WO2023282283A1 - Composition pour améliorer l'environnement buccal - Google Patents

Composition pour améliorer l'environnement buccal Download PDF

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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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English (en)
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/fr

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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).

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Abstract

L'invention concerne une composition pour améliorer un environnement buccal. La composition comprend un analogue du nicotinamide adénine dinucléotide (NAD). Cette composition peut être utilisée pour améliorer la salivation et/ou réduire le nombre de bactéries dans la bouche. Un exemple préféré de l'analogue de nicotinamide adénine dinucléotide (NAD) est le nicotinamide mononucléotide (NMN).
PCT/JP2022/026809 2021-07-07 2022-07-06 Composition pour améliorer l'environnement buccal WO2023282283A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016175901A (ja) * 2015-03-18 2016-10-06 第一三共ヘルスケア株式会社 Ｌ−アスパラギン酸またはその塩、及びニコチンアミドを含有する口腔ケア用組成物
CN109045033A (zh) * 2018-07-19 2018-12-21 大连医科大学附属第二医院 烟酰胺在预防唾液腺放射损伤方面的新用途
WO2019078177A1 (fr) * 2017-10-16 2019-04-25 めぐみ 田中 Composition cosmétique comprenant du nicotinamide mononucléotide
WO2021070829A1 (fr) * 2019-10-11 2021-04-15 国立大学法人静岡大学 Bactéries d'acide lactique qui produisent du nicotinamide riboside, et bactéries d'acide lactique qui produisent du nicotinamide mononucléotide et du nicotinamide riboside

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016175901A (ja) * 2015-03-18 2016-10-06 第一三共ヘルスケア株式会社 Ｌ−アスパラギン酸またはその塩、及びニコチンアミドを含有する口腔ケア用組成物
WO2019078177A1 (fr) * 2017-10-16 2019-04-25 めぐみ 田中 Composition cosmétique comprenant du nicotinamide mononucléotide
CN109045033A (zh) * 2018-07-19 2018-12-21 大连医科大学附属第二医院 烟酰胺在预防唾液腺放射损伤方面的新用途
WO2021070829A1 (fr) * 2019-10-11 2021-04-15 国立大学法人静岡大学 Bactéries d'acide lactique qui produisent du nicotinamide riboside, et bactéries d'acide lactique qui produisent du nicotinamide mononucléotide et du nicotinamide riboside

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Extension of healthy longevity in body and periodontal tissue by NMN supplementation and senolytic treatment", RESEARCH PROJECTS PUBLISHED IN GRANTS-IN-AID FOR SCIENTIFIC RESEARCH DATABASE, 19 February 2021 (2021-02-19), XP093022589, Retrieved from the Internet <URL:https://kaken.nii.ac.jp/ja/file/KAKENHI-PROJECT-18K19644/18K19644seika.pdf> [retrieved on 20230209] *
BJORNSTROM M, AXELL T, BIRKHED D: "COMPARISON BETWEEN SALIVA STIMULANTS AND SALIVA SUBSTITUTES IN PATIENTS WITH SYMPTOMS RELATED TO DRY MOUTH", SWEDISH DENTAL JOURNAL, SN, STOCKHOLM, SE, vol. 14, no. 04, 1 January 1990 (1990-01-01), SE , pages 153 - 161, XP009055994, ISSN: 0347-9994 *

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