WO2023282283A1 - Composition for improving oral environment - Google Patents

Composition for improving oral environment Download PDF

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Publication number
WO2023282283A1
WO2023282283A1 PCT/JP2022/026809 JP2022026809W WO2023282283A1 WO 2023282283 A1 WO2023282283 A1 WO 2023282283A1 JP 2022026809 W JP2022026809 W JP 2022026809W WO 2023282283 A1 WO2023282283 A1 WO 2023282283A1
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composition
nad
nmn
group
oral
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PCT/JP2022/026809
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French (fr)
Japanese (ja)
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潤 若林
雅史 森藤
智子 萩原
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明治ホールディングス株式会社
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Priority to JP2023533164A priority Critical patent/JPWO2023282283A1/ja
Publication of WO2023282283A1 publication Critical patent/WO2023282283A1/en

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Definitions

  • the present invention relates to a composition used for improving oral environment.
  • the oral cavity is closely related to the maintenance of homeostasis of the functions of the whole body, and it can be said that maintaining the oral environment is essential for leading a healthy daily life.
  • Saliva secreted into the oral cavity contains antibacterial substances and antioxidant substances, and plays an important role in maintaining the oral environment through multiple actions such as cleaning the oral cavity.
  • the amount of saliva secreted decreases with aging, and a decrease in the amount of saliva secreted may trigger the development of dysphagia, glossalgia, and the like.
  • the cleaning function of the oral cavity decreases, which increases the number of bacteria in the oral cavity and increases the risk of caries, periodontal disease, and the like. That is, increasing the amount of salivary secretion, which declines with aging, leads to maintenance of the oral environment and can improve people's quality of life (QOL).
  • Patent Document 1 describes aloe extract, gentian extract, rhubarb extract, meadowsweet extract, arnica extract, gardenia extract, button extract, carrot extract, orange extract, peach extract, and seaweed extract.
  • natto extract levan, inulin, polyglutamic acid, Bacillus natto, fermented rice extract, wheat germ extract, wheat hydrolyzate, soybean hydrolysate, glycine, L-methionine, L-alanine, L-citrulline , propolis, polyphenols, purine nucleic acid-related substances, milk proteins, casein, casein hydrolysates, whey proteins, whey protein hydrolysates, lactoperoxidase, lysozyme and lactoferrin.
  • a human ⁇ -defensin production-enhancing agent comprising: It also describes that this human ⁇ -defensin production promoter is useful as an oral care product, an eye care product, and a nasal care product for maintaining a healthy environment of the oral cavity, eyes, or nose.
  • US Pat. No. 6,200,000 describes oral care compositions comprising at least one green tea polyphenol and at least one salivary gland activator. This document also describes pilocarpine, muscarine, acetylcholine, ryanodine, caffeine, Cola acuminata, Cola nitida, jaborandi, white birch as examples of salivary gland activators.
  • US Pat. No. 5,300,000 describes oral care compositions comprising aloe vera extract, gluconate, citrate, hydrogen peroxide, Matricaria chamomilla extract, cranberry extract. This document also states that this oral care composition can be used to prevent and treat mucositis, gingivitis, periodontitis, xerostomia (xerostomia), oral infections, oral inflammation, and bad breath, It is described as being particularly useful for treating oral complications in cancer patients who have undergone chemotherapy or radiation therapy.
  • Patent Document 4 describes oral care pharmaceutical compositions (including quasi-drugs) for promoting saliva secretion containing L-aspartic acid or a salt thereof and nicotinamide.
  • This document describes that when a nicotinamide administration solution, a sodium L-aspartate administration solution, a administration solution containing nicotinamide and sodium L-aspartate, or a control administration solution was administered to 6-week-old rats, nicotinamide and This shows the experimental result that the administration of the administration solution containing sodium L-aspartate exhibited a saliva secretion promoting effect.
  • NMN is a precursor of nicotinamide adenine dinucleotide (NAD) that humans need to maintain life functions, and many useful effects have been reported when administered to mice.
  • NAD nicotinamide adenine dinucleotide
  • the present invention provides the following.
  • a composition for improving oral environment containing a nicotinamide adenine dinucleotide (NAD) analogue.
  • NAD nicotinamide adenine dinucleotide
  • the composition according to 1 wherein the oral environment improvement is at least one of an increase in saliva secretion and a reduction in the number of oral bacteria.
  • the NAD analogue is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, NAD, nicotinamide, and food- or pharmaceutical-acceptable salts thereof.
  • composition according to any one of 1 to 4 which is to be ingested continuously for 2 weeks or longer.
  • composition according to any one of 1 to 5 which is to be ingested by a person aged 40 or over, or by a person with symptoms of dry mouth.
  • composition according to any one of 1 to 6, which is a food composition.
  • composition according to any one of 1 to 7, which contains 130 mg or more of the NAD-like substance as NMN per unit.
  • the present invention also provides the following.
  • NAD analogues in the manufacture of compositions for improving the oral environment.
  • a method for improving an oral environment comprising the step of administering a composition containing an NAD-like substance to a subject.
  • the composition, use, or method according to 9, wherein the improvement of the oral environment is at least one of an increase in salivary secretion and a reduction in the number of oral bacteria.
  • NAD analogue is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, nicotinamide, and food- or pharmaceutical-acceptable salts thereof;
  • NAD analogue is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, nicotinamide, and food- or pharmaceutical-acceptable salts thereof;
  • a composition, use, or method according to [12] The composition, use, or method according to any one of items 9 to 11, for ingesting 100 to 1000 mg of NMN as NMN per day.
  • compositions, use or method according to any one of 9 to 14, wherein the composition is a food composition.
  • composition, use or method according to any one of items 9 to 16, wherein the composition is in the form of a chewable tablet or a sublingual tablet.
  • composition of the present invention achieves at least one of an increase in saliva secretion and a reduction in the number of oral bacteria.
  • the composition of the present invention contains a nicotinamide adenine dinucleotide (NAD) analogue as an active ingredient.
  • NAD nicotinamide adenine dinucleotide
  • An NAD analogue refers to NAD or a substance that can be converted to NAD in vivo.
  • NAD functions as a coenzyme for various dehydrogenases in vivo and can take two states, oxidized (NAD + ) and reduced (NADH).
  • the composition contains nicotinamide mononucleotide (NMN), nicotinamide riboside, NAD, nicotinamide (also referred to as niacinamide) as NAD analogues, and foods, cosmetics, and pharmaceuticals thereof. quasi-products, or any selected from the group consisting of pharmaceutically acceptable salts.
  • NAD may refer to either oxidized NAD + or reduced NADH, unless otherwise specified.
  • the NAD-like substance in the composition is any selected from the group consisting of nicotinamide mononucleotide derivatives, which are compounds represented by general formula (I), and food- or pharmaceutical-acceptable salts thereof. including. Such compounds have sufficient lipid and water solubility.
  • R 1 and R 2 are each independently an acyl group having 6 to 16 carbon atoms, and the hydrocarbon group bonded to the carbonyl carbon of the acyl group is a linear or branched saturated or It is an unsaturated hydrocarbon group.
  • a compound is prepared by binding NMN to a carbonyl carbon in a solvent containing 20% by mass or more of a strongly acidic liquid with a pKa of 2.0 or less, and a linear or branched saturated or unsaturated hydrocarbon group is bonded to the carbonyl carbon.
  • acylating agent selected from the group consisting of a carboxylic acid having an acyl group having 6 to 16 carbon atoms, a halide of the carboxylic acid, and an anhydride of the carboxylic acid (See WO2017/110317).
  • foods, cosmetics, quasi-drugs, or pharmaceutically acceptable salts include nitrates, sulfates, carbonates, hydrogen carbonates, halides, formates, acetates, citrates, tartrates. , oxalates, fumarate salts, salts of saturated or unsaturated fatty acids with 3 to 20 carbon atoms, salts of carnitine and its derivatives, salts of hydroxycitric acid and its derivatives, salts of ascorbic acid and its derivatives, ascorbyl phosphate and salts thereof, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, and ammonium salts thereof.
  • the composition comprises NMN as the NAD analogue.
  • NMN has two optical isomers, ⁇ -type and ⁇ -type.
  • NMN means ⁇ -type NMN ( ⁇ -Nicotinamide mononucleotide) unless otherwise specified.
  • NMN is an intermediate metabolite of NAD + .
  • NAD + is present in all species and functions as a coenzyme, but in recent years, attention has been paid to its relationship with sirtuin genes, which are called longevity genes. Sirtuins are NAD + dependent. NAD + is also a substrate for Poly (ADP-ribose) polymerase 1 (PARP1). PARP-1 binds ADP ribose to an acceptor protein using intracellular NAD + as a substrate. Since this reaction is frequently observed when single-strand breaks occur in DNA, it is considered to be an in vivo response mechanism to DNA damage. PARP1 has also been suggested to be involved in the suppression of imprecise DNA repair leading to mutagenesis due to DNA deletion during aging.
  • PARP1 has also been suggested to be involved in the suppression of imprecise DNA repair leading to mutagenesis due to DNA deletion during aging.
  • the NAD-like substance contained in the composition of the present invention can be produced by various methods. It may be synthesized, or extracts or cultures of yeast, plants, etc. containing NAD-like substances may be used.
  • the composition of the present invention can be used for improving the oral environment.
  • Improvement of the oral environment includes maintaining the oral environment, preventing deterioration of the oral environment/reducing the risk of deterioration (preventive), and improving the poor oral environment (therapeutic). . Improvement of the oral environment can be rephrased as oral care.
  • the improvement of the oral environment can be evaluated by achieving at least one of an increase in saliva secretion and a reduction in the number of bacteria in the oral cavity.
  • Whether or not a certain composition increases the amount of saliva secreted is determined by measuring the amount of saliva secreted by a subject (including humans and non-human mammals) before and after ingesting the subject composition for a certain period of time. can be compared to determine whether or not the latter is greater than the former.
  • the composition of the present invention is suitable for increasing the amount of salivary secretion that has decreased with age, and is particularly suitable for use in humans aged 40 or older, preferably 50 or older, or 60 or older. ing.
  • the increase in salivary secretion due to the composition of the present invention is considered to occur when the resting saliva volume is less than the average value, and when the saliva volume is within the average range but decreases with age. including cases where it is increased when it is possible.
  • the average resting saliva volume of adults is about 0.3 to 0.5 mL/min. May increase salivary flow.
  • Whether a certain composition reduces the number of bacteria in the oral cavity can be determined by measuring the saliva of a subject (including humans and non-human mammals) before and after ingesting the subject composition for a certain period of time. By counting the number of bacteria in the medium, it can be determined whether the number of bacteria in the latter is smaller than that of the former.
  • the composition of the present invention can also be used for the treatment of at least one of xerostomia (dry mouth) and halitosis.
  • xerostomia dry mouth
  • the compositions of the present invention can be used in either case.
  • diseases that cause xerostomia include diabetes, thyroid dysfunction, diabetes insipidus, and Sjögren's syndrome.
  • drugs that may have dry mouth side effects include antidepressants, antianxiety drugs, antihypertensives, and analgesics.
  • salivary glands when salivary glands are exposed to radiation in cancer treatment, salivary gland tissue may be damaged and xerostomia tends to occur, and the composition of the present invention can also be used in such cases. .
  • composition of the present invention can also be used for any treatment selected from the group consisting of oral mucositis, gingivitis, periodontitis, oral infection, oral inflammation, and halitosis.
  • treatment of a disease or condition includes reduction of risk of onset, delay of onset, prevention, treatment, arrest of progression, and delay.
  • Treatment includes medical activities performed by doctors for the purpose of treating illnesses, and non-doctors such as dieticians, registered dietitians, public health nurses, midwives, nurses, clinical laboratory technologists, beauty consultants, estheticians, and food manufacturers. non-medical actions performed by persons, food sellers, etc.
  • treatment includes recommending the administration or intake of specific foods, guidance on dietary methods, health guidance, nutritional guidance (nutrition guidance necessary for medical treatment for the sick and injured, and nutritional guidance for maintaining and improving health). ), school lunch management, and guidance necessary for nutritional improvement related to school lunch.
  • Subjects for treatment in the present invention include humans (individuals) and non-human mammals (companion animals, etc.).
  • composition of the present invention is also useful for keeping any oral tissue consisting of the oral cavity, oral mucosa, tongue, gums and the like strong and healthy, helping to maintain good oral environment, or improving the oral environment. It can be used to keep well and help maintain gum health.
  • compositions of the present invention are particularly suitable for ingestion by subjects in need of oral care.
  • Such subjects include adults (ages 15 and over), middle-aged and elderly (ages 40 to 65), seniors (ages 65 and over), persons during and after illness, pregnant women, women in childbirth, infants, children, men, and women. is included.
  • composition of the present invention is suitable for ingestion by subjects who desire or need an increase in salivary secretion, such as those with symptoms of dry mouth. Thirst is a condition in which the mouth and throat are severely thirsty and require water. Dry mouth can be associated with polyuria and dehydration, can be a side effect of medications, and can be age-related. Most saliva is secreted from the major salivary glands (parotid, submandibular, and sublingual), but saliva in an unstimulated state (resting saliva) is mostly secreted from the submandibular gland.
  • Dry mouth is known as a side effect of certain pharmaceuticals (drugs).
  • the composition of the present invention is suitable for ingestion by a person receiving mouth-drying medicaments.
  • drugs with dry mouth properties include drugs with anticholinergic properties, more particularly tricyclic antidepressants, antiparkinson drugs with anticholinergic properties, antimuscarinic drugs, and the like.
  • tricyclic antidepressants include amitriptyline, imipramine, clomipramine, trimipramine, nortriptyline, amoxapine, dosulepin, lofepramine and pharmaceutically acceptable salts thereof.
  • compositions of the present invention are also suitable for ingestion by persons receiving the following medicaments.
  • composition of the present invention is suitable for long-term intake because the active ingredient is an NAD-like substance that has a long history of eating, and is therefore particularly suitable for those who want to care for their oral cavity on a daily basis.
  • compositions of the invention are used in a variety of routes.
  • routes of administration include oral, sublingual, rectal, eye drops, nasal, inhalation, transdermal, transmucosal, subcutaneous, intramuscular, and intravenous.
  • the compositions are used orally or sublingually or subcutaneously.
  • compositions of the present invention can be used even when administered in conjunction with other oral care regimens.
  • Such other therapies include ingestion of other ingredients, oral cleaning, oral sterilization (with oral sprays, etc.), tooth brushing, oral massage, ingestion of other ingredients, health foods, supplements, etc. , exercise therapy, etc.
  • the composition of the present invention may be used in combination with other oral compositions. Examples of other oral compositions include dentifrices, mouthwashes, oral ointments, mouthwashes, artificial saliva, and denture fixatives.
  • composition of the present invention can be a food, cosmetic, quasi-drug, or pharmaceutical composition.
  • Foods or pharmaceuticals include those for humans as well as non-human animals, unless otherwise specified.
  • foods include general foods, functional foods, nutritional compositions, and therapeutic foods (things that serve the purpose of treatment.
  • a doctor gives a diet prescription and a dietitian etc. prepares a menu according to it).
  • Foods include not only solids but also liquids such as beverages, drinks, liquid foods, and soups, unless otherwise specified.
  • Functional foods refer to foods that can impart predetermined functionality to living organisms.
  • Functional foods special purpose foods, dietary supplements, health supplements, supplements (for example, tablets, coated tablets, sugar-coated tablets, capsules, liquids, etc.), beauty foods (for example, diet foods), etc. It includes general health foods.
  • “functional food” includes health foods to which health claims based on food standards of Codex (FAO/WHO Joint Food Standards Committee) are applied.
  • Cosmetics include cosmeceuticals.
  • NAD-like substance in the composition of the present invention may be any amount as long as the intended effect is exhibited.
  • the dosage or intake of the composition can be appropriately set in consideration of various factors such as age, body weight and symptoms of the subject.
  • NAD analogous substance can be contained as NMN at 5 mg or more, may contain 10 mg or more, preferably 100 mg or more, more preferably 130 mg or more, more preferably 200 mg or more per dose/intake). Containing is more preferable.
  • the upper limit is not particularly limited, in any case, it can be 5000 mg or less, may be 2500 mg or less, is preferably 1000 mg or less, more preferably 500 mg or less, and further preferably 300 mg or less.
  • the amount of the NAD-like substance when the amount of the NAD-like substance is referred to as "as NMN", the amount is the amount of NMN that can be generated from the NAD-like substance. This conversion can be easily performed by those skilled in the art. If the NAD analogue is NMN, the amount is the amount of NMN.
  • the daily dose of the composition of the present invention may contain, for example, 5 mg or more, may contain 10 mg or more, preferably 100 mg or more, and may contain 130 mg or more of the NAD-like substance as NMN. More preferably, it is contained in an amount of 200 mg or more.
  • the upper limit is not particularly limited, in any case, it can be 5000 mg or less, may be 2500 mg or less, is preferably 1000 mg or less, more preferably 500 mg or less, and further preferably 300 mg or less.
  • Such daily dose may be divided into multiple portions, eg, three portions, suitable for ingestion and administration three times a day.
  • the administration and intake of the composition may be performed at any time of the day.
  • the concentration of NAD in the body is thought to fluctuate during the day, and from the viewpoint that it increases during the active period, it is considered preferable to take the composition in the morning, which is the start of the active period.
  • the composition contains an NAD-like substance that has a lot of food experience as an active ingredient, it may be administered and taken repeatedly or over a long period of time, for example, 3 days or more, preferably 1 week or more, more preferably 4 weeks or more, More preferably, it can be ingested continuously for 8 weeks or more.
  • composition of the present invention may contain other active ingredients and nutritional ingredients that are acceptable as foods or pharmaceuticals.
  • active ingredients e.g. resveratrol
  • quercetin e.g. quercetin
  • astaxanthin e.g. astaxanthin
  • chlorella e.g. astaxanthin
  • coenzyme Q10 e.g. vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C.
  • amino acids e.g., lysine, arginine, glycine, alanine, glutamic acid, leucine, isoleucine, valine
  • carbohydrates glucose, sucrose , fructose, maltose, trehalose, erythritol, maltitol, palatinose, xylitol, dextrin
  • electrolytes e.g. sodium, potassium, calcium, magnesium
  • minerals e.g. copper, zinc, iron, cobalt, manganese
  • antibiotics Dietary fiber, protein, lipid, and the like.
  • the composition may further contain food, cosmetics, quasi-drugs, or pharmaceutically acceptable additives.
  • additives include inert carriers (solid and liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, solubilizers, suspending agents, coating agents, coloring agents. agents, preservatives, buffers, pH adjusters, emulsifiers, stabilizers, sweeteners, antioxidants, flavors, acidulants, natural products.
  • water other aqueous solvents, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, water-soluble dextrin, sodium carboxymethyl starch, Pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petroleum jelly, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, sucralose, stevia, aspartame, acesulfame potassium, Citric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, acetic acid, fruit juice, vegetable juice, and the like.
  • composition of the present invention may be prepared in any form such as solid, liquid, mixture, suspension, emulsion, gel, sol and the like.
  • Specific forms of the composition include chewable tablets, sublingual tablets, tablets, pills, capsules, granules, powders, powders, solutions, suspensions, emulsions, syrups, liniments, lotions, Gels, aerosols, sprays, ointments, creams, tapes, poultices, eye drops, nose drops, and suppositories.
  • the composition when it is a food, it can be in any form such as dairy products, supplements, confectionery, beverages, drinkable preparations, seasonings, processed foods, side dishes, soups, and the like.
  • the composition of the present invention can be used as gummies, tablets, drinks, fermented milk, dairy drinks, dairy drinks, soft drinks, ice cream, cheese, bread, biscuits, crackers, pizza crust, prepared milk powder, liquid It can be in the form of food, food for the sick, nutritional food, frozen food, processed food, etc., and granules, powders, or powders for mixing with beverages or foods, or for preparing beverages by dilution. It can be in the form of a paste, a concentrate, or the like.
  • composition of the present invention can be appropriately produced by those skilled in the art using existing equipment and the like.
  • the step of adding the NAD analogue is not particularly limited as long as the properties of the NAD analogue are not significantly impaired.
  • a product containing the composition of the present invention can be labeled with its function and purpose of use (use), and can be labeled with recommendations for administration and intake to specific subjects. Labeling can be done directly or indirectly. Examples of direct labeling are descriptions on tangible objects such as the product itself, packages, containers, labels, tags, etc. Examples of indirect labeling are: Websites, storefronts, pamphlets, exhibitions, seminars such as media seminars, books, newspapers, magazines, television, radio, mail, e-mail, voice, etc., including advertising and publicity activities by place or means.
  • Examples of the intended use (purpose) displayed include “improving the oral environment”, “oral care”, “oral care”, “promoting the secretion of saliva”, and “reducing the number of bacteria in the oral cavity”. .
  • Evaluation example 1 Study 1: Animal study [Methods] 1) Administration material ⁇ -Nicotinamide Mononucleotide (NMN) to be administered to mice was manufactured by Bontac, dissolved in distilled water, and then administered to mice through drinking water. The administration dose was set at 300 mg/kg/day, and the administration concentration was calculated based on the water intake and body weight of mice measured in advance.
  • NPN ⁇ -Nicotinamide Mononucleotide
  • mice Animals We purchased 10 male young mice, 24 weeks old, C57BL/6J strain, and 20 old male mice, 84 weeks old, C57BL/6J strain.
  • 24-week-old and 84-week-old mice correspond to around 30 years old and around 60 years old in humans, respectively. Mice were individually housed in a breeding room with room temperature of 22 ⁇ 2°C, humidity of 55 ⁇ 15%, light period from 7:00 to 19:00 and dark period from 19:00 to 7:00 until the end of the test. Feed and water were allowed to be taken freely without restriction.
  • the aged mice were divided into 2 groups (aged control group: OC group, aged NMN group: ON group) of 10 mice per group so that the mean body weight and salivary secretion were equal. After grouping, NMN was administered to the ON group in drinking water, and the young mice (young control group: YC group) and the OC group were fed normal water for 8 weeks in the same manner as the preliminary breeding.
  • Saliva salivary secretion amount
  • Saliva was collected from all animals during preliminary breeding and 8 weeks after the start of the test. After weight measurement, they fasted for 1 hour, and also fasted for the last 30 minutes. Mice were anesthetized by intraperitoneal administration of a triple anesthetic (Domitol, Betorfal, Midazolam) at a volume of 10 mL/kg. Mice were left for about 5 minutes until they fell under deep anesthesia, and pilocarpine hydrochloride was administered intraperitoneally at a dose of 1 mg/kg (5 mL/kg).
  • a triple anesthetic Domitol, Betorfal, Midazolam
  • mice were laid with their mouths facing upward and opened, and saliva secreted into the oral cavity of the mice was collected using a capillary (manufactured by Hirschmann Laborgerate) for 15 minutes after administration of pilocarpine.
  • the secretion amount (mg) of the collected saliva was measured (converting 1 mg to 1 ⁇ L).
  • the amount of saliva secreted was calculated by correcting the amount of saliva secreted per minute by the body weight of the mouse.
  • [result] 1) Amount of saliva secretion The amount of saliva secretion at the time of preliminary feeding (0W) was lower in the OC group and ON group than in the YC group, though not significantly. On the other hand, 8 weeks after the start of the study, the OC group had significantly lower values than the YC group, but no difference was observed between the YC group and the ON group. In addition, when comparing the OC group and the ON group, the ON group tended to have higher values (Fig. 1).
  • Study 2 (clinical study) [Method] 1) Ingested material
  • Saliva was collected from all the subjects before (pre) and two weeks after the start of ingestion (post) of NMN, and the secretion amount was measured. Saliva collection was performed between 9:30 and 10:00, and no food or drink except water was allowed for 1 hour before saliva collection. Five minutes before saliva collection, they rinsed their mouths with water and sat down to relax. At the time of saliva collection, the subjects were seated on a chair and slouched slightly forward, and the saliva that was naturally secreted for 5 minutes was collected in a dedicated container. After collection, the amount of fluid was measured and the amount of saliva secreted per minute was calculated.
  • Evaluation Example 2 Evaluation of the effect of NMN on salivary secretion using a dry mouth model It has been reported that the amount of salivary secretion is reduced by ingestion of pharmaceuticals (especially pharmaceuticals having anticholinergic action). Therefore, using thirst model mice created by administering amitriptyline (an antidepressant), one of the drugs whose anticholinergic action has been clarified, the amount of salivary secretion was affected by prior administration of NMN. It was verified whether or not to give
  • ⁇ -Nicotinamide Mononucleotide (NMN) to be administered to mice was manufactured by Bontac, and was subcutaneously administered to mice after being dissolved in physiological saline. The administration dose was set at 300 mg/kg, the administration volume was set at 10 mL/kg, and the administration concentration was 30 mg/mL.
  • amitriptyline hydrochloride (amitriptyline hydrochloride can be purchased from Sigma Aldrich, Tokyo Kasei Kogyo Co., Ltd.) was dissolved in distilled water and administered to mice by gavage. The administration dose was set at 10 mg/kg, the administration volume was set at 10 mL/kg, and the administration concentration was 1 mg/mL.
  • mice Animals We purchased 24 male, 12-week-old C57BL/6J strain mice. Mice were reared in groups (4 mice/cage) until the end of the test in a breeding room with room temperature of 22 ⁇ 2°C, humidity of 55 ⁇ 15%, light period from 7:00 to 19:00 and dark period from 19:00 to 7:00. rice field. Feed and water were allowed to be taken freely without restriction. After preliminary breeding, the animals were divided into 3 groups of 8 animals per group (non-treated group: NT group, drug-treated group: A group, drug-treated + NMN group: AN group) so that the average body weight was even. .
  • NMN solution to AN group and physiological saline (vehicle) to NT and A groups was started.
  • Subcutaneous administration was performed once a day for 8 days until the end of the test, 8 times in total.
  • subcutaneous administration was performed 3 hours before the measurement of salivary secretion.
  • Saliva was collected from all animals on the 8th day after the start of the test. After the last subcutaneous administration, food was fasted (3 hours before saliva collection), and 1 hour before saliva collection, amitriptyline aqueous solution was forcibly administered to the A and AN groups, and distilled water (vehicle) to the NT group. Water deprivation was also performed after gavage administration. One hour after oral gavage, the mice were anesthetized by an intraperitoneal injection of a triple anesthetic (Domitol, Betorfal, Midazolam) at a volume of 10 mL/kg.
  • a triple anesthetic Domitol, Betorfal, Midazolam
  • mice were left to fall under deep anesthesia for approximately 5 minutes, and pilocarpine hydrochloride was administered intraperitoneally at a dose of 0.5 mg/kg (5 mL/kg).
  • the mice were laid with their mouths facing upward and opened, and saliva secreted into the oral cavity of the mice was collected using a capillary (manufactured by Hirschmann Laborgerate) for 15 minutes after administration of pilocarpine.
  • the amount of saliva secreted ( ⁇ L) was measured (converting 1 mg to 1 ⁇ L).
  • the amount of saliva secreted was calculated by correcting the amount of saliva secreted per minute by the body weight of the mouse.
  • [result] 1) Amount of salivary secretion The amount of salivary secretion was significantly decreased in the drug-treated group (Group A) compared to the non-treated group (NT group). On the other hand, there was no difference in saliva secretion between the NT group and the drug treatment + NMN group (AN group). Although there was no difference in the amount of salivary secretion between the A group and the AN group, administration of NMN tended to increase salivary secretion (Fig. 4).

Abstract

A composition for improving an oral environment is provided. The composition includes a nicotinamide-adenine dinucleotide (NAD) analogue. This composition can be used for enhancing salivation and/or reducing the number of bacteria in the mouth. A preferred example of the nicotinamide-adenine dinucleotide (NAD) analogue is nicotinamide mononucleotide (NMN).

Description

口腔環境改善用組成物Composition for improving oral environment
　本発明は、口腔環境の改善のために用いる組成物に関する。 The present invention relates to a composition used for improving oral environment.
　口腔は全身の機能の恒常性維持に深く関連しており、健康な日常生活を送るうえで口腔環境の維持は必要不可欠といえる。口腔内に分泌される唾液は、抗菌物質や抗酸化物質を含んでおり、口腔内の洗浄など複数の作用により口腔環境の維持に重要な働きをしている。しかし、唾液の分泌量は加齢により減少することが報告されており、唾液分泌量の減少を引き金として嚥下障害や舌痛症などを発症する可能性がある。また、唾液分泌量の減少に伴い口腔内の洗浄機能が低下することで、口腔内の細菌が増加してう蝕や歯周病などに罹患するリスクも高まる。すなわち、加齢により低下する唾液分泌量を増加させることは、口腔環境の維持につながり人々の生活の質（Quality of life：QOL）を向上させることができる。 The oral cavity is closely related to the maintenance of homeostasis of the functions of the whole body, and it can be said that maintaining the oral environment is essential for leading a healthy daily life. Saliva secreted into the oral cavity contains antibacterial substances and antioxidant substances, and plays an important role in maintaining the oral environment through multiple actions such as cleaning the oral cavity. However, it has been reported that the amount of saliva secreted decreases with aging, and a decrease in the amount of saliva secreted may trigger the development of dysphagia, glossalgia, and the like. In addition, as the amount of saliva secreted decreases, the cleaning function of the oral cavity decreases, which increases the number of bacteria in the oral cavity and increases the risk of caries, periodontal disease, and the like. That is, increasing the amount of salivary secretion, which declines with aging, leads to maintenance of the oral environment and can improve people's quality of life (QOL).
　口腔内の環境の維持のため、いくつかの有効成分が知られている。例えば、特許文献１は、アロエ抽出物、ゲンチアナ抽出物、ジオウ抽出物、シモツケ抽出物、アルニカ抽出物、クチナシ抽出物、ボタン抽出物、キャロット抽出物、オレンジ抽出物、ピーチ抽出物、海藻抽出物、納豆抽出物、レバン、イヌリン、ポリグルタミン酸、納豆菌、米抽出物の発酵物、小麦胚芽抽出物、小麦加水分解物、大豆加水分解物、グリシン、Ｌ-メチオニン、Ｌ-アラニン、Ｌ-シトルリン、プロポリス、ポリフェノール、プリン系核酸関連物質、乳タンパク質、カゼイン、カゼイン加水分解物、ホエータンパク、ホエータンパク加水分解物、ラクトパーオキシダーゼ、リゾチーム及びラクトフェリンよりなる群から選択される少なくとも一種の成分を有効成分とすることを特徴とする、ヒトβディフェンシン産生促進剤を記載する。そしてこのヒトβディフェンシン産生促進剤が、健康な口腔、眼又は鼻の環境を保つためのオーラルケア製品、アイケア製品、鼻ケア製品として有用であると記載している。また特許文献２は、少なくとも１種の緑茶ポリフェノールと少なくとも１種の唾液腺活性化剤を含む口腔ケア組成物を記載する。またこの文献は、唾液腺活性化剤の例として、ピロカルピン、ムスカリン、アセチルコリン、リアノジン、カフェイン、コーラ・アクミナータ（Cola acuminata）、コーラ・ニチダ（Cola nitida）、ジャボランディ（jaborandi）、ホワイトバーチ（white birch）、スイカズラ（Honeysuckle）、アメリカ人参（American ginseng）、ハウトゥイニア・コルダ（houttuynia cordata）、ニンニク（garlic）、ハイビスカス（hibiscus）、ホップ（hop）、アクチニジア・ポリガマ（Actinidia polygama）、リンデン（linden）、ローズヒップ（rose hip）等の植物の抽出物を列記する。さらに特許文献３は、アロエベラエキス、グルコン酸塩、クエン酸塩、過酸化水素、Matricaria chamomilla（カミツレ）抽出物、クランベリー抽出物を含む口腔ケア組成物を記載する。またこの文献は、この口腔ケア組成物が、粘膜炎、歯肉炎、歯周炎、口腔乾燥（口腔乾燥症）、口腔感染、口腔炎症、及び口臭の予防並びに治療にも使用することができ、化学療法や放射線療法を受けたがん患者の口腔合併症の治療に特に有用であると記載する。さらに特許文献４は、Ｌ－アスパラギン酸又はその塩、及びニコチンアミドを含有する唾液分泌を促進するための口腔ケア用医薬組成物（医薬部外品を含む）を記載する。この文献は、６週齢のラットに対し、ニコチンアミド投与液、Ｌ－アスパラギン酸ナトリウム投与液、ニコチンアミドとＬ－アスパラギン酸ナトリウムを含む投与液、又は対照投与液を投与したところ、ニコチンアミドとＬ－アスパラギン酸ナトリウムを含む投与液の投与により唾液分泌促進作用が発現したという実験結果を示している。 Several active ingredients are known to maintain the oral environment. For example, Patent Document 1 describes aloe extract, gentian extract, rhubarb extract, meadowsweet extract, arnica extract, gardenia extract, button extract, carrot extract, orange extract, peach extract, and seaweed extract. , natto extract, levan, inulin, polyglutamic acid, Bacillus natto, fermented rice extract, wheat germ extract, wheat hydrolyzate, soybean hydrolysate, glycine, L-methionine, L-alanine, L-citrulline , propolis, polyphenols, purine nucleic acid-related substances, milk proteins, casein, casein hydrolysates, whey proteins, whey protein hydrolysates, lactoperoxidase, lysozyme and lactoferrin. A human β-defensin production-enhancing agent is described, comprising: It also describes that this human β-defensin production promoter is useful as an oral care product, an eye care product, and a nasal care product for maintaining a healthy environment of the oral cavity, eyes, or nose. Also, US Pat. No. 6,200,000 describes oral care compositions comprising at least one green tea polyphenol and at least one salivary gland activator. This document also describes pilocarpine, muscarine, acetylcholine, ryanodine, caffeine, Cola acuminata, Cola nitida, jaborandi, white birch as examples of salivary gland activators. birch), Honeysuckle, American ginseng, houttuynia cordata, garlic, hibiscus, hops, Actinidia polygama, linden , rose hips and other plant extracts. In addition, US Pat. No. 5,300,000 describes oral care compositions comprising aloe vera extract, gluconate, citrate, hydrogen peroxide, Matricaria chamomilla extract, cranberry extract. This document also states that this oral care composition can be used to prevent and treat mucositis, gingivitis, periodontitis, xerostomia (xerostomia), oral infections, oral inflammation, and bad breath, It is described as being particularly useful for treating oral complications in cancer patients who have undergone chemotherapy or radiation therapy. Furthermore, Patent Document 4 describes oral care pharmaceutical compositions (including quasi-drugs) for promoting saliva secretion containing L-aspartic acid or a salt thereof and nicotinamide. This document describes that when a nicotinamide administration solution, a sodium L-aspartate administration solution, a administration solution containing nicotinamide and sodium L-aspartate, or a control administration solution was administered to 6-week-old rats, nicotinamide and This shows the experimental result that the administration of the administration solution containing sodium L-aspartate exhibited a saliva secretion promoting effect.
WO2005/077349 A1WO2005/077349 A1 WO2010/099062 A1WO2010/099062 A1 WO2016/106313 A1WO2016/106313 A1 特開2016-175901号公報(特許第6795316号)Japanese Patent Application Laid-Open No. 2016-175901 (Patent No. 6795316)
　NMNは、人間が生命機能を維持するために必要なNicotinamide Adenine Dinucleotide（NAD）の前駆物質であり、マウス等に投与することで多くの有用な作用が報告されている。NADは加齢により生体中の量が低下し、その維持あるいは増加にはNADの前駆物質であるNMNを摂取することが効果的であることが知られている。しかし、NMNの口腔環境に及ぼす影響や効果はほとんど知られていない。 NMN is a precursor of nicotinamide adenine dinucleotide (NAD) that humans need to maintain life functions, and many useful effects have been reported when administered to mice. The amount of NAD in the body decreases with aging, and it is known that ingesting NMN, which is a precursor of NAD, is effective in maintaining or increasing it. However, little is known about the effects of NMN on the oral environment.
　そこで、老齢マウスあるいは成人にNMNを摂取させることで、唾液分泌量や口腔内細菌に影響を与えるか否かを検証し、本発明を完成した。 Therefore, we verified whether ingesting NMN to aged mice or adults affects the amount of salivary secretion and oral bacteria, and completed the present invention.
　本発明は以下を提供する。
［１］　ニコチンアミドアデニンジヌクレオチド（ＮＡＤ）類似物質を含む、口腔環境改善用組成物。
［２］　口腔環境改善が、唾液分泌量増加、及び口腔内細菌数低減の少なくとも一方である、１に記載の組成物。
［３］　ＮＡＤ類似物質が、ニコチンアミドモノヌクレオチド（ＮＭＮ）、ニコチンアミドリボシド、ＮＡＤ、ニコチンアミド、及びこれらの食品又は医薬品として許容可能な塩からなる群から選択されるいずれかである、１又は２に記載の組成物。
［４］　ＮＡＤ類似物質を、一日当たりＮＭＮとして１００～１０００ｍｇ摂取させるための、１～３のいずれか１項に記載の組成物。
［５］　２週間以上継続して摂取させるための、１～４のいずれか１項に記載の組成物。
［６］　４０歳以上の者に摂取させるための、又は口渇症状を有する者に摂取させるための、１～５のいずれか１項に記載の組成物。
［７］  食品組成物である、１～６のいずれか１項に記載の組成物。
［８］　ＮＡＤ類似物質を、１単位当たりＮＭＮとして１３０ｍｇ以上含む、１～７のいずれか１項に記載の組成物。
［９］　チュアブル錠、又は舌下錠である、１～８のいずれか１項に記載の組成物。 The present invention provides the following.
[1] A composition for improving oral environment, containing a nicotinamide adenine dinucleotide (NAD) analogue.
[2] The composition according to 1, wherein the oral environment improvement is at least one of an increase in saliva secretion and a reduction in the number of oral bacteria.
[3] The NAD analogue is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, NAD, nicotinamide, and food- or pharmaceutical-acceptable salts thereof. Or the composition according to 2.
[4] The composition according to any one of [1] to [3], for ingesting 100 to 1000 mg of NMN as NAD per day.
[5] The composition according to any one of 1 to 4, which is to be ingested continuously for 2 weeks or longer.
[6] The composition according to any one of 1 to 5, which is to be ingested by a person aged 40 or over, or by a person with symptoms of dry mouth.
[7] The composition according to any one of 1 to 6, which is a food composition.
[8] The composition according to any one of 1 to 7, which contains 130 mg or more of the NAD-like substance as NMN per unit.
[9] The composition according to any one of 1 to 8, which is a chewable tablet or a sublingual tablet.
　また本発明は、下記を提供する。
［９］　口腔環境改善方法に用いるための、ニコチンアミドアデニンジヌクレオチド（ＮＡＤ）類似物質を含む、組成物。ＮＡＤ類似物質の、口腔環境を改善する組成物の製造における、使用。ＮＡＤ類似物質を含む組成物を対象に投与する工程を含む、口腔環境の改善方法。
［１０］　口腔環境の改善が、唾液分泌量増加、及び口腔内細菌数低減の少なくとも一方である、９に記載の組成物、使用、又は方法。
［１１］　ＮＡＤ類似物質が、ニコチンアミドモノヌクレオチド（ＮＭＮ）、ニコチンアミドリボシド、ニコチンアミド、及びこれらの食品又は医薬品として許容可能な塩からなる群から選択されるいずれかである、９又は１０に記載の組成物、使用、又は方法。
［１２］　ＮＡＤ類似物質を、一日当たりＮＭＮとして１００～１０００ｍｇ摂取させるための、９～１１のいずれか１項に記載の組成物、使用、又は方法。
［１３］　２週間以上継続して摂取させるための、９～１２のいずれか１項に記載の組成物、使用、又は方法。
［１４］　４０歳以上の者に摂取させるための、又は口渇症状を有する者に摂取させるための、９～１３のいずれか１項に記載の組成物、使用、又は方法。
［１５］  組成物が食品組成物である、９～１４のいずれか１項に記載の組成物、使用、又は方法。
［１６］　ＮＡＤ類似物質を、組成物１単位当たりＮＭＮとして１３０ｍｇ以上含む、９～１５のいずれか１項に記載の組成物、使用、又は方法。
［１７］　組成物の形態が、チュアブル錠、又は舌下錠である、９～１６のいずれか１項に記載の組成物、使用、又は方法。 The present invention also provides the following.
[9] A composition containing a nicotinamide adenine dinucleotide (NAD) analogue for use in a method for improving oral environment. Use of NAD analogues in the manufacture of compositions for improving the oral environment. A method for improving an oral environment, comprising the step of administering a composition containing an NAD-like substance to a subject.
[10] The composition, use, or method according to 9, wherein the improvement of the oral environment is at least one of an increase in salivary secretion and a reduction in the number of oral bacteria.
[11] 9 or 10, wherein the NAD analogue is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, nicotinamide, and food- or pharmaceutical-acceptable salts thereof; A composition, use, or method according to .
[12] The composition, use, or method according to any one of items 9 to 11, for ingesting 100 to 1000 mg of NMN as NMN per day.
[13] The composition, use, or method according to any one of 9 to 12, for continuous ingestion for 2 weeks or more.
[14] The composition, use, or method according to any one of items 9 to 13, for intake by persons aged 40 or over, or for intake by persons with symptoms of dry mouth.
[15] The composition, use or method according to any one of 9 to 14, wherein the composition is a food composition.
[16] The composition, use, or method according to any one of items 9 to 15, which contains 130 mg or more of the NAD-like substance as NMN per unit of the composition.
[17] The composition, use or method according to any one of items 9 to 16, wherein the composition is in the form of a chewable tablet or a sublingual tablet.
　本発明の組成物により、口腔環境が改善される。また本発明の組成物により、唾液分泌量の増加、及び口腔内細菌数の低減の少なくとも一方が達成される。 The oral environment is improved by the composition of the present invention. In addition, the composition of the present invention achieves at least one of an increase in saliva secretion and a reduction in the number of oral bacteria.
唾液分泌量を示したグラフである。予備飼育時（0W）と試験開始8週間後（8W）に唾液を採取して唾液分泌量を測定したデータを示す。YC：若齢コントロール群、OC：老齢コントロール群、ON：老齢NMN群。値は平均値±標準誤差、*：P<0.05Tukey-KramertestIt is the graph which showed the amount of saliva secretion. Data obtained by collecting saliva at the time of preliminary breeding (0W) and at 8 weeks after the start of the test (8W) and measuring the amount of saliva secretion are shown. YC: young control group, OC: old control group, ON: old NMN group. Values are mean ± standard error, *: P < 0.05 Tukey-Kramertest 口腔内細菌数を示したグラフである。予備飼育時（0W）と試験開始8週間後（8W）にマイクロブラシを用いて口腔内をスワブして口腔内細菌数を測定したデータを示す。YC：若齢コントロール群、OC：老齢コントロール群、ON：老齢NMN群。値は平均値±標準誤差、*：P<0.05Tukey-KramertestIt is the graph which showed the intraoral bacterial count. Data obtained by swabbing the oral cavity with a microbrush at the time of preliminary feeding (0W) and 8 weeks after the start of the test (8W) are shown. YC: young control group, OC: old control group, ON: old NMN group. Values are mean ± standard error, *: P < 0.05 Tukey-Kramertest 唾液分泌量と口腔内細菌数を示したグラフである。（A）はNMN摂取前（pre）と2週間摂取後（post）に唾液を採取して唾液分泌量を測定したデータを示す。平均値±標準偏差、*：P<0.05 paired t-test、（B）は採取した唾液を使用して唾液中細菌数も測定したデータを示す。中央値±最大値と最小値、*：P<0.05 Wilcoxon signed rank testIt is the graph which showed the amount of saliva secretion, and the intraoral bacterial count. (A) shows data obtained by collecting saliva before ingestion of NMN (pre) and after ingestion for 2 weeks (post) and measuring the amount of salivary secretion. Mean value ± standard deviation, *: P<0.05 paired t-test, (B) shows data obtained by measuring the number of bacteria in saliva using the collected saliva. Median ± max and min, *: P<0.05Wilcoxonsignedranktest 唾液分泌量を示したグラフである。NMN又は生理食塩水投与8日目に唾液分泌量を測定した。NT：無処置群、A：薬剤投与群、AN：薬剤投与＋NMN群、各群n=8、値は平均値±標準誤差、**：p<0.01 Tukey testIt is the graph which showed the amount of saliva secretion. Eight days after administration of NMN or physiological saline, the amount of salivary secretion was measured. NT: no treatment group, A: drug administration group, AN: drug administration + NMN group, each group n = 8, values are mean ± standard error, **: p < 0.01 Tukey test
［有効成分］
  本発明の組成物は、有効成分として、ニコチンアミドアデニンジヌクレオチド（ＮＡＤ）類似物質を含む。ＮＡＤ類似物質とは、ＮＡＤ、又は生体内でＮＡＤに変換されうる物質をいう。ＮＡＤは、生体内で種々の脱水素酵素の補酵素として機能し、酸化型（ＮＡＤ＋）及び還元型（ＮＡＤＨ）の２つの状態を取り得る。 [Active ingredient]
The composition of the present invention contains a nicotinamide adenine dinucleotide (NAD) analogue as an active ingredient. An NAD analogue refers to NAD or a substance that can be converted to NAD in vivo. NAD functions as a coenzyme for various dehydrogenases in vivo and can take two states, oxidized (NAD + ) and reduced (NADH).
　好ましい態様において、組成物はＮＡＤ類似物質として、ニコチンアミドモノヌクレオチド（ＮＭＮ）、ニコチンアミドリボシド、ＮＡＤ、ニコチンアミド（ナイアシンアミド(niacinamide)ということもある。）、及びこれらの食品、化粧品、医薬部外品、又は医薬品として許容可能な塩からなる群から選択されるいずれかを含む。本発明に関し、ＮＡＤというときは、特に記載した場合を除き、酸化型ＮＡＤ＋である場合と還元型ＮＡＤＨである場合とがある。 In a preferred embodiment, the composition contains nicotinamide mononucleotide (NMN), nicotinamide riboside, NAD, nicotinamide (also referred to as niacinamide) as NAD analogues, and foods, cosmetics, and pharmaceuticals thereof. quasi-products, or any selected from the group consisting of pharmaceutically acceptable salts. In the context of the present invention, NAD may refer to either oxidized NAD + or reduced NADH, unless otherwise specified.
　好ましい態様において、組成物はＮＡＤ類似物質として、一般式（Ｉ）で表される化合物であるニコチンアミドモノヌクレオチド誘導体、及びこれらの食品又は医薬品として許容可能な塩からなる群から選択されるいずれかを含む。このような化合物は、十分な脂溶性および水溶性を有する。 In a preferred embodiment, the NAD-like substance in the composition is any selected from the group consisting of nicotinamide mononucleotide derivatives, which are compounds represented by general formula (I), and food- or pharmaceutical-acceptable salts thereof. including. Such compounds have sufficient lipid and water solubility.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　式中、Ｒ１及びＲ２は、それぞれ独立に炭素数６～１６のアシル基であり、該アシル基のカルボニル炭素に結合している炭化水素基は、直鎖状若しくは分岐鎖状の飽和又は不飽和の炭化水素基である。このような化合物は、ＮＭＮを、ｐＫａが２．０以下の強酸性液体を２０質量％以上含む溶媒中で、直鎖状若しくは分岐鎖状の飽和又は不飽和の炭化水素基がカルボニル炭素に結合している炭素数６～１６のアシル基を有するカルボン酸、該カルボン酸のハロゲン化物、該カルボン酸の無水物からなる群より選択される選ばれるいずれかのアシル化剤を用いてアシル化反応させることにより製造できる（WO2017/110317参照）。 In the formula, R 1 and R 2 are each independently an acyl group having 6 to 16 carbon atoms, and the hydrocarbon group bonded to the carbonyl carbon of the acyl group is a linear or branched saturated or It is an unsaturated hydrocarbon group. Such a compound is prepared by binding NMN to a carbonyl carbon in a solvent containing 20% by mass or more of a strongly acidic liquid with a pKa of 2.0 or less, and a linear or branched saturated or unsaturated hydrocarbon group is bonded to the carbonyl carbon. Acylation reaction using any acylating agent selected from the group consisting of a carboxylic acid having an acyl group having 6 to 16 carbon atoms, a halide of the carboxylic acid, and an anhydride of the carboxylic acid (See WO2017/110317).
　本発明に関し、食品、化粧品、医薬部外品、又は医薬品として許容可能な塩とは、硝酸塩、硫酸塩、炭酸塩、炭酸水素塩、ハロゲン塩、ギ酸塩、酢酸塩、クエン酸塩、酒石酸塩、シュウ酸塩、フマル酸塩、炭素数３～２０の飽和又は不飽和脂肪酸の塩、カルニチン及びその誘導体の塩、ヒドロキシクエン酸及びその誘導体の塩、アスコルビン酸及びその誘導体の塩、アスコルビルリン酸及びその誘導体の塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、亜鉛塩、並びにアンモニウム塩からなる群より選択されるいずれかの塩をいう。 In the context of the present invention, foods, cosmetics, quasi-drugs, or pharmaceutically acceptable salts include nitrates, sulfates, carbonates, hydrogen carbonates, halides, formates, acetates, citrates, tartrates. , oxalates, fumarate salts, salts of saturated or unsaturated fatty acids with 3 to 20 carbon atoms, salts of carnitine and its derivatives, salts of hydroxycitric acid and its derivatives, salts of ascorbic acid and its derivatives, ascorbyl phosphate and salts thereof, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, and ammonium salts thereof.
　特に好ましい態様において、組成物はＮＡＤ類似物質として、ＮＭＮを含む。ＮＭＮは光学異性体としてα型、β型の２種類が存在するが、本発明に関し、ＮＭＮというときは、特に記載した場合を除き、β型のＮＭＮ(β-Nicotinamide mononucleotide)を指す。ＮＭＮは、ＮＡＤ＋の中間代謝産物である。 In a particularly preferred embodiment, the composition comprises NMN as the NAD analogue. NMN has two optical isomers, α-type and β-type. In the present invention, NMN means β-type NMN (β-Nicotinamide mononucleotide) unless otherwise specified. NMN is an intermediate metabolite of NAD + .
　ＮＡＤ＋はすべての生物種に存在し、補酵素として働くが、近年、長寿遺伝子といわれるサーチュイン遺伝子との関係が注目されている。サーチュインは、ＮＡＤ＋依存性である。またＮＡＤ＋は、ポリADP-リボシル化酵素（Poly (ADP-ribose) polymerase 1, PARP1　）の基質でもある。ＰＡＲＰ－１は細胞内のＮＡＤ＋を基質としてＡＤＰリボースをアクセプタータンパク質に結合させる。この反応はＤＮＡに一本鎖切断が生じたとき高頻度に認められることから、ＤＮＡ損傷に対する生体内応答機構であると考えられている。ＰＡＲＰ１はまた、加齢下でのＤＮＡの欠失による変異発生につながる不正確なＤＮＡ修復の抑制に関与する可能性が示唆されている。 NAD + is present in all species and functions as a coenzyme, but in recent years, attention has been paid to its relationship with sirtuin genes, which are called longevity genes. Sirtuins are NAD + dependent. NAD + is also a substrate for Poly (ADP-ribose) polymerase 1 (PARP1). PARP-1 binds ADP ribose to an acceptor protein using intracellular NAD + as a substrate. Since this reaction is frequently observed when single-strand breaks occur in DNA, it is considered to be an in vivo response mechanism to DNA damage. PARP1 has also been suggested to be involved in the suppression of imprecise DNA repair leading to mutagenesis due to DNA deletion during aging.
　本発明の組成物に含まれるＮＡＤ類似物質は、種々の方法で製造し得る。合成してもよく、ＮＡＤ類似物質を含む酵母や植物等の抽出物、培養物を利用してもよい。 The NAD-like substance contained in the composition of the present invention can be produced by various methods. It may be synthesized, or extracts or cultures of yeast, plants, etc. containing NAD-like substances may be used.
［用途］
（口腔環境改善）
　本発明の組成物は、口腔環境の改善のために用いることができる。口腔環境の改善は、口腔環境を維持すること、口腔環境が悪くなるのを防ぐこと・悪くなるリスクを低減すること（予防的）、口腔環境が悪い状態を良くすること（治療的）を含む。口腔環境の改善は、口腔ケアと言い換えることができる。 [Use]
(improvement of oral environment)
The composition of the present invention can be used for improving the oral environment. Improvement of the oral environment includes maintaining the oral environment, preventing deterioration of the oral environment/reducing the risk of deterioration (preventive), and improving the poor oral environment (therapeutic). . Improvement of the oral environment can be rephrased as oral care.
　口腔環境の改善は、唾液の分泌量の増加、及び口腔内の細菌の数が低減することのうち、少なくとも一方が為されることにより、評価することができる。 The improvement of the oral environment can be evaluated by achieving at least one of an increase in saliva secretion and a reduction in the number of bacteria in the oral cavity.
　ある組成物により、唾液の分泌量が増加するか否かは、対象者（ヒト及び非ヒト哺乳類動物を含む）において、対象組成物を摂取する前と一定期間摂取した後のそれぞれの唾液分泌量を比較して、前者よりも後者のほうが多くなったか否かにより判断することができる。本発明の組成物は、加齢により低下した唾液分泌量を増加させるのに適しており、特に、ヒトであれば40歳以上、好ましくは50歳以上、60歳以上の者において用いるのに適している。 Whether or not a certain composition increases the amount of saliva secreted is determined by measuring the amount of saliva secreted by a subject (including humans and non-human mammals) before and after ingesting the subject composition for a certain period of time. can be compared to determine whether or not the latter is greater than the former. INDUSTRIAL APPLICABILITY The composition of the present invention is suitable for increasing the amount of salivary secretion that has decreased with age, and is particularly suitable for use in humans aged 40 or older, preferably 50 or older, or 60 or older. ing.
　本発明の組成物による唾液の分泌量の増加は、安静時唾液量が平均値未満である場合に増加させる場合と、唾液量が平均の範囲内ではあるが加齢により低下していると考えられる場合に増加させる場合とを含む。成人の安静時唾液量の平均は約0.3～0.5 mL/minであるが、本発明の組成物は、この範囲内ではあるが加齢により低下している対象者に摂取させることにより、安静時唾液量を増加させうる。 The increase in salivary secretion due to the composition of the present invention is considered to occur when the resting saliva volume is less than the average value, and when the saliva volume is within the average range but decreases with age. including cases where it is increased when it is possible. The average resting saliva volume of adults is about 0.3 to 0.5 mL/min. May increase salivary flow.
　ある組成物により、口腔内の細菌の数が低減するか否かは、対象者（ヒト及び非ヒト哺乳類動物を含む）において、対象組成物を摂取する前と一定期間摂取した後のそれぞれにおいて唾液中の細菌数を計数し、前者よりも後者のほうが少なくなったか否かにより判断することができる。 Whether a certain composition reduces the number of bacteria in the oral cavity can be determined by measuring the saliva of a subject (including humans and non-human mammals) before and after ingesting the subject composition for a certain period of time. By counting the number of bacteria in the medium, it can be determined whether the number of bacteria in the latter is smaller than that of the former.
　本発明の組成物はまた、口腔乾燥症（ドライマウス）、及び口臭の少なくとも一方の処置のために用いうる。口腔乾燥症の原因は様々であり、口呼吸、水分不足、脱水、加齢、加齢に伴う衰え、加齢に伴う服薬、ストレス、疾患によるもの、薬の副作用によるもの、それらが複合的に関与しているものがあるが、本発明の組成物はいずれの場合にも用いうる。口腔乾燥症の原因となる疾患の例として、糖尿病、甲状腺機能障害、尿崩症、シェーグレン症候群が挙げられる。口腔乾燥の副作用が伴いうる薬の例として、抗うつ剤、抗不安薬、降圧剤、鎮痛剤が挙げられる。また、がん治療で唾液腺に放射線が当たるような場合には、唾液腺組織が傷害を受け、口腔乾燥症を生じやすくなる場合があるが、本発明の組成物はそのような場合にも用いうる。 The composition of the present invention can also be used for the treatment of at least one of xerostomia (dry mouth) and halitosis. There are various causes of xerostomia, including mouth breathing, dehydration, dehydration, aging, age-related decline, age-related medication use, stress, disease, side effects of drugs, and a combination of these. Although some are involved, the compositions of the present invention can be used in either case. Examples of diseases that cause xerostomia include diabetes, thyroid dysfunction, diabetes insipidus, and Sjögren's syndrome. Examples of drugs that may have dry mouth side effects include antidepressants, antianxiety drugs, antihypertensives, and analgesics. In addition, when salivary glands are exposed to radiation in cancer treatment, salivary gland tissue may be damaged and xerostomia tends to occur, and the composition of the present invention can also be used in such cases. .
　本発明の組成物はまた、口腔粘膜炎、歯肉炎、歯周炎、口腔感染、口腔炎症、及び口臭からなる群より選択されるいずれかの処置のためにも用いうる。 The composition of the present invention can also be used for any treatment selected from the group consisting of oral mucositis, gingivitis, periodontitis, oral infection, oral inflammation, and halitosis.
　なお本発明に関し、疾患又は状態について処置というときは、発症リスクの低減、発症の遅延、予防、治療、進行の停止、遅延を含む。処置には、医師が行う、病気の治療を目的とした医療行為と、医師以外の者、例えば栄養士、管理栄養士、保健師、助産師、看護師、臨床検査技師、美容部員、エステティシャン、食品製造者、食品販売者等が行う、非医療的行為とが含まれる。また処置には、特定の食品の投与又は摂取の推奨、食餌方法指導、保健指導、栄養指導（傷病者に対する療養のために必要な栄養の指導、及び健康の保持増進のための栄養の指導を含む。）、給食管理、給食に関する栄養改善上必要な指導が含まれる。本発明における処置の対象は、ヒト（個体）と非ヒト哺乳類動物（コンパニオンアニマル等）を含む。 In the context of the present invention, treatment of a disease or condition includes reduction of risk of onset, delay of onset, prevention, treatment, arrest of progression, and delay. Treatment includes medical activities performed by doctors for the purpose of treating illnesses, and non-doctors such as dieticians, registered dietitians, public health nurses, midwives, nurses, clinical laboratory technologists, beauty consultants, estheticians, and food manufacturers. non-medical actions performed by persons, food sellers, etc. In addition, treatment includes recommending the administration or intake of specific foods, guidance on dietary methods, health guidance, nutritional guidance (nutrition guidance necessary for medical treatment for the sick and injured, and nutritional guidance for maintaining and improving health). ), school lunch management, and guidance necessary for nutritional improvement related to school lunch. Subjects for treatment in the present invention include humans (individuals) and non-human mammals (companion animals, etc.).
　本発明の組成物はまた、口腔、口腔粘膜、舌、及び歯ぐき等からなるいずれかの口腔組織を、丈夫で健康に保つため、口腔内環境を良好に保つ働きを助けるため、又は口腔環境を良好に保ち、歯肉の健康を維持するのを助けるために、用いることができる。 The composition of the present invention is also useful for keeping any oral tissue consisting of the oral cavity, oral mucosa, tongue, gums and the like strong and healthy, helping to maintain good oral environment, or improving the oral environment. It can be used to keep well and help maintain gum health.
（対象） 
　本発明の組成物は、口腔ケアの必要がある対象に摂取させるのに、特に適している。このような対象には、成人（１５歳以上）、中高年者（４０歳～６５歳未満）、高齢者（６５歳以上）、病中病後の者、妊婦、産婦、乳幼児、子ども、男性、女性が含まれる。 (subject)
The compositions of the present invention are particularly suitable for ingestion by subjects in need of oral care. Such subjects include adults (ages 15 and over), middle-aged and elderly (ages 40 to 65), seniors (ages 65 and over), persons during and after illness, pregnant women, women in childbirth, infants, children, men, and women. is included.
　本発明の組成物は、唾液分泌量増加が望ましい又は必要がある対象、例えば口渇症状を有する者に摂取させるのに適している。口渇とは、口中やのどが激しくかわき、水分を欲しがる状態をいう。口渇は、多尿症及び脱水症にともなう場合、薬の副作用による場合、加齢による場合がある。唾液の多くは大唾液腺（耳下腺、顎下腺、舌下腺）から分泌されるが、無刺激状態での唾液（安静時唾液）は、多くは顎下腺から分泌される。 The composition of the present invention is suitable for ingestion by subjects who desire or need an increase in salivary secretion, such as those with symptoms of dry mouth. Thirst is a condition in which the mouth and throat are severely thirsty and require water. Dry mouth can be associated with polyuria and dehydration, can be a side effect of medications, and can be age-related. Most saliva is secreted from the major salivary glands (parotid, submandibular, and sublingual), but saliva in an unstimulated state (resting saliva) is mostly secreted from the submandibular gland.
　ある種の医薬品（薬剤）の副作用として、口渇が知られている。本発明の組成物は、口渇作用のある医薬品を投与されている者に摂取させるのに適している。口渇作用のある医薬品の例として、抗コリン作用を有する医薬品、より特定すると三環系抗うつ薬、抗コリン作用を有する抗パーキンソン薬、抗ムスカリン作用薬等が挙げられる。三環系抗うつ薬の例として、アミトリプチリン、イミプラミン、クロミプラミン、トリミプラミン、ノルトリプチリン、アモキサピン、ドスレピン、ロフェプラミン及びこれらの医薬として許容される塩が挙げられる。 Dry mouth is known as a side effect of certain pharmaceuticals (drugs). The composition of the present invention is suitable for ingestion by a person receiving mouth-drying medicaments. Examples of drugs with dry mouth properties include drugs with anticholinergic properties, more particularly tricyclic antidepressants, antiparkinson drugs with anticholinergic properties, antimuscarinic drugs, and the like. Examples of tricyclic antidepressants include amitriptyline, imipramine, clomipramine, trimipramine, nortriptyline, amoxapine, dosulepin, lofepramine and pharmaceutically acceptable salts thereof.
　また、口渇の副作用が知られている医薬品の例として、下記が報告されている。本発明の組成物は、下記の医薬品を投与されている者に摂取させるのにも適している。アキシチニブ、アジスロマイシン水和物、アスピリン、アセトアミノフェン、アセトアミノフェン、アデホビル　ピボキシル、アトモキセチン塩酸塩、アビラテロン酢酸エステル、アミトリプチリン塩酸塩、アムロジピンベシル酸塩、アモキサピン、アリピプラゾール、アレンドロン酸ナトリウム水和物、アロプリノール、イオパミドール、イオヘキソール、イコサペント酸エチル、イトラコナゾール、イピリムマブ（遺伝子組換え）、イプラグリフロジン　Ｌ－プロリン、イミプラミン塩酸塩、イルベサルタン・アムロジピンベシル酸塩配合剤、インスリン　デグルデク（遺伝子組換え）、インスリン　ヒト（遺伝子組換え）、インターフェロン　アルファ（ＮＡＭＡＬＷＡ）、インフルエンザＨＡワクチン、ウメクリジニウム臭化物・ビランテロールトリフェニル酢酸塩、エスシタロプラムシュウ酸塩、エチゾラム、エトポシド、エナラプリルマレイン酸塩、エベロリムス、エルデカルシトール、オキシコドン塩酸塩水和物、オクトレオチド酢酸塩、オシメルチニブメシル酸塩、オムビタスビル水和物・パリタプレビル水和物・リトナビル、オランザピン、カナグリフロジン水和物、カルバマゼピン、カルムスチン、クエチアピンフマル酸塩、クロザピン、クロチアゼパム、クロピドグレル硫酸塩、ケトコナゾール、コハク酸ソリフェナシン、コロナウイルス修飾ウリジンＲＮＡワクチン（ＳＡＲＳ－ＣｏＶ－２）、コロナウイルス修飾ウリジンＲＮＡワクチン（ＳＡＲＳ－ＣｏＶ－２）、サリドマイド、サルポグレラート塩酸塩、サルメテロールキシナホ酸塩・フルチカゾンプロピオン酸エステル、シクロホスファミド水和物、シスプラチン、シタグリプチンリン酸塩水和物、シプロヘプタジン塩酸塩水和物、シロスタゾール、シロドシン、ジアゼパム、ジクロフェナクナトリウム、ジソピラミド、ジフェニドール塩酸塩、ジフェンヒドラミンサリチル酸塩・ジプロフィリン、スピロノラクトン、スボレキサント、スルピリド、セチリジン塩酸塩、セルトラリン塩酸塩、センノシド、ソフピロニウム臭化物、ゾルピデム酒石酸塩、ゾレドロン酸水和物、タフルプロスト、タムスロシン塩酸塩、タモキシフェンクエン酸塩、タンドスピロンクエン酸塩、ダクラタスビル塩酸塩、ダパグリフロジンプロピレングリコール水和物、ダプトマイシン、チキジウム臭化物、テノホビル　アラフェナミドフマル酸塩、テラプレビル、テルビナフィン塩酸塩、デキサメタゾンリン酸エステルナトリウム、デスモプレシン酢酸塩水和物、デノスマブ（遺伝子組換え）、デュロキセチン塩酸塩、トスフロキサシントシル酸塩水和物、トリアゾラム、トルバプタン、ドセタキセル水和物、ドネペジル塩酸塩、ドンペリドン、ナプロキセン、ニトラゼパム、ニボルマブ（遺伝子組換え）、バゼドキシフェン酢酸塩、バラシクロビル塩酸塩、バルサルタン、パノビノスタット乳酸塩、パリペリドン、パリペリドンパルミチン酸エステル、パルボシクリブ、パロキセチン塩酸塩水和物、ヒドロキシジン塩酸塩、ビソプロロールフマル酸塩、ビペリデン塩酸塩、ビランテロールトリフェニル酢酸塩・フルチカゾンフランカルボン酸エステル、ビルダグリプチン、ファモチジン、フィナステリド、フェソテロジンフマル酸塩、フェニトイン、フェンタニル、フルチカゾンフランカルボン酸エステル、フルチカゾンプロピオン酸エステル、フルニトラゼパム、フルバスタチンナトリウム、フルボキサミンマレイン酸塩、フルマゼニル、フロセミド、フロセミド、ブレクスピプラゾール、ブロチゾラム、ブロナンセリン、ブロマゼパム、プラバスタチンナトリウム、プラミペキソール塩酸塩水和物、プレガバリン、プレドニゾロン、プロパンテリン臭化物、プロプラノロール塩酸塩、ベタヒスチンメシル酸塩、ベタメタゾン吉草酸エステル・ゲンタマイシン硫酸塩、ベンダムスチン塩酸塩、ベンラファキシン塩酸塩、ペグインターフェロン　アルファ－２ａ（遺伝子組換え）、ペグインターフェロン　アルファ－２ｂ（遺伝子組換え）、ペムブロリズマブ（遺伝子組換え）、ペランパネル水和物、ペンタミジンイセチオン酸塩、ボルテゾミブ、マプロチリン塩酸塩、ミアンセリン塩酸塩、ミグリトール、ミラベグロン、ミルタザピン、メシル酸ガレノキサシン水和物、メチルフェニデート塩酸塩、メチルプレドニゾロン、メチルプレドニゾロンコハク酸エステルナトリウム、メトクロプラミド、メトトレキサート、メトホルミン塩酸塩、モザバプタン塩酸塩、モンテルカストナトリウム、ラパチニブトシル酸塩水和物、ラモトリギン、ランソプラゾール、リスペリドン、リセドロン酸ナトリウム水和物、リトドリン塩酸塩、リドカイン塩酸塩・アドレナリン、リネゾリド、リュープロレリン酢酸塩、リラグルチド（遺伝子組換え）、リン酸ジソピラミド、ルセオグリフロジン水和物、レンバチニブメシル酸塩、ロキソプロフェンナトリウム水和物、ロサルタンカリウム・ヒドロクロロチアジド配合剤、ロメリジン塩酸塩、ロラゼパム、ロラタジン、ワクシニアウイルス接種家兎炎症皮膚抽出液、乾燥弱毒生麻しん風しん混合ワクチン、塩酸メトクロプラミド、抗ヒト胸腺細胞ウサギ免疫グロブリン、消化性潰瘍用剤（一般薬）、混合ビタミン剤（ビタミンＡ・Ｄ混合製剤を除く。）（一般薬）、漢方製剤（一般薬）、炭酸リチウム、硫酸マグネシウム水和物・ブドウ糖、組換え沈降２価ヒトパピローマウイルス様粒子ワクチン（イラクサギンウワバ細胞由来）、酸化マグネシウム、Ａ型ボツリヌス毒素、Ｌ－アスパラギン酸カルシウム水和物。 In addition, the following has been reported as an example of a drug known to have dry mouth side effects. The compositions of the present invention are also suitable for ingestion by persons receiving the following medicaments. axitinib, azithromycin hydrate, aspirin, acetaminophen, acetaminophen, adefovir pivoxil, atomoxetine hydrochloride, abiraterone acetate, amitriptyline hydrochloride, amlodipine besilate, amoxapine, aripiprazole, alendronate sodium hydrate, allopurinol , iopamidol, iohexol, ethyl icosapentate, itraconazole, ipilimumab (genetical recombination), ipragliflozin L-proline, imipramine hydrochloride, irbesartan/amlodipine besilate, insulin degludec (genetical recombination), insulin human (genetic recombinant), interferon alpha (NAMALWA), influenza HA vaccine, umeclidinium bromide/vilanterol triphenyl acetate, escitalopram oxalate, etizolam, etoposide, enalapril maleate, everolimus, eldecalcitol, oxycodone hydrochloride hydrate, Octreotide acetate, osimertinib mesylate, ombitasvir hydrate/paritaprevir hydrate/ritonavir, olanzapine, canagliflozin hydrate, carbamazepine, carmustine, quetiapine fumarate, clozapine, clotiazepam, clopidogrel sulfate, ketoconazole , solifenacin succinate, coronavirus-modified uridine RNA vaccine (SARS-CoV-2), coronavirus-modified uridine RNA vaccine (SARS-CoV-2), thalidomide, sarpogrelate hydrochloride, salmeterol xinafoate/fluticasone propionate, Cyclophosphamide hydrate, cisplatin, sitagliptin phosphate hydrate, cyproheptadine hydrochloride hydrate, cilostazol, silodosin, diazepam, diclofenac sodium, disopyramide, diphenidol hydrochloride, diphenhydramine salicylate/diprophylline, spironolactone, suvorexant, sulpiride, cetirizine hydrochloride, sertraline hydrochloride, sennoside, sofpironium bromide, zolpidem tartrate, zoledronic acid hydrate, tafluprost, tamsulosin hydrochloride, tamoxifen citrate, tandospirone citrate, daclatasvir hydrochloride, dapagliflozin propylene glycol water hydrate, daptomycin, thikidium bromide, tenofovir alafenamide fumarate, telaprevir , terbinafine hydrochloride, dexamethasone sodium phosphate, desmopressin acetate hydrate, denosumab (genetical recombination), duloxetine hydrochloride, tosufloxacin tosilate hydrate, triazolam, tolvaptan, docetaxel hydrate, donepezil hydrochloride, domperidone , naproxen, nitrazepam, nivolumab (genetical recombination), bazedoxifene acetate, valacyclovir hydrochloride, valsartan, panobinostat lactate, paliperidone, paliperidone palmitate, palbociclib, paroxetine hydrochloride hydrate, hydroxyzine hydrochloride, bisoprolol fumarate , biperiden hydrochloride, vilanterol triphenylacetate/fluticasone furoate, vildagliptin, famotidine, finasteride, fesoterodine fumarate, phenytoin, fentanyl, fluticasone furoate, fluticasone propionate, flunitrazepam, fluvastatin sodium, fluvoxamine maleate, flumazenil, furosemide, furosemide, brexpiprazole, brotizolam, blonanserin, bromazepam, pravastatin sodium, pramipexole hydrochloride hydrate, pregabalin, prednisolone, propantheline bromide, propranolol hydrochloride, betahistine mesylate , betamethasone valerate/gentamicin sulfate, bendamustine hydrochloride, venlafaxine hydrochloride, peginterferon alfa-2a (genetical recombination), peginterferon alfa-2b (genetical recombination), pembrolizumab (genetical recombination), Peran Panel hydrate, pentamidine isethionate, bortezomib, maprotiline hydrochloride, mianserin hydrochloride, miglitol, mirabegron, mirtazapine, galenoxacin mesilate hydrate, methylphenidate hydrochloride, methylprednisolone, methylprednisolone sodium succinate, Metoclopramide, methotrexate, metformin hydrochloride, mozavaptan hydrochloride, montelukast sodium, lapatini butosilate hydrate, lamotrigine, lansoprazole, risperidone, risedronate sodium hydrate, ritodrine hydrochloride, lidocaine hydrochloride/adrenaline, linezolid, leuprorelin Acetate, liraglutide (genetical recombination), disopyramide phosphate, luseogliflozin water hydrate, lenvatinib mesylate, loxoprofen sodium hydrate, losartan potassium/hydrochlorothiazide combination, lomerizine hydrochloride, lorazepam, loratadine, vaccinia virus-inoculated rabbit inflammatory skin extract, dried live attenuated measles-rubella mixed vaccine, hydrochloric acid Metoclopramide, anti-human thymocyte rabbit immunoglobulin, anti-peptic ulcer drug (over-the-counter drug), mixed vitamin preparation (excluding vitamin A/D mixed preparations. ) (over-the-counter drugs), Chinese herbal preparations (over-the-counter drugs), lithium carbonate, magnesium sulfate hydrate/glucose, recombinant precipitated bivalent human papillomavirus-like particle vaccine (derived from stinging nettle cells), magnesium oxide, botulinum toxin type A, Calcium L-aspartate hydrate.
　また本発明の組成物は、有効成分が食経験の長いＮＡＤ類似物質であるため、長期間の摂取に適しているため、日常的に口腔をケアしたい者に、特に適している。 In addition, the composition of the present invention is suitable for long-term intake because the active ingredient is an NAD-like substance that has a long history of eating, and is therefore particularly suitable for those who want to care for their oral cavity on a daily basis.
（投与経路）
  本発明の組成物は、種々の経路で用いられる。投与経路の例として、経口、舌下、経直腸、点眼、経鼻、吸入、経皮、経粘膜、皮下、筋肉、静脈が挙げられる。好ましい態様においては、組成物は経口的に又は舌下投与、又は皮下投与に用いられる。 (Administration route)
The compositions of the invention are used in a variety of routes. Examples of routes of administration include oral, sublingual, rectal, eye drops, nasal, inhalation, transdermal, transmucosal, subcutaneous, intramuscular, and intravenous. In preferred embodiments, the compositions are used orally or sublingually or subcutaneously.
（その他）
　本発明の組成物は、口腔ケアに関する他の療法と一緒に行われる場合であっても、用いることができる。そのような他の療法には、他の成分の摂取、口腔内の洗浄、口腔内の殺菌（口腔用スプレー等による）、歯磨き、口腔内のマッサージ、他の成分、健康食品、サプリメント等の摂取、運動療法等がある。本発明の組成物は、他の口腔用組成物と併用してもよい。他の口腔用組成物の例として、歯磨類、洗口剤、口腔用軟膏、うがい剤、人工唾液、義歯安定剤が挙げられる。 (others)
The compositions of the present invention can be used even when administered in conjunction with other oral care regimens. Such other therapies include ingestion of other ingredients, oral cleaning, oral sterilization (with oral sprays, etc.), tooth brushing, oral massage, ingestion of other ingredients, health foods, supplements, etc. , exercise therapy, etc. The composition of the present invention may be used in combination with other oral compositions. Examples of other oral compositions include dentifrices, mouthwashes, oral ointments, mouthwashes, artificial saliva, and denture fixatives.
［組成物］
（食品組成物等）
　本発明の組成物は、食品、化粧品、医薬部外品、又は医薬品である組成物とすることができる。食品、又は医薬品は、特に記載した場合を除き、ヒトのためのもののみならず、ヒト以外の動物のためのものを含む。食品は、特に記載した場合を除き、一般食品、機能性食品、栄養組成物を含み、また治療食（治療の目的を果たすもの。医師が食事箋を出し、それに従い栄養士等が作成した献立に基づいて調理されたもの。）、食事療法食、成分調整食、介護食、治療支援用食品を含む。食品は、特に記載した場合を除き、固形物のみならず、液状のもの、例えば飲料、ドリンク剤、流動食、及びスープを含む。機能性食品とは、生体に所定の機能性を付与できる食品をいい、例えば、特定保健用食品（条件付きトクホ［特定保健用食品］を含む）、機能性表示食品、栄養機能食品を含む保健機能食品、特別用途食品、栄養補助食品、健康補助食品、サプリメント（例えば、錠剤、被覆錠、糖衣錠、カプセル、液剤等の各種の剤型のもの）、美容食品（例えば、ダイエット食品）等の、健康食品の全般を包含している。また、本発明において「機能性食品」とは、コーデックス（FAO/WHO合同食品規格委員会）の食品規格に基づく健康強調表示（Health claim）が適用される健康食品を包含している。化粧品は、薬用化粧品を含む。 [Composition]
(Food composition, etc.)
The composition of the present invention can be a food, cosmetic, quasi-drug, or pharmaceutical composition. Foods or pharmaceuticals include those for humans as well as non-human animals, unless otherwise specified. Unless otherwise specified, foods include general foods, functional foods, nutritional compositions, and therapeutic foods (things that serve the purpose of treatment. A doctor gives a diet prescription and a dietitian etc. prepares a menu according to it). foods cooked according to the above), dietary therapy foods, ingredient-adjusted foods, nursing care foods, and therapeutic support foods. Foods include not only solids but also liquids such as beverages, drinks, liquid foods, and soups, unless otherwise specified. Functional foods refer to foods that can impart predetermined functionality to living organisms. Functional foods, special purpose foods, dietary supplements, health supplements, supplements (for example, tablets, coated tablets, sugar-coated tablets, capsules, liquids, etc.), beauty foods (for example, diet foods), etc. It includes general health foods. In the present invention, "functional food" includes health foods to which health claims based on food standards of Codex (FAO/WHO Joint Food Standards Committee) are applied. Cosmetics include cosmeceuticals.
（有効成分の含有量・用量）
　本発明の組成物における、ＮＡＤ類似物質の含有量は、目的の効果が発揮される量であればよい。組成物は、その被験体の年齢、体重、症状等の種々の要因を考慮して、その投与量又は摂取量を適宜設定することができるが、例えば、１単位（１錠、１剤、１回投与量・摂取量）あたり、ＮＡＤ類似物質をＮＭＮとして５ｍｇ以上含有することができ、１０ｍｇ以上含有してもよく、１００ｍｇ以上含有することが好ましく、１３０ｍｇ以上含有することがより好ましく、２００ｍｇ以上含有することがさらに好ましい。上限値は特に限定されないが、いずれの場合であっても、５０００ｍｇ以下とすることができ、２５００ｍｇ以下としてもよく、１０００ｍｇ以下が好ましく、５００ｍｇ以下がより好ましく、３００ｍｇ以下がさらに好ましい。なお本発明に関し、ＮＡＤ類似物質の量について「ＮＭＮとして」というときは、その量は、ＮＡＤ類似物質から生じうるＮＭＮの量である。この換算は当業者であれば容易に行うことができる。ＮＡＤ類似物質がＮＭＮである場合は、その量はＮＭＮの量である。 (Content and dose of active ingredient)
The content of the NAD-like substance in the composition of the present invention may be any amount as long as the intended effect is exhibited. The dosage or intake of the composition can be appropriately set in consideration of various factors such as age, body weight and symptoms of the subject. NAD analogous substance can be contained as NMN at 5 mg or more, may contain 10 mg or more, preferably 100 mg or more, more preferably 130 mg or more, more preferably 200 mg or more per dose/intake). Containing is more preferable. Although the upper limit is not particularly limited, in any case, it can be 5000 mg or less, may be 2500 mg or less, is preferably 1000 mg or less, more preferably 500 mg or less, and further preferably 300 mg or less. In the context of the present invention, when the amount of the NAD-like substance is referred to as "as NMN", the amount is the amount of NMN that can be generated from the NAD-like substance. This conversion can be easily performed by those skilled in the art. If the NAD analogue is NMN, the amount is the amount of NMN.
　本発明の組成物の一日量は、ＮＡＤ類似物質を、ＮＭＮとして、例えば５ｍｇ以上とすることができ、１０ｍｇ以上含有してもよく、１００ｍｇ以上含有することが好ましく、１３０ｍｇ以上含有することがより好ましく、２００ｍｇ以上含有することがさらに好ましい。上限値は特に限定されないが、いずれの場合であっても、５０００ｍｇ以下とすることができ、２５００ｍｇ以下としてもよく、１０００ｍｇ以下が好ましく、５００ｍｇ以下がより好ましく、３００ｍｇ以下がさらに好ましい。このような一日量は、複数に、例えば一日３回の摂取・投与に適するように、３つに分割してもよい。 The daily dose of the composition of the present invention may contain, for example, 5 mg or more, may contain 10 mg or more, preferably 100 mg or more, and may contain 130 mg or more of the NAD-like substance as NMN. More preferably, it is contained in an amount of 200 mg or more. Although the upper limit is not particularly limited, in any case, it can be 5000 mg or less, may be 2500 mg or less, is preferably 1000 mg or less, more preferably 500 mg or less, and further preferably 300 mg or less. Such daily dose may be divided into multiple portions, eg, three portions, suitable for ingestion and administration three times a day.
　組成物の投与・摂取は一日のうちのどの時点で実施してもよい。体内のＮＡＤ濃度には日内変動があると考えられ、活動期に高まるとの観点からは、組成物は、活動期の開始にあたる朝に摂取することが好ましいと考えられる。 The administration and intake of the composition may be performed at any time of the day. The concentration of NAD in the body is thought to fluctuate during the day, and from the viewpoint that it increases during the active period, it is considered preferable to take the composition in the morning, which is the start of the active period.
　組成物は、食経験豊富なＮＡＤ類似物質を有効成分としているため、繰り返し、又は長期間にわたって投与・摂取させてもよく、例えば３日以上、好ましくは１週間以上、より好ましくは４週間以上、さらに好ましくは８週間以上続けて摂取させることができる。 Since the composition contains an NAD-like substance that has a lot of food experience as an active ingredient, it may be administered and taken repeatedly or over a long period of time, for example, 3 days or more, preferably 1 week or more, more preferably 4 weeks or more, More preferably, it can be ingested continuously for 8 weeks or more.
（他の成分、添加剤）
　本発明の組成物は、食品又は医薬品として許容可能な他の有効成分や栄養成分を含んでいてもよい。そのような成分の例は、サーチュイン活性化成分（例えば、レスベラトロール）、ケルセチン、アスタキサンチン、クロレラ、コエンザイムQ10、ビタミン（例えば、ビタミンＡ、ビタミンＢ１、ビタミンＢ２、ビタミンＢ６、ビタミンＢ１２、ビタミンＣ、ビタミンＤ、ビタミンＥ、ビタミンＫ、ビオチン、葉酸、パントテン酸及びニコチン酸類）、アミノ酸類（例えば、リジン、アルギニン、グリシン、アラニン、グルタミン酸、ロイシン、イソロイシン、バリン）、糖質（グルコース、ショ糖、果糖、麦芽糖、トレハロース、エリスリトール、マルチトール、パラチノース、キシリトール、デキストリン）、電解質（例えば、ナトリウム、カリウム、カルシウム、マグネシウム）、ミネラル（例えば、銅、亜鉛、鉄、コバルト、マンガン）、抗生物質、食物繊維、タンパク質、脂質等である。 (other ingredients, additives)
The composition of the present invention may contain other active ingredients and nutritional ingredients that are acceptable as foods or pharmaceuticals. Examples of such ingredients are sirtuin-activating ingredients (e.g. resveratrol), quercetin, astaxanthin, chlorella, coenzyme Q10, vitamins (e.g. vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C). , vitamin D, vitamin E, vitamin K, biotin, folic acid, pantothenic acid and nicotinic acid), amino acids (e.g., lysine, arginine, glycine, alanine, glutamic acid, leucine, isoleucine, valine), carbohydrates (glucose, sucrose , fructose, maltose, trehalose, erythritol, maltitol, palatinose, xylitol, dextrin), electrolytes (e.g. sodium, potassium, calcium, magnesium), minerals (e.g. copper, zinc, iron, cobalt, manganese), antibiotics, Dietary fiber, protein, lipid, and the like.
  また組成物は、食品、化粧品、医薬部外品、又は医薬として許容される添加物をさらに含んでいてもよい。そのような添加物の例は、不活性担体（固体や液体担体）、賦形剤、界面活性剤、結合剤、崩壊剤、滑沢剤、溶解補助剤、懸濁化剤、コーティング剤、着色剤、保存剤、緩衝剤、pH調整剤、乳化剤、安定剤、甘味料、酸化防止剤、香料、酸味料、天然物である。より具体的には、水、他の水性溶媒、製薬上で許容される有機溶媒、コラーゲン、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、アルギン酸ナトリウム、水溶性デキストラン、水溶性デキストリン、カルボキシメチルスターチナトリウム、ペクチン、キサンタンガム、アラビアゴム、カゼイン、ゼラチン、寒天、グリセリン、プロピレングリコール、ポリエチレングリコール、ワセリン、パラフィン、ステアリルアルコール、ステアリン酸、ヒト血清アルブミン、マンニトール、ソルビトール、ラクトース、スクラロース、ステビア、アスパルテーム、アセスルファムカリウム、クエン酸、乳酸、りんご酸、酒石酸、リン酸、酢酸、果汁、野菜汁等である。 The composition may further contain food, cosmetics, quasi-drugs, or pharmaceutically acceptable additives. Examples of such additives include inert carriers (solid and liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, solubilizers, suspending agents, coating agents, coloring agents. agents, preservatives, buffers, pH adjusters, emulsifiers, stabilizers, sweeteners, antioxidants, flavors, acidulants, natural products. More specifically, water, other aqueous solvents, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, water-soluble dextrin, sodium carboxymethyl starch, Pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petroleum jelly, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, sucralose, stevia, aspartame, acesulfame potassium, Citric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, acetic acid, fruit juice, vegetable juice, and the like.
（剤型・形態）
  本発明の組成物は、固体、液体、混合物、懸濁物、乳化物、ゲル、ゾル等の任意の形態に調製されたものであってよい。組成物の具体的な形態の例として、チュアブル錠、舌下錠、錠剤、丸剤、カプセル、顆粒剤、散剤、粉末剤、液剤、懸濁剤、乳剤、シロップ剤、リニメント剤、ローション剤、ジェル剤、エアゾール剤、スプレー剤、軟膏剤、クリーム剤、テープ剤、ハップ剤、点眼剤、点鼻剤、坐剤が挙げられる。 (dosage form/form)
The composition of the present invention may be prepared in any form such as solid, liquid, mixture, suspension, emulsion, gel, sol and the like. Specific forms of the composition include chewable tablets, sublingual tablets, tablets, pills, capsules, granules, powders, powders, solutions, suspensions, emulsions, syrups, liniments, lotions, Gels, aerosols, sprays, ointments, creams, tapes, poultices, eye drops, nose drops, and suppositories.
  また組成物が食品である場合、乳製品、サプリメント、菓子、飲料、ドリンク剤、調味料、加工食品、惣菜、スープ等の任意の形態にすることができる。具体的には、本発明の組成物は、グミ、タブレット、ドリンク剤、発酵乳、乳性飲料、乳飲料、清涼飲料、アイスクリーム、チーズ、パン、ビスケット、クラッカー、ピッツァクラスト、調製粉乳、流動食、病者用食品、栄養食品、冷凍食品、加工食品等の形態とすることができ、また飲料や食品に混合するための、又は希釈して飲料等を調製するための、顆粒、粉末、ペースト、濃厚液等の形態とすることができる。 In addition, when the composition is a food, it can be in any form such as dairy products, supplements, confectionery, beverages, drinkable preparations, seasonings, processed foods, side dishes, soups, and the like. Specifically, the composition of the present invention can be used as gummies, tablets, drinks, fermented milk, dairy drinks, dairy drinks, soft drinks, ice cream, cheese, bread, biscuits, crackers, pizza crust, prepared milk powder, liquid It can be in the form of food, food for the sick, nutritional food, frozen food, processed food, etc., and granules, powders, or powders for mixing with beverages or foods, or for preparing beverages by dilution. It can be in the form of a paste, a concentrate, or the like.
（その他）
　本発明の組成物は、当業者であれば既存の設備等を利用して適宜製造することができる。組成物の製造において、ＮＡＤ類似物質の配合の段階は、ＮＡＤ類似物質の特性を著しく損なわない限り、特に制限されない。 (others)
The composition of the present invention can be appropriately produced by those skilled in the art using existing equipment and the like. In the production of the composition, the step of adding the NAD analogue is not particularly limited as long as the properties of the NAD analogue are not significantly impaired.
　本発明の組成物を含む製品には、機能、及び使用目的（用途）を表示することができ、また特定の対象に対して投与・摂取を薦める旨を表示することができる。表示は、直接的に又は間接的にすることができ、直接的な表示の例は、製品自体、パッケージ、容器、ラベル、タグ等の有体物への記載であり、間接的な表示の例は、ウェブサイト、店頭、パンフレット、展示会、メディアセミナー等のセミナー、書籍、新聞、雑誌、テレビ、ラジオ、郵送物、電子メール、音声等の、場所又は手段による、広告・宣伝活動を含む。 A product containing the composition of the present invention can be labeled with its function and purpose of use (use), and can be labeled with recommendations for administration and intake to specific subjects. Labeling can be done directly or indirectly. Examples of direct labeling are descriptions on tangible objects such as the product itself, packages, containers, labels, tags, etc. Examples of indirect labeling are: Websites, storefronts, pamphlets, exhibitions, seminars such as media seminars, books, newspapers, magazines, television, radio, mail, e-mail, voice, etc., including advertising and publicity activities by place or means.
　表示される使用目的（用途）の例として、「口腔環境改善」、「口腔ケア」、「オーラルケア」、「唾液の分泌を促進する」、「口腔内の細菌数を低減する」が挙げられる。 Examples of the intended use (purpose) displayed include "improving the oral environment", "oral care", "oral care", "promoting the secretion of saliva", and "reducing the number of bacteria in the oral cavity". .
  以下、実施例を用いて、本発明をさらに具体的に説明する。 The present invention will be described in more detail below using examples.
評価例１
試験1：動物試験
［方法]
１）投与物
　マウスに投与するβ-Nicotinamide Mononucleotide（NMN）は、Bontac社製を使用し、蒸留水に溶解後マウスに飲水にて投与した。投与用量は300 mg/kg/dayに設定し、投与濃度は事前に測定したマウスの飲水量と体重を元に算出した。 Evaluation example 1
Study 1: Animal study [Methods]
1) Administration material β-Nicotinamide Mononucleotide (NMN) to be administered to mice was manufactured by Bontac, dissolved in distilled water, and then administered to mice through drinking water. The administration dose was set at 300 mg/kg/day, and the administration concentration was calculated based on the water intake and body weight of mice measured in advance.
２）動物
　若齢マウスは雄性で24週齢、C57BL/6J系統を10匹、老齢マウスは雄性で84週齢、C57BL/6J系統を20匹購入した。目安として、マウスの24週齢、及び84週齢は、それぞれヒトの30歳前後、及び60歳前後に相当する。マウスは、室温22±2℃、湿度55±15%、明期7時～19時、暗期19時～7時の飼育室で、個別飼いで試験終了まで飼育を行った。また、飼料と水は制限せず自由に摂取させた。予備飼育終了後、老齢マウスは体重の平均値、唾液分泌量が均等となるように1群10匹の2群（老齢コントロール群：OC群、老齢NMN群：ON群）に群分けした。群分け後、ON群にはNMNの飲水投与を開始し、若齢マウス（若齢コントロール群：YC群）とOC群は予備飼育と同様に通常の水を与えて8週間飼育を行った。 2) Animals We purchased 10 male young mice, 24 weeks old, C57BL/6J strain, and 20 old male mice, 84 weeks old, C57BL/6J strain. As a guideline, 24-week-old and 84-week-old mice correspond to around 30 years old and around 60 years old in humans, respectively. Mice were individually housed in a breeding room with room temperature of 22±2°C, humidity of 55±15%, light period from 7:00 to 19:00 and dark period from 19:00 to 7:00 until the end of the test. Feed and water were allowed to be taken freely without restriction. After preliminary breeding, the aged mice were divided into 2 groups (aged control group: OC group, aged NMN group: ON group) of 10 mice per group so that the mean body weight and salivary secretion were equal. After grouping, NMN was administered to the ON group in drinking water, and the young mice (young control group: YC group) and the OC group were fed normal water for 8 weeks in the same manner as the preliminary breeding.
３）唾液分泌量の測定
　予備飼育中及び試験開始8週間後に全個体より唾液を採取した。体重測定を実施後に1時間の絶食を行い、最後の30分は絶水も行った。三種混合麻酔薬（ドミトール、ベトルファール、ミダゾラム）を10 mL/kgの容量で腹腔内投与してマウスに麻酔をかけた。深麻酔下に陥るまでマウスを約5分間放置し、ピロカルピン塩酸塩を1 mg/kg(5 mL/kg)の用量で腹腔内投与した。マウスの口を上に向けるように寝かせて口を開かせ、ピロカルピン投与から15分間マウスの口腔内に分泌された唾液をキャピラリー(Hirschmann Laborgerate社製)を用いて採取した。採取した唾液は分泌量（mg）を測定した（1 mgを1 μLと換算）。唾液分泌量は、1分あたりの分泌量をマウスの体重で補正して算出した。 3) Measurement of salivary secretion amount Saliva was collected from all animals during preliminary breeding and 8 weeks after the start of the test. After weight measurement, they fasted for 1 hour, and also fasted for the last 30 minutes. Mice were anesthetized by intraperitoneal administration of a triple anesthetic (Domitol, Betorfal, Midazolam) at a volume of 10 mL/kg. Mice were left for about 5 minutes until they fell under deep anesthesia, and pilocarpine hydrochloride was administered intraperitoneally at a dose of 1 mg/kg (5 mL/kg). The mice were laid with their mouths facing upward and opened, and saliva secreted into the oral cavity of the mice was collected using a capillary (manufactured by Hirschmann Laborgerate) for 15 minutes after administration of pilocarpine. The secretion amount (mg) of the collected saliva was measured (converting 1 mg to 1 µL). The amount of saliva secreted was calculated by correcting the amount of saliva secreted per minute by the body weight of the mouse.
４）口腔内細菌数の測定
　予備飼育中及び試験開始8週間後に全個体の口腔内細菌数を測定した。マウスを手で保定した状態でマイクロブラシ(松風社製)を用いて口腔内をスワブ(両頬を軽くこする)した。マイクロブラシを150μLの2×YT培地が入ったチューブ内でよく撹拌した。2×YT培地を希釈してLB agar Lennoxに50μL塗抹し、37℃、好気下で20時間培養した。培養後、コロニー数をカウントして生菌数（cfu/mL-YT培地）を算出した。 4) Measurement of Oral Bacteria Count During preliminary breeding and 8 weeks after the start of the test, the number of oral bacteria was measured for all individuals. The mouth was swabbed (lightly rubbed both cheeks) with a microbrush (manufactured by Shofu Co., Ltd.) while the mouse was held by hand. The microbrush was agitated well in a tube containing 150 μL of 2×YT medium. 50 μL of diluted 2×YT medium was smeared on LB agar Lennox and cultured at 37° C. under aerobic conditions for 20 hours. After culturing, the number of colonies was counted to calculate the number of viable cells (cfu/mL-YT medium).
［結果］
１）唾液分泌量
　予備飼育時（0W）の唾液分泌量は、YC群と比較してOC群及びON群は有意ではないものの低値であった。一方で、試験開始8週間後では、YC群と比較してOC群は有意に低値であったが、YC群とON群に差は認められなかった。また、OC群とON群の比較ではON群のほうが高値である傾向が見られた（図1）。 [result]
1) Amount of saliva secretion The amount of saliva secretion at the time of preliminary feeding (0W) was lower in the OC group and ON group than in the YC group, though not significantly. On the other hand, 8 weeks after the start of the study, the OC group had significantly lower values than the YC group, but no difference was observed between the YC group and the ON group. In addition, when comparing the OC group and the ON group, the ON group tended to have higher values (Fig. 1).
２）口腔内細菌数
　予備飼育時の口腔内細菌数は、YC群と比較してOC群及びON群で有意ではないものの低値であった。一方で、試験開始8週間後では、OC群と比較してYC群及びON群は有意に低値であった（図2）。 2) Number of oral bacteria The number of oral bacteria during preliminary breeding was lower in the OC group and ON group than in the YC group, although not significantly. On the other hand, 8 weeks after the start of the test, the YC group and ON group had significantly lower values than the OC group (Fig. 2).
［考察］
　NMN投与前の予備飼育時は、唾液分泌量では若齢マウス（YC群）より老齢マウス（OC群及びON群）のほうが有意ではないが低値で、口腔細菌数は老齢マウスのほうが有意ではないが高値であったため、加齢により唾液分泌量が減少して口腔環境が悪化していると考えられた。試験開始8週間後では、NMNを投与していないOC群は、YC群と比較して唾液分泌量と口腔内細菌で差が見られた。一方で、NMNを投与したON群は唾液分泌量と口腔内細菌数でYC群との差は見られなかった。すなわち、老齢マウスにNMNを投与することで、唾液分泌量と口腔内細菌数が若齢マウスと同等の値を示し、加齢により悪化していた口腔環境が改善されることが明らかとなった。 [Discussion]
During the preliminary breeding before NMN administration, the amount of saliva secreted was not significantly lower in the old mice (OC group and ON group) than in the young mice (YC group), and the oral bacterial count was not significantly higher in the old mice. However, due to the high value, it was considered that the amount of saliva secreted decreased with aging and the oral environment deteriorated. Eight weeks after the start of the study, differences in salivary secretion volume and oral bacteria were observed in the OC group, to which NMN was not administered, compared to the YC group. On the other hand, the ON group to which NMN was administered showed no difference from the YC group in the amount of saliva secreted and the number of oral bacteria. In other words, administration of NMN to aged mice showed salivary secretion and oral bacterial counts equivalent to those of young mice, and it was clarified that the oral environment, which had deteriorated with age, was improved. .
試験2（臨床試験）
［方法］
１）摂取物
　被験者に摂取してもらうβ-Nicotinamide Mononucleotide（NMN）は、Bontac社製を使用し、1粒あたり600 mgのチュアブル錠（NMN 250 mg、マルチトース 229 mg、ステアリン酸カルシウム 12 mg、結晶化セルロース 89.9 mg、ゲル化剤 12 mg、アセスルファムカリウム 0.2 mg、スクラロース 0.9 mg、香料 6 mg）に成形した。チュアブル錠を1日1回朝食前に摂取してもらい、1日あたりのNMN摂取量は250 mgとした。 Study 2 (clinical study)
[Method]
1) Ingested material The β-Nicotinamide Mononucleotide (NMN) to be ingested by the subjects was manufactured by Bontac, and 600 mg chewable tablets (NMN 250 mg, maltitose 229 mg, calcium stearate 12 mg, crystallized Cellulose 89.9 mg, gelling agent 12 mg, acesulfame potassium 0.2 mg, sucralose 0.9 mg, fragrance 6 mg). They were asked to take chewable tablets once daily before breakfast, and the daily intake of NMN was 250 mg.
２）被験者
　健康状態に異常が見られない50歳代の男女8名（男性5名、女性3名）を試験に参加してもらった。試験は前後比較としたため、被験者は全員NMNのチュアブル錠を2週間摂取した。 2) Subjects Eight males and females in their 50s (5 males and 3 females) with no abnormal health conditions were asked to participate in the test. Since the study was a before-and-after comparison, all subjects took NMN chewable tablets for two weeks.
３）唾液分泌量の測定
　NMN摂取前（pre）及び摂取開始から2週間後（post）に被験者全員から唾液を採取して分泌量を測定した。唾液の採取は、9:30から10:00の間に実施して、唾液採取の1時間前から水を除き飲食を禁止した。唾液採取5分前に水で口をゆすぎ、座ってリラックスしてもらった。唾液採取時は、椅子に座った状態で少し前かがみの姿勢で5分間自然に分泌されてくる唾液を専用の容器に採取した。採取後、液量を測定して1分あたりの唾液分泌量を算出した。 3) Measurement of salivary secretion amount Saliva was collected from all the subjects before (pre) and two weeks after the start of ingestion (post) of NMN, and the secretion amount was measured. Saliva collection was performed between 9:30 and 10:00, and no food or drink except water was allowed for 1 hour before saliva collection. Five minutes before saliva collection, they rinsed their mouths with water and sat down to relax. At the time of saliva collection, the subjects were seated on a chair and slouched slightly forward, and the saliva that was naturally secreted for 5 minutes was collected in a dedicated container. After collection, the amount of fluid was measured and the amount of saliva secreted per minute was calculated.
４）唾液中細菌数の測定
　採取した唾液を使用して、唾液中細菌数を測定した。唾液は生理食塩水で希釈後、LB agar Lennoxに100 μL塗抹し、37℃、好気下で20時間培養した。培養後、コロニー数をカウントして生菌数（cfu/mL-唾液）を算出した。 4) Measurement of Bacterial Count in Saliva Using the collected saliva, the bacterial count in saliva was measured. After diluting the saliva with physiological saline, 100 µL of the saliva was smeared on LB agar Lennox and cultured at 37°C under aerobic conditions for 20 hours. After culturing, the number of colonies was counted to calculate the number of viable bacteria (cfu/mL-saliva).
［結果]
１）唾液分泌量
　NMN摂取前と比較して摂取後では唾液分泌量が有意に増加した（図3A）。また、被験者8名のうち7名でNMN摂取後に唾液分泌量が増加していた。 [result]
1) Amount of salivary secretion The amount of salivary secretion increased significantly after ingestion compared to before ingestion of NMN (Fig. 3A). In addition, 7 out of 8 subjects showed an increase in salivary secretion after ingesting NMN.
２）唾液中細菌数
　NMN摂取前と比較して摂取後では唾液中細菌数が有意に減少した（図3B）。また、被験者8名のうち7名でNMN摂取後に唾液中細菌数が減少していた。 2) Number of bacteria in saliva The number of bacteria in saliva decreased significantly after ingestion compared to before ingestion of NMN (Fig. 3B). In addition, 7 out of 8 subjects showed a decrease in the number of bacteria in saliva after ingesting NMN.
［考察]
　NMN摂取前と摂取後で唾液分泌量の増加と唾液中細菌数の減少が見られた。この結果から、NMNを摂取することで唾液腺の機能を向上させている可能性が示唆された。加えて、唾液中細菌数が減少していることから、唾液中の抗菌物質が増加している可能性も考えられた。おそらくチュアブル錠として摂取したNMNが、口腔内や腸管より吸収されて血液を介して唾液腺組織に到達し、Nicotinamide Adenine Dinucleotide (NAD)に変換されてサーチュインやPoly (ADP-ribose) polymerase 1（PARP1)の基質となることで、唾液腺の機能が向上したと推察された。 [Discussion]
An increase in salivary secretion and a decrease in the number of bacteria in saliva were observed before and after NMN intake. These results suggested that ingestion of NMN may improve the function of salivary glands. In addition, the number of bacteria in saliva decreased, suggesting the possibility of an increase in antibacterial substances in saliva. NMN, probably ingested as a chewable tablet, is absorbed from the oral cavity and intestinal tract, reaches salivary gland tissue via blood, and is converted to nicotinamide adenine dinucleotide (NAD), which is converted into sirtuins and Poly (ADP-ribose) polymerase 1 (PARP1). It was inferred that the function of salivary glands was improved by becoming a substrate for
結論
　マウス及びヒトを対象とした試験にて、NMNの摂取により口腔環境が改善することを明らかとした。本発明は、老齢化が進行する世界で高齢者のQOLを向上させるために有用である。 Conclusion It was clarified that the oral environment was improved by ingestion of NMN in the studies on mice and humans. INDUSTRIAL APPLICABILITY The present invention is useful for improving the QOL of elderly people in an aging world.
評価例２：口渇モデルを用いたNMNによる唾液分泌への影響評価
　唾液の分泌量は医薬品（特に抗コリン作用を有する医薬品）の摂取により減少することが報告されている。そこで、抗コリン作用が明らかとされている医薬品のひとつであるアミトリプチリン（抗うつ薬）を投与することにより作出した口渇モデルマウスを用いて、NMNを事前に投与することにより唾液分泌量に影響を与えるか否かを検証した。 Evaluation Example 2: Evaluation of the effect of NMN on salivary secretion using a dry mouth model It has been reported that the amount of salivary secretion is reduced by ingestion of pharmaceuticals (especially pharmaceuticals having anticholinergic action). Therefore, using thirst model mice created by administering amitriptyline (an antidepressant), one of the drugs whose anticholinergic action has been clarified, the amount of salivary secretion was affected by prior administration of NMN. It was verified whether or not to give
［方法］
1)　投与物
　マウスに投与するβ-Nicotinamide Mononucleotide（NMN）は、Bontac社製を使用し、生理食塩水に溶解後マウス皮下投与した。投与用量は300 mg/kg、投与容量は10 mL/kgに設定し、投与濃度は30 mg/mLになった。また、アミトリプチリン塩酸塩（アミトリプチリン塩酸塩はSigma Aldrich、東京化成工業から購入可能である）は、蒸留水に溶解しマウスに強制経口投与した。投与用量は10 mg/kg、投与容量は10 mL/kgに設定し、投与濃度は1 mg/mLになった。 [Method]
1) Administration material β-Nicotinamide Mononucleotide (NMN) to be administered to mice was manufactured by Bontac, and was subcutaneously administered to mice after being dissolved in physiological saline. The administration dose was set at 300 mg/kg, the administration volume was set at 10 mL/kg, and the administration concentration was 30 mg/mL. In addition, amitriptyline hydrochloride (amitriptyline hydrochloride can be purchased from Sigma Aldrich, Tokyo Kasei Kogyo Co., Ltd.) was dissolved in distilled water and administered to mice by gavage. The administration dose was set at 10 mg/kg, the administration volume was set at 10 mL/kg, and the administration concentration was 1 mg/mL.
2)　動物
　マウスは雄性で12週齢、C57BL/6J系統を24匹購入した。マウスは、室温22±2℃、湿度55±15%、明期7時～19時、暗期19時～7時の飼育室で、群飼育（4匹/ケージ）で試験終了まで飼育を行った。また、飼料と水は制限せず自由に摂取させた。予備飼育終了後、体重の平均値が均等となるように1群8匹の3群（無処置群：NT群、薬剤処置群：A群、薬剤処置+NMN群：AN群）に群分けした。群分け後、AN群にはNMN溶液、NT及びA群には生理食塩水（溶媒）の皮下投与を開始した。皮下投与は、1日1回の頻度で試験終了日までの8日間、計8回実施した。なお、試験終了日は唾液分泌量の測定3時間前に皮下投与を実施した。 2) Animals We purchased 24 male, 12-week-old C57BL/6J strain mice. Mice were reared in groups (4 mice/cage) until the end of the test in a breeding room with room temperature of 22±2°C, humidity of 55±15%, light period from 7:00 to 19:00 and dark period from 19:00 to 7:00. rice field. Feed and water were allowed to be taken freely without restriction. After preliminary breeding, the animals were divided into 3 groups of 8 animals per group (non-treated group: NT group, drug-treated group: A group, drug-treated + NMN group: AN group) so that the average body weight was even. . After the grouping, subcutaneous administration of NMN solution to AN group and physiological saline (vehicle) to NT and A groups was started. Subcutaneous administration was performed once a day for 8 days until the end of the test, 8 times in total. On the test termination day, subcutaneous administration was performed 3 hours before the measurement of salivary secretion.
3)　唾液分泌量の測定
　試験開始8日目に全個体より唾液を採取した。最後の皮下投与後から絶食し（唾液採取3時間前）、唾液採取1時間前にアミトリプチリン水溶液をA及びAN群、蒸留水（溶媒）をNT群に強制経口投与した。強制経口投与後から絶水も実施した。強制経口投与から1時間後、三種混合麻酔薬（ドミトール、ベトルファール、ミダゾラム）を10 mL/kgの容量で腹腔内投与してマウスに麻酔をかけた。深麻酔下に陥るまでマウスを約5分間放置し、ピロカルピン塩酸塩を0.5 mg/kg(5 mL/kg)の用量で腹腔内投与した。マウスの口を上に向けるように寝かせて口を開かせ、ピロカルピン投与から15分間マウスの口腔内に分泌された唾液をキャピラリー(Hirschmann Laborgerate社製)を用いて採取した。採取した唾液は分泌量（μL）を測定した（1 mgを1 μLと換算）。唾液分泌量は、1分あたりの分泌量をマウスの体重で補正して算出した。 3) Measurement of salivary secretion amount Saliva was collected from all animals on the 8th day after the start of the test. After the last subcutaneous administration, food was fasted (3 hours before saliva collection), and 1 hour before saliva collection, amitriptyline aqueous solution was forcibly administered to the A and AN groups, and distilled water (vehicle) to the NT group. Water deprivation was also performed after gavage administration. One hour after oral gavage, the mice were anesthetized by an intraperitoneal injection of a triple anesthetic (Domitol, Betorfal, Midazolam) at a volume of 10 mL/kg. Mice were left to fall under deep anesthesia for approximately 5 minutes, and pilocarpine hydrochloride was administered intraperitoneally at a dose of 0.5 mg/kg (5 mL/kg). The mice were laid with their mouths facing upward and opened, and saliva secreted into the oral cavity of the mice was collected using a capillary (manufactured by Hirschmann Laborgerate) for 15 minutes after administration of pilocarpine. The amount of saliva secreted (μL) was measured (converting 1 mg to 1 μL). The amount of saliva secreted was calculated by correcting the amount of saliva secreted per minute by the body weight of the mouse.
［結果］
1)　唾液分泌量
　無処置群（NT群）と比較して薬剤処置群（A群）は唾液分泌量が有意に減少していた。一方で、NT群と薬剤処置＋NMN群（AN群）では唾液分泌量に差は見られなかった。A群とAN群の唾液分泌量では差が見られなかったものの、NMNを投与することによって唾液分泌量が増加する傾向が見られた（図4）。 [result]
1) Amount of salivary secretion The amount of salivary secretion was significantly decreased in the drug-treated group (Group A) compared to the non-treated group (NT group). On the other hand, there was no difference in saliva secretion between the NT group and the drug treatment + NMN group (AN group). Although there was no difference in the amount of salivary secretion between the A group and the AN group, administration of NMN tended to increase salivary secretion (Fig. 4).
 [考察]
　 通常のマウスにアミトリプチリンを10 mg/kgの用量で唾液採取1時間前に投与することで、唾液分泌量が有意に減少した（NT群とA群の比較）。一方で、NMNを唾液採取の8日前から300 mg/kgの用量で皮下投与することにより、アミトリプチリンの投与により減少する唾液分泌量を増加させることができた。NMNを投与することで、唾液腺組織中のNAD+量の増加に伴いATP産生が促進され、唾液分泌に関わるトランスポーターやイオンチャネルなどの活性化につながったのではないかと推測された。 [Discussion]
Administration of amitriptyline at a dose of 10 mg/kg to normal mice 1 hour before saliva collection significantly decreased salivary secretion (comparison between NT and A groups). On the other hand, subcutaneous administration of NMN at a dose of 300 mg/kg starting 8 days before saliva collection increased salivary secretion, which was decreased by administration of amitriptyline. It was speculated that administration of NMN promoted ATP production as the amount of NAD+ in salivary gland tissue increased, leading to the activation of transporters and ion channels involved in salivary secretion.
結論
　薬剤摂取による唾液分泌量の減少を、NMNを投与することにより改善できることを明らかとした。本発明は、副作用として抗コリン効果を有する薬剤を摂取している患者のQOLを向上させるために有用である。 Conclusion It was clarified that the decrease in salivary secretion due to drug intake can be improved by administering NMN. INDUSTRIAL APPLICABILITY The present invention is useful for improving the QOL of patients taking drugs having anticholinergic effects as side effects.

Claims (10)

  1. 　ニコチンアミドアデニンジヌクレオチド（ＮＡＤ）類似物質を含む、口腔環境改善用組成物。 A composition for improving the oral environment, containing nicotinamide adenine dinucleotide (NAD) analogues.
  2. 　口腔環境改善が、唾液分泌量増加、及び口腔内細菌数低減の少なくとも一方である、請求項１に記載の組成物。 The composition according to claim 1, wherein the oral environment improvement is at least one of an increase in saliva secretion and a reduction in the number of oral bacteria.
  3. 　ＮＡＤ類似物質が、ニコチンアミドモノヌクレオチド（ＮＭＮ）、ニコチンアミドリボシド、ＮＡＤ、ニコチンアミド、及びこれらの食品又は医薬品として許容可能な塩からなる群から選択されるいずれかである、請求項１に記載の組成物。 Claim 1, wherein the NAD analogue is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, NAD, nicotinamide, and food or pharmaceutical acceptable salts thereof. The described composition.
  4. 　ＮＡＤ類似物質を、一日当たりＮＭＮとして１００～１０００ｍｇ摂取させるための、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, for ingesting 100 to 1000 mg of the NAD-like substance as NMN per day.
  5. 　２週間以上継続して摂取させるための、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, which is to be ingested continuously for 2 weeks or more.
  6. 　４０歳以上の者に摂取させるための、又は口渇症状を有する者に摂取させるための、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, which is to be ingested by a person aged 40 or over or by a person with dry mouth symptoms.
  7.   食品組成物である、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, which is a food composition.
  8. 　ＮＡＤ類似物質を、１単位当たりＮＭＮとして１３０ｍｇ以上含む、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, which contains 130 mg or more of the NAD-like substance as NMN per unit.
  9. 　チュアブル錠、又は舌下錠である、請求項１～３のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 3, which is a chewable tablet or a sublingual tablet.
  10. 　ニコチンアミドアデニンジヌクレオチド（ＮＡＤ）類似物質を含む、唾液分泌量増加用組成物であって、
    　ＮＡＤ類似物質が、ニコチンアミドモノヌクレオチド（ＮＭＮ）、ニコチンアミドリボシド、ＮＡＤ、ニコチンアミド、及びこれらの食品又は医薬品として許容可能な塩からなる群から選択されるいずれかであり、
    　４０歳以上の者に摂取させるための、又は口渇症状を有する者に摂取させるための、組成物。     A composition for increasing salivation comprising a nicotinamide adenine dinucleotide (NAD) analog,
    The NAD analog is any selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide riboside, NAD, nicotinamide, and food or pharmaceutical acceptable salts thereof;
    A composition for intake by persons aged 40 and over, or for intake by persons with symptoms of dry mouth.
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