestinal environment becomes disordered, which is called imbalance. Disharmony is the abnormality of the bacterial species that constitute the intestinal flora, and refers to the reduction of the diversity of normally existing bacterial species, the abnormal proliferation of usually scarce bacterial species, and the abnormal reduction of usually abundant bacterial species.

[0006] Medications such as antimicrobials and proton pump inhibitors, a Western diet, and environmental factors have been pointed out as causes of the disorder.

[0007] It is believed that the administration of drugs such as antimicrobials and proton pump inhibitors disrupts the uniformity and diversity of the intestinal flora and leads to a dysbiotic state, resulting in the paralysis of the host's defense mechanisms.

[0008] Western diet is characterized by low dietary fiber and high fat, and low dietary fiber means that lactic acid and short-chain fatty acids such as acetic acid produced by fermentation are low. It has been reported that short-chain fatty acids show anti-inflammatory effects and can also reduce the permeability of the intestine, thereby protecting the intestine. Therefore, it can be said that insufficient dietary fiber intake can reduce the production of short-chain fatty acids, thereby more easily leading to imbalance. It has also been reported that a high-fat diet can reduce Bacteroidetes and induce the increase of Firmicutes and Proteobacteria, thereby leading to a disorder of the balance of intestinal flora. In addition, Western diet contains food additives, such as artificial sweeteners, emulsifiers and preservatives. It is revealed that some of these are related to imbalance. It is believed that such additives can increase membrane permeability, promote harmful substances such as lipopolysaccharides (LPS) to be absorbed into the gastrointestinal tract, reduce the barrier function of the intestinal mucosa, thereby leading to imbalance.

[0009] Regarding environmental factors, associations between air pollutants and dysbiosis or inflammatory diseases have been reported.

[0010] In recent years, the number of patients suffering from inflammatory bowel diseases such as ulcerative colitis has exploded, and it has been revealed that the cause is closely related to the Western diet pattern. As described above, the Western diet has been pointed out as one of the causes of the imbalance that is believed to easily lead to inflammatory bowel disease. In other words, one of the causes of inflammatory bowel disease (which is steadily increasing in the number of patients) is believed to be the destruction of the intestinal mucosal barrier and the disorder of the balance of intestinal flora.

[0011] The intestinal mucosal barrier is an infection defense mechanism present on the surface of the gastrointestinal tract (through which foreign microorganisms pass with the intake of food, and many microorganisms coexist therein), and protects the intestinal tissue from the invasion of these microorganisms, or avoids excessive immune response to inherent microorganisms. This intestinal mucosal barrier is roughly divided into two types, physical barriers and chemical barriers, according to their functions or characteristics. The physical barrier is a barrier that acts as a physical wall to prevent microbial invasion, and includes a mucus layer (mucin layer) covering the epithelial layer of the intestine, a sugar layer as an assembly of sugar chains present on the surface of epithelial cells, and a tight junction as an intercellular adhesion device. For example, in the large intestine where there are many intestinal bacteria, the mucus layer as one of the intestinal mucosal barriers covers the surface thickly, and it is known that intestinal bacteria are not easy to invade the large intestine tissue. On the other hand, the chemical barrier is a group of molecules that cause chemical changes in microorganisms by secreting antimicrobial peptides, and exhibit antimicrobial activity to inhibit bacterial invasion. These antimicrobial peptides include defensin family molecules and Reg3 family molecules, and these molecules are mainly produced by Paneth cells, which are one of the intestinal epithelial cells.

[0012] As mentioned above, intestinal epithelial cells have the barrier function of the intestinal mucosa that prevents pathogen invasion, and therefore play an important role in host defense and maintaining homeostasis. In addition, the intestinal mucosal barrier is also very important in avoiding the excessive immune response to host intestinal bacteria by separating intestinal bacteria from the epithelium of the intestine. Therefore, when the intestinal mucosal barrier becomes abnormal, intestinal bacteria and the epithelium of the intestine are close to each other spatially, which makes it easier to produce an immune response to intestinal bacteria. Then, strong immune response causes the disorder of intestinal flora balance, thereby causes various diseases, such as the outbreak or the weight of inflammatory bowel disease (comprising intestinal inflammation), metabolic diseases and autoimmune diseases.

[0013] Furthermore, even if the composition of the healthy intestinal flora is disturbed, it has the ability to return to a normal, balanced state, the so-called symbiotic state, over a certain period of time. However, when the imbalance persists for a long period of time, it is believed that this can trigger the breakdown of the intestinal barrier or the migration of abnormally increased bacterial toxins and metabolites into the body due to the imbalance, leading to systemic chronic inflammation and the onset of inflammatory and metabolic diseases.

[0014] Therefore, the intestinal mucosal barrier and intestinal flora are closely related to health and disease, and even affect human life span. Therefore, it can be said that making the intestinal mucosal barrier function normally, improving the disorders involved in the onset of various diseases, correcting the intestinal flora to the good balance existing in a healthy host and thus maintaining homeostasis will affect the prevention and treatment of diseases and is very important for the host to live a long and healthy life.

[0015] In the past, as drugs for improving human intestinal flora, active probiotic preparations that serve as intestinal resident bacteria and regulate the intestinal environment have been widely known. Commonly used probiotic preparations include lactobacillus (Streptococcus faecalis and Lactobacillus acidophilus), Bifidobacterium bifidum, Clostridium butyricum (Miyairi), Lactobacillus casei, and resistant lactobacillus.

[0016] Furthermore, as a composition for promoting the production of short-chain fatty acids produced by intestinal bacteria and for improving intestinal flora, a composition for promoting the production of intestinal short-chain fatty acids containing fucose as an active ingredient has been reported (Patent Document 1).

[0017] As another example, an agent for improving intestinal flora for preventing or improving at least one selected from the group consisting of obesity, hypertension and constipation has been reported, which contains Chlorella, which is a microalgae belonging to the genus Euglena and has a particular effect of reducing the ratio of Firmicutes bacteria to Bacteroidetes bacteria (Patent Document 2).

[0018] Prior art literature

[0019] Patent Document 1: JP 2019-170335 A

[0020] Patent Document 2: JP 2019-89733A Summary of the invention

[0021] Technical issues

[0022] Based on the above, it is believed that in order to protect the health of the host, it is important to maintain a good intestinal mucosal barrier function and keep the composition of the intestinal flora in a healthy state. However, as mentioned above, there are various causes for the decline and disorder of the intestinal mucosal barrier function, and effective countermeasures against them have not yet been established.

[0023] Therefore, an object of the present invention is to provide a preparation which will effectively improve the intestinal flora and enhance the barrier function of the intestinal mucosa and is safe for long-term intake.

[0024] Means used to solve problems

[0025] As a result of diligent research to solve the above problems, the present inventors have found that nicotinamide mononucleotide, an intermediate metabolite associated with the biosynthesis of the coenzyme nicotinamide adenine dinucleotide (NAD), is effective in improving intestinal flora and enhancing the barrier function of the intestinal mucosa, and that the use of an enteric-coated capsule preparation as a dosage form can solve the above problems. Thus, the present inventors have completed the present invention.

[0026] The present invention is as follows.

[0027] [1] An enteric-coated capsule preparation for improving intestinal flora, comprising:

[0028] Nicotinamide mononucleotide is enclosed in it as an active ingredient.

[0029] [2] The enteric-coated capsule preparation for improving intestinal flora according to [1], wherein:

[0030] The improvement of the intestinal flora reduces the presence ratio of bacteria of the genus Mycobacterium in the intestinal flora.

[0031] [3] The enteric-coated capsule preparation for improving intestinal flora according to [1], wherein:

[0032] The improvement of the intestinal flora increases the presence ratio of Phascolarctobacterium bacteria in the intestinal flora.

[0033] [4] The enteric-coated capsule preparation for improving intestinal flora according to [1], wherein:

[0034] The improvement of the intestinal flora inhibits the reduction of the presence ratio of Dorea bacteria and / or Lachnospira bacteria in the intestinal flora.

[0035] [5] The enteric-coated capsule preparation for improving intestinal flora according to [1], comprising:

[0036] The intestinal bacteria enclosed within.

[0037] [6] The enteric-coated capsule preparation for improving intestinal flora according to [1], comprising:

[0038] The probiotics enclosed within.

[0039] [7] The enteric-coated capsule preparation for improving intestinal flora according to [6], wherein:

[0040] The probiotics are selected from one or more strains belonging to the phylum Acidobacteria, Actinobacteria, Firmicutes, Bacteroidetes, Ascomycota, Fusobacteria, Chlamydia, Chloroflexi, Cyanobacteria, Deferrobacillaceae, Deinococcus-Thermus, Fibrobacter, Gemmatimonadetes, Mycosphaeria, Planctomycetes, Spirochetes, Soft-walled Fungi, Verrucomicrobia and Proteobacteria.

[0041] [8] The enteric-coated capsule preparation for improving intestinal flora according to [6], wherein:

[0042] The probiotics are selected from one or more strains belonging to the genera Lactobacillus, Bacillus, Bifidobacterium, Escherichia, Saccharomyces, Enterococcus, Clostridium, Prevotella, Acidococcus, Fusobacterium, Veillonella, Klebsiella, Streptococcus, Megasphaera, Aeromonas, Aspergillus, Bacteroides, Lactococcus, Leuconostoc, Debaryomyces, Oenococcus, Pediococcus, Weissella and Eubacterium.

[0043] [9] The enteric-coated capsule preparation for improving intestinal flora according to [6], comprising:

[0044] Prebiotics sealed in it.

[0045]

[10] The enteric-coated capsule preparation for improving intestinal flora according to [9], wherein:

[0046] The prebiotics are one or more selected from fructooligosaccharides, lactofructooligosaccharides, isomaltosyl fructoside, galacto-oligosaccharides, lactulose, isomalto-oligosaccharides, gentio-oligosaccharides, trehalose, xylo-oligosaccharides, soybean oligosaccharides, maltitol, lactitol, reduced isomaltose, sorbitol and xylitol.

[0047]

[11] The enteric-coated capsule preparation for improving intestinal flora according to [1], wherein:

[0048] The enteric-coated capsule preparation is used for enhancing the barrier function of the intestinal mucosa.

[0049]

[12] The enteric-coated capsule preparation for improving intestinal flora according to [1], wherein:

[0050] The enteric-coated capsule preparation is a food.

[0051]

[13] The enteric-coated capsule preparation for improving intestinal flora according to [1], wherein:

[0052] The enteric-coated capsule preparation is a medicine.

[0053]

[14] A method for improving intestinal flora or a method for enhancing the barrier function of intestinal mucosa, the method comprising:

[0054] A subject is made to ingest the enteric-coated capsule preparation for improving intestinal flora according to any one of [1] to

[13] .

[0055] Effects of the Invention

[0056] The present invention is effective in improving intestinal flora and enhancing the barrier function of the intestinal mucosa, and contains nicotinamide mononucleotide as an active ingredient, which is a nicotinamide mononucleotide that binds to NAD in the body. + Biosynthesis-related intermediate metabolites. Therefore, the present invention is safe and can be taken for a long time. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 FIG. 1 is an illustrative diagram illustrating a metabolic pathway associated with niacin (a general term for nicotinamide and nicotinic acid). DETAILED DESCRIPTION

[0058] The enteric-coated capsule preparation for improving intestinal flora according to the present invention (i.e., an acid-resistant capsule, hereinafter referred to as an "enteric-coated capsule preparation") is a capsule preparation, wherein nicotinamide mononucleotide is enclosed in the capsule as an active ingredient, and other suitable components, and the capsule preparation is configured to be dissolved from the small intestine to the large intestine to expose the capsule contents. Therefore, the active ingredient is not inactivated by gastric acid before reaching the small intestine or the large intestine, and the function of the capsule contents is maintained, so that it can play its function in the small intestine or the large intestine. Here, the type of the enteric-coated capsule preparation may be any one of a hard capsule, a soft capsule, and a seamless capsule.

[0059] The detailed reasons why the inclusion of nicotinamide mononucleotide as an active ingredient produces improvements in intestinal flora or enhancement of the barrier function of the intestinal mucosa are still under consideration. However, as one of the main reasons, it is considered that nicotinamide mononucleotide accelerates the production of NAD +The invention activates intestinal epithelial cells by activating the intestinal flora or enhancing the barrier function of the intestinal mucosa. The invention is described in detail below.

[0060] Nicotinamide mononucleotide (chemical formula: C 11 H 15 N2O8P) is a compound produced in the body of many organisms including humans, and is represented by the following structural formula [Chemical Formula 1]. Nicotinamide mononucleotide, commonly referred to as NMN (Nicotinamide mononucleotide), is a + intermediate metabolites in the biosynthesis of

[0061] [Chemical formula 1]

[0062]

[0063] Nicotinamide mononucleotide contained as an active ingredient in the enteric-coated capsule formulation is produced in vivo by liver tissue in a pathway involved in the NAD metabolic pathway, namely, the synthesis of nicotinamide adenine dinucleotide (NAD) from quinolinic acid via the kynurenine pathway. Figure 1 This will be described in detail. Figure 1 It is an illustration of the metabolic pathways involved in niacin (a general term for niacinamide and nicotinic acid), which is called vitamin B3. Niacinic acid ingested through the diet is absorbed by the liver to be converted into niacinamide, which is supplied to the whole body through the bloodstream. Each cell absorbs niacinamide from the blood and converts it into NAD and NADP to use them. Nicotinamide can also be biosynthesized from tryptophan.

[0064] like Figure 1 As shown, in vivo, when tryptophan is used as a starting material, tryptophan is converted into quinolinic acid (QA) through the kynurenine pathway as a tryptophan metabolic pathway, and is further converted into nicotinic acid mononucleotide (NaMN). At the same time, when nicotinic acid (Na) is used as a starting material, nicotinic acid is directly converted into NaMN. Afterwards, NaMN is mutually converted into NAD, nicotinamide (NaM) and nicotinamide mononucleotide in the NAD cycle through nicotinic acid adenine dinucleotide (NaAD). Nicotinamide (NaM) is converted into nicotinamide mononucleotide by nicotinamide phosphoribosyltransferase (NAMPT), and subsequently, nicotinamide mononucleotide is converted by nicotinamide mononucleotide adenosyltransferase (NMNAT) to produce NAD. Note that nicotinamide mononucleotide is also produced by nicotinamide riboside (NR), which is an intermediate metabolite of NAD.

[0065] Nicotinamide mononucleotide includes two types, α-type and β-type, as optical isomers, and the β-type is used in the present invention. Nicotinamide mononucleotide is obtained, for example, by the following process: nicotinamide ribose is synthesized from nicotinamide and ribose (see Bioorg. Med. Chem. Lett., 12, 1135-1137 (2002)), followed by phosphorylation of the 5-hydroxyl group of the ribose moiety (see Chem. Comm., 1999, 729-730). Specifically, for example, first, a reaction solution is prepared by the following process: nicotinamide and L-ribose tetraacetate are dissolved in anhydrous acetonitrile, trimethylsilyl trifluorosulfonic acid is added in excess under a nitrogen stream, then stirred at room temperature, and methanol is added to stop the reaction. The above reaction solution is poured into a column filled with activated carbon, washed with distilled water, then eluted with methanol, and the product is collected. Next, in order to carry out the phosphorylation reaction of the 5-hydroxyl group of the L-ribose part of the product, the above product is dissolved in trimethoxyphosphoric acid, phosphorus oxychloride is added dropwise at freezing point, and stirred under a nitrogen stream, and an aqueous sodium hydroxide solution is added for neutralization, thereby stopping the reaction and preparing a reaction solution. A cold acetonitrile-ether solution is added to the above reaction solution. Afterwards, the lower layer (aqueous phase) is passed through an anion exchange resin to collect the reactants, and the reactants are further purified with a cation exchange resin, so that high-purity nicotinamide mononucleotide can be collected. Nicotinamide mononucleotide can be purchased from Oriental Yeast Industry Co., Ltd. and Bontai Biotechnology (Shenzhen) Co., Ltd., and these commercial products can be purchased for use.

[0066] Nicotinamide mononucleotide is a purified product containing a low content of impurities, and in particular, its purity is preferably 90% or more, more preferably 95% or more. When the purity is lower than 90%, an unpleasant odor may be generated, or the effect of nicotinamide mononucleotide may be weakened, and thus the effect of the present invention may not be fully obtained.

[0067] The enteric capsule preparation according to the present invention can be easily prepared by using nicotinamide mononucleotide alone or mixing other components. As long as the enteric capsule preparation exhibits the effects of the present invention, other components are not particularly limited.

[0068] Examples of other components include intestinal bacteria. Regarding the selection of specific intestinal bacteria, the composition of the bacterial species of the intestinal flora varies from person to person, and it is now believed that the presence of a variety of intestinal bacteria is beneficial to health. Based on this, it is preferred that when each person is healthy, based on the composition of the intestinal flora, a strain that is considered to be lacking compared to the current intestinal flora is appropriately selected. Broadly and generally, Bacillus subtilis natto variant, lactobacillus and Bifidobacterium bifidum are applied. These three types of good bacteria work together to produce metabolites (organic acids such as lactic acid and acetic acid) that keep the intestinal environment slightly acidic, and the slightly acidic environment is expected to have a high health effect of preventing the proliferation of bad bacteria that are intolerant to acid and enhancing the barrier function of the intestine.

[0069] In addition, preferred examples of other components include probiotics. In the present invention, probiotics are defined as "microorganisms having a positive effect on the human body or products containing the microorganisms". This corresponds to so-called useful bacteria and fermentation products containing the useful bacteria. In the present invention, probiotics include not only living bacteria but also dead bacteria, and also include not only bacteria but also cell wall components such as peptidoglycan, and components such as DNA and RNA.

[0070] As specific examples of probiotics, strains belonging to one or more of the phyla Acetobacter, Actinobacteria, Firmicutes, Bacteroidetes, Ascomycota, Fusobacteria, and Proteobacteria may be selected.

[0071] In addition, as specific examples of probiotics, strains belonging to one or more of the following can be selected: Lactobacillus (e.g., various lactobacilli), Bacillus (e.g., Bacillus subtilis var. natto and Bacillus amylolyticus), Bifidobacterium (e.g., various Bifidobacterium bifidum), Escherichia (e.g., Escherichia coli), Saccharomyces (e.g., Saccharomyces cerevisiae), Enterococcus (e.g., Enterococcus faecalis and Enterococcus faecium), Clostridium (e.g., Clostridium butyricum, Clostridium pseudosphaeroides, Clostridium tenuissima, Clostridium multibranchium and Clostridium perfringens), Prevotella (e.g., Prevotella copri), Aminosphaeroides (e.g., and Streptococcus (e.g., Streptococcus thermophilus and Streptococcus faecalis), Macrosphaera (e.g., Macrosphaera elsdenii), Aerococcus (e.g., Aerococcus viride), Aspergillus (e.g., Aspergillus oryzae), Bacteroides (e.g., Bacteroides vulgaris), Lactococcus (e.g., Lactococcus lactis), Leuconostoc (e.g., Leuconostoc mesenteroides), Debaryomyces (e.g., Debaryomyces tamarii), Oenococcus (e.g., Oenococcus oeni), Pediococcus (e.g., Pediococcus acidilactici), Weissella (e.g., Weissella sinusovorans), and Eubacterium (e.g., Eubacterium mucosum).

[0072] In particular, when probiotics are contained, it is preferred that the probiotics are also contained in combination with prebiotics. When probiotics and prebiotics (synbiotics) are taken at the same time, the intestinal environment can be improved more effectively. Prebiotics are generally defined as "digestible food ingredients that have beneficial effects on the host by proliferating good bacteria normally present in the large intestine or inhibiting the proliferation of bad bacteria." "Beneficial effects" include a wide range of effects, such as preventing infection, regulating immune response, regulating blood pressure and blood sugar, promoting mineral absorption, skin health and relieving mental stress.

[0073] Specific examples of prebiotics include one or more selected from oligofructose, lactulose oligosaccharide, isomaltose fructoside, galacto-oligosaccharide, lactulose, isomalto-oligosaccharide, oligogentiosaccharide, trehalose, oligoxylose, soybean oligosaccharide, maltitol, lactitol, reduced isomaltulose, sorbitol and xylitol. Prebiotics suitable for enhancing the proliferation of the probiotics used are preferably selected.

[0074] The enteric-coated capsule preparation according to the present invention can be used to improve intestinal flora or to enhance the barrier function of intestinal mucosa. In the present invention, "improving intestinal flora" not only means returning to or approaching the diversity or balance of healthy intestinal bacteria in the intestinal flora when compared with the intestinal flora of a healthy host, but also means preventing or delaying the deterioration of the state of intestinal flora in a broad sense. In addition, "enhancing the barrier function of intestinal mucosa" not only means enhancing the barrier function of intestinal mucosa in a narrow sense (recovering to or approaching the barrier function of the intestinal mucosa of a healthy host) when compared with the barrier function of the intestinal mucosa of a healthy host, but also means preventing or delaying the deterioration of the barrier function of the intestinal mucosa in a broad sense.

[0075] In the present invention, specific examples of improving the intestinal flora include reducing the presence ratio of Alternaria bacteria in the intestinal flora, increasing the presence ratio of Phallacinus bacteria, and inhibiting the reduction of the presence ratio of Dorea bacteria and / or Lachnospira bacteria.

[0076] The enteric capsule preparations according to the present invention are roughly classified into: an enteric capsule preparation in which the capsule contents (enteric granules) coated with an enteric polymer are enclosed in a capsule, and an enteric capsule preparation in which the capsule contents are enclosed in an enteric capsule coated with an enteric polymer (i.e., a capsule that dissolves in the small intestine or large intestine). In addition, enteric capsule preparations in which enteric granules are enclosed in an enteric capsule coated with an enteric polymer are also included.

[0077] In the former enteric capsule preparation, examples of the enteric polymer include substances that show good solubility in aqueous solvents having neutral to alkaline pH values ​​assumed to be the intestinal environment. Specific examples thereof include methacrylic acid polymers (e.g., methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S) that dissolve in the pH range of about 5 to 12.0, cellulose polymers (e.g., carboxymethylethylcellulose, hypromellose phthalate, and hypromellose acetate succinate), and vinyl polymers (i.e., polyvinyl acetate phthalate and polyvinyl butyrate phthalate).

[0078] The latter enteric capsule preparations include those in which the surface of the capsule is acid-resistantly coated with an enteric polymer, and those in which the surface of the capsule is acid-resistant itself and therefore does not need to be acid-resistantly coated with an enteric polymer.

[0079] The former enteric capsule preparation in which the capsule contents (enteric granules) coated with an enteric polymer are enclosed in a capsule is manufactured by, for example, the following method. First, as a method for obtaining enteric granules by coating the capsule contents with an enteric polymer, a conventional fine-particle coating method, such as a fluidized bed granulation method and a fine-particle coating method, can be used. For example, in the fine-particle coating method, a coating solution containing, for example, an enteric polymer is sprayed and dried on the particulate raw material loaded into a fluidized bed granulation device to coat. Then, enteric granules can be obtained. The coating amount can be appropriately set to achieve the function of releasing the particulate raw material for the first time in the small intestine or large intestine. Then, the enteric granules (if necessary together with additives) are enclosed in a gelatin capsule, a common capsule or an enteric capsule formed by, for example, a cellulose derivative or starch, to manufacture an enteric capsule preparation.

[0080] The latter enteric capsule preparation in which the capsule contents are enclosed in an enteric capsule is manufactured by, for example, the following method. An enteric polymer is coated on a non-enteric gelatin capsule or an ordinary capsule containing a cellulose derivative, etc., using a fluidized bed coating device, a rotary disc coating device, etc., to obtain an enteric capsule. The coating amount can be appropriately set to achieve the function of releasing the capsule contents for the first time in the small intestine or the large intestine. Then, the capsule contents are enclosed in an enteric capsule to manufacture an enteric capsule preparation. Note that commercially available products as enteric capsules can be used as long as the function of releasing the capsule contents for the first time in the small intestine or the large intestine is achieved.

[0081] In the enteric capsule preparation according to the present invention, the respective amounts of nicotinamide mononucleotide, probiotics, and prebiotics to be blended may be appropriately determined in consideration of the number of daily intakes and the like, with reference to the respective daily intakes described below.

[0082] The enteric-coated capsule preparation according to the present invention can be used as food or medicine. When the enteric-coated capsule preparation of the present invention is taken daily in the form of food, the effect of the present invention can be repeatedly provided, which is particularly effective in improving the balance or diversity of intestinal flora. The type of food as the object of the present invention is not particularly limited, and in addition to general food, the object also includes functional food, food for designated health purposes, dietary supplements, food additives, feed, nursing food, dietetic food, therapeutic diet, weight loss food, etc.

[0083] The intake of food varies depending on the type of food, the age, sex, weight, expected effect, etc. of the subject taking the food. However, the daily intake of nicotinamide mononucleotide contained in food is generally 1 mg to 500 mg per adult, preferably 5 mg to 400 mg, and more preferably 50 mg to 300 mg. Less than 1 mg may not provide the effect of the present invention, while more than 500 mg only provides almost similar effects, but causes economic disadvantages. The ratio of nicotinamide mononucleotide in food can be appropriately set within the range of less than 100% relative to the total weight of the food.

[0084] The intake amount of probiotics contained in food only needs to be appropriately determined according to the type of strain, etc. For example, the daily intake amount per adult can be 10 7 cfu to 10 11 cfu, or 10 9 cfu to 10 10 cfu.

[0085] The intake amount of prebiotics contained in food is preferably an amount suitable for promoting the proliferation of the probiotics used. The daily intake per adult is generally in the range of 1 mg to 20 g, and only needs to be appropriately determined according to the type of strain and the like.

[0086] The food is safe and has no particular side effects, so it can be taken for a long time. It is suitable not only for the elderly but also for young people.

[0087] On the other hand, the enteric capsule preparation according to the present invention can be taken orally as a medicine (including quasi-drugs) to improve intestinal flora or enhance the barrier function of intestinal mucosa in the pharmaceutical field. In addition, considering the physicochemical properties, biological properties, etc., the medicine can be appropriately mixed with pharmaceutically acceptable known drug additives.

[0088] The dosage of the drug varies depending on, for example, the age, sex and weight of the subject, the expected effect, symptoms and the number of administrations, and cannot be specified equally. However, as the dosage of the drug, the amount of nicotinamide mononucleotide to be administered per adult per day is generally 1 mg to 500 mg, preferably 5 mg to 400 mg, and more preferably 50 mg to 300 mg. Less than 1 mg may not provide the effect of the present invention, while more than 500 mg can only provide almost similar effects, but will cause economic disadvantages. The ratio of nicotinamide mononucleotide in the drug can be appropriately set according to the dosage form and dosage of the drug, etc.

[0089] The dosage of the probiotics contained in the medicine only needs to be appropriately determined depending on the type of strain, etc. For example, the daily dosage per adult may be 10 7 cfu to 10 11cfu, or 10 9 cfu to 10 10 cfu.

[0090] The dosage of the prebiotic contained in the medicine is preferably such an amount as to be suitable for promoting the proliferation of the probiotics used. The daily dosage per adult is generally in the range of 1 mg to 20 g, and only needs to be appropriately determined depending on the kind of strain and the like.

[0091] The number of times the drug is administered can be appropriately set according to, for example, the age, weight, and symptoms of the subject and the amount of the drug administered each time. The number of times the drug is administered per day can be exemplified as once to three times.

[0092] The present invention also provides a method for improving intestinal flora or a method for enhancing the barrier function of intestinal mucosa, wherein an enteric-coated capsule preparation is applied to an object. The object of intake is preferably a mammal, such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs and monkeys, and is particularly preferably humans. In the method, the intake amount of the enteric-coated capsule preparation, the daily intake number of times, etc. are as described for the enteric-coated capsule preparation. In any case, the enteric-coated capsule preparation can be taken in at any time, and can be taken in by the object for a long time.

[0093] Example

[0094] The present invention will be described in detail below by way of Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[0095] [Example]

[0096] 58 ordinary male and female subjects aged 45 years and over and under 65 years were divided into Group I subjects (intake group of enteric-coated capsule preparation (capsule preparation 1) containing NMN: 30 subjects) and Group II subjects (intake group of placebo (capsule preparation 2): 28 subjects), and each capsule preparation was orally taken for four weeks in a placebo-controlled double-blind comparative trial. Group I subjects took two capsule preparations 1 per day, and Group II subjects took two capsule preparations 2 per day. As capsule preparations 1 and 2, enteric-coated capsule preparations containing the following components were used.

[0097] Capsule formulation 1: 150 mg NMN, 50 mg starch and 60 mg hydroxypropyl methylcellulose (per capsule)

[0098] Capsule Formulation 2: 200 mg starch and 60 mg hydroxypropyl methylcellulose (per capsule)

[0099] Feces were collected at the beginning of intake and 4 weeks after the beginning of intake, and the changes in the intestinal flora of the subjects caused by the administration of the enteric-coated capsule preparation of the present invention were analyzed. The bacteria belonging to the genus were analyzed, and the genera of Mycobacterium, Phascolarctobacterium, Dorea bacteria and Lachnospira, which were bacteria with a presence ratio of more than 0.1% in the intestinal flora, were analyzed, and their relative presence ratio relative to the total bacterial species was investigated. The intestinal flora was analyzed using a next-generation sequencer. The analysis of the flora in the feces was outsourced to Medical Systems Co., Ltd.

[0100] [Results and discussion]

[0101] Table 1 shows the mean ± SD of the presence ratio of each of the above bacterial species for subjects in group I (NMN) and subjects in group II (placebo). Table 2 shows the difference between before and after the start of intake and 4 weeks of intake, the before-after comparison between before and after the start of intake and 4 weeks of intake for each group; and the intergroup comparison between group I and group II for the difference between before and after the start of intake, after 4 weeks of intake, and before and after the start of intake. Note that the values ​​of the before-after comparisons were determined by the Wilcoxon signed rank test. The values ​​of the intergroup comparisons were determined by the Wilcoxon-Mann-Whitney test.

[0102] As can be seen from Tables 1 and 2, the change of the genus Mycobacterium before and after taking the enteric-coated capsule preparation was significantly higher in Group II than in Group I, and a significant increase was observed in Group II before and after taking the enteric-coated capsule preparation. Mycobacterium is an intestinal bacterium that has been reported to be associated with various diseases and has been reported to play a pathogenic role in hypertension, cardiovascular disease, mental illness, and colon cancer. Therefore, it is believed that the presence of Mycobacterium can cause adverse effects on humans. In addition, it was confirmed that the intake of an enteric-coated capsule preparation containing NMN inhibited Mycobacterium and provided an effect of reducing Mycobacterium.

[0103] Compared with Group II, the change of Phascolarctobacterium before and after taking the enteric-coated capsule preparation was significantly higher in Group I, and a significant increase was observed in Group I before and after taking the enteric-coated capsule preparation. Phascolarctobacterium is a bacterium known to use succinic acid as the only fermentation substrate, and it has been reported that excessive succinic acid in the intestine can induce diarrhea. Therefore, it is believed that the existence of Phascolarctobacterium that utilizes succinic acid is beneficial to humans. In addition, it was confirmed that ingestion of an enteric-coated capsule preparation containing NMN provided an effect of increasing Phascolarctobacterium.

[0104] There was no significant difference between the two groups regarding the changes in Dorea bacteria and Lachnospira before and after taking the enteric-coated capsule preparation, but in Group II, a significant reduction was observed regarding the change before and after taking the enteric-coated capsule preparation. It has been reported that Dorea bacteria are positively correlated with the amount of human defensin HD5 in feces, which is a marker of human intestinal immunity and an antimicrobial peptide that decreases with age, and it has been reported that the relative proportion increases in low-sugar therapy that has been shown to improve the symptoms of irritable bowel syndrome. Therefore, it is believed that the presence of Dorea bacteria provides beneficial effects on humans. Lachnospira is known as a bacterium that produces butyric acid, and butyric acid has beneficial effects in the intestine, such as anti-inflammatory effects and the absorption of minerals. Therefore, it is believed that the presence of Lachnospira provides beneficial effects on humans. In addition, it was confirmed that ingestion of an enteric-coated capsule preparation containing NMN provided an effect of inhibiting the reduction of Dorea bacteria and Lachnospira as seen in Group II.

[0105] As described above, it was found that ingestion of an enteric-coated capsule preparation containing NMN had the desired effects on Mycobacterium, Phascolarctobacterium, Dorea bacteria, and Lachnospiraceae, and was effective in improving intestinal flora compared to the placebo control group.

[0106] [Table 1]

[0107]

[0108] [Table 2]

[0109]

Claims

1. An enteric-coated capsule preparation for improving intestinal flora, comprising: Nicotinamide mononucleotide is enclosed in it as an active ingredient.

2. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: The improvement of the intestinal flora reduces the presence ratio of bacteria of the genus Mycobacterium in the intestinal flora.

3. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: The improvement of the intestinal flora increases the presence ratio of Phascolarctobacterium bacteria in the intestinal flora.

4. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: The improvement of the intestinal flora inhibits the reduction of the presence ratio of Dorea bacteria and / or Lachnospira bacteria in the intestinal flora.

5. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: Include: The intestinal bacteria enclosed within.

6. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: Include: The probiotics enclosed within.

7. The enteric-coated capsule preparation for improving intestinal flora according to claim 6, wherein: The probiotics are selected from one or more strains belonging to the phylum Acidobacteria, Actinobacteria, Firmicutes, Bacteroidetes, Ascomycota, Fusobacteria, Chlamydia, Chloroflexi, Cyanobacteria, Deferrobacillaceae, Deinococcus-Thermus, Fibrobacter, Gemmatimonadetes, Mycosphaeria, Planctomycetes, Spirochetes, Soft-walled Fungi, Verrucomicrobia and Proteobacteria.

8. The enteric-coated capsule preparation for improving intestinal flora according to claim 6, wherein: The probiotics are selected from one or more strains belonging to the genera Lactobacillus, Bacillus, Bifidobacterium, Escherichia, Saccharomyces, Enterococcus, Clostridium, Prevotella, Acidococcus, Fusobacterium, Veillonella, Klebsiella, Streptococcus, Megasphaera, Aeromonas, Aspergillus, Bacteroides, Lactococcus, Leuconostoc, Debaryomyces, Oenococcus, Pediococcus, Weissella and Eubacterium.

9. The enteric-coated capsule preparation for improving intestinal flora according to claim 6, wherein: Include: Prebiotics sealed in it.

10. The enteric-coated capsule preparation for improving intestinal flora according to claim 9, wherein: The prebiotics are one or more selected from fructooligosaccharides, lactofructooligosaccharides, isomaltosyl fructoside, galacto-oligosaccharides, lactulose, isomalto-oligosaccharides, gentio-oligosaccharides, trehalose, xylo-oligosaccharides, soybean oligosaccharides, maltitol, lactitol, reduced isomaltulose, sorbitol and xylitol.

11. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: The enteric-coated capsule preparation is used for enhancing the barrier function of the intestinal mucosa.

12. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: The enteric-coated capsule preparation is a food.

13. The enteric-coated capsule preparation for improving intestinal flora according to claim 1, wherein: The enteric-coated capsule preparation is a medicine.

14. A method for improving intestinal flora or a method for enhancing intestinal mucosal barrier function, the method comprising: A subject is made to ingest the enteric-coated capsule preparation for improving intestinal flora according to any one of claims 1 to 13.

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