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WO2018030389A1 - Utilisation d'un métabolite associé à nad - Google Patents

Utilisation d'un métabolite associé à nad Download PDF

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Publication number
WO2018030389A1
WO2018030389A1 PCT/JP2017/028727 JP2017028727W WO2018030389A1 WO 2018030389 A1 WO2018030389 A1 WO 2018030389A1 JP 2017028727 W JP2017028727 W JP 2017028727W WO 2018030389 A1 WO2018030389 A1 WO 2018030389A1
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Prior art keywords
nad
eye
food
health
corneal
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English (en)
Japanese (ja)
Inventor
一男 坪田
絵海 稲垣
岡野　栄之
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Keio University
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Keio University
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Priority to JP2018533489A priority Critical patent/JP7090336B2/ja
Publication of WO2018030389A1 publication Critical patent/WO2018030389A1/fr
Anticipated expiration legal-status Critical
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/13—Nucleic acids or derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to the use of NAD-related metabolites.
  • Physical countermeasures such as blue light and cut glasses have also been proposed, but as countermeasures that can be carried out easily and continuously every day, compounds that maintain eye health or promote health or prevent eye aging are included. It is desirable to take it as a supplement, food, beverage or the like, or as an external preparation such as cosmetics or cream.
  • extracts such as blueberries and grapes containing a large amount of polyphenols or dried products, extracts containing lutein (a carotenoid contained in green-yellow vegetables), etc. are widely known and used, A single component that does not contain extra components requires less intake, and there are currently few supplements that are highly effective.
  • the nerve fiber in the optic nerve decreases, the retinal nerve fiber layer becomes thinner, ganglion cells also fall off, and the number of photoreceptor cells decreases. These once impaired optic nerve functions do not recover and are difficult to treat.
  • the causes of blindness have been reported as glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, and choroidal atrophy associated with high myopia, all of which are a group of diseases that worsen with aging. Further, cataract, retinal movement / venous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, etc. are also age-related blindness diseases.
  • glaucoma According to the glaucoma medical care guide of the Japan Glaucoma Society, glaucoma has a characteristic change in the optic nerve and visual field, and usually has a functional structural abnormality of the eye that can improve or suppress optic nerve damage by sufficiently lowering intraocular pressure. It is a characteristic disease. It has been suggested that glaucoma or optic neuropathy that progresses acutely or chronically involves age-related changes in the optic nerve. Glaucoma is the number one cause of blindness in Japan, but the pathophysiology has not been clarified yet. The prevalence of glaucoma increases with age, with 12.7% for men and 8.9% for women over 80 years of age.
  • glaucoma treatments already in use include major drugs such as prostaglandin preparations, beta-receptor blockers, or carbonic anhydrase inhibitors, and their combinations. Agents. Recently, the development of a novel glaucoma therapeutic drug using a Rock inhibitor has also been reported.
  • the corneal endothelium is an important cell that contributes to the transparency of the eye, but has no ability to proliferate after birth in humans.
  • the number of corneal endothelial cells is markedly reduced by aging, cataract surgery, or Fuchs corneal endothelial degeneration. When the number of cells decreases beyond a certain threshold, the cornea becomes cloudy and exhibits bullous keratopathy. At present, there is no preventive or therapeutic agent that succeeds in the aging phenomenon symbolized by the decrease in corneal endothelial cells, and corneal transplantation is the only treatment.
  • Non-patent Document 1 describes the relationship between various age-related diseases such as weight gain and insulin sensitivity and NAD and NAD-related metabolites.
  • Patent Document 1 merely shows an increase in tear volume in mice.
  • the object of the present invention is to use NAD-related metabolites for maintaining or promoting the health of eyes or preventing the aging of eyes.
  • Another object of the present invention is to provide preventive or therapeutic agents for various eye diseases containing NAD-related metabolites.
  • preventive or therapeutic drugs for eye diseases containing NAD-related metabolites, health supplements, health functional foods, and supplements that correspond to an aging society are essential.
  • the inventors of the present invention focused on the profile of NAD-related metabolites in the anterior aqueous humor in the eye, and as a result of analysis, they detected a higher concentration of NAD-related metabolites in the anterior aqueous humor than in plasma. Furthermore, they found the physiological significance of these NAD-related metabolites in the eye and their usefulness as therapeutic targets for eye diseases, and completed the present invention.
  • the anterior aqueous humor is in contact with the ciliary body, Schlemm's canal, retina, and lens in addition to the cornea, and NAD-related metabolites are expected to be effective for diseases of these tissues, such as presbyopia and cataracts.
  • the present invention includes the subject matter described in the following section.
  • Item 1 Use of NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof for maintaining eye health, promoting eye health, or preventing eye aging (excluding medical practice).
  • Item 2 Foods supplemented with NAD-related metabolites, pharmaceutically acceptable salts, or prodrugs thereof.
  • Item 3. The food according to Item 2, which is a beverage, a supplement, a health supplement, a food for specified health use, a nutritional functional food, or a functional labeling food.
  • Item 4. The food according to Item 3, which is in the form of a tablet, hard capsule, soft capsule, seamless capsule, powder, fine granule, granule, chewable, gummy, jelly, liquid (drink), troche, or paste.
  • Item 5. The food according to any one of Items 2 to 4, wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg.
  • Item 6 A food composition containing an NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof for use in maintaining ocular health, promoting ocular health, or preventing ocular aging.
  • Item 7 Use of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof for preparing a food used for maintaining eye health, promoting eye health, or preventing eye aging.
  • Item 8 An external preparation containing a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • Item 9 The external preparation according to Item 8, which is a quasi-drug or cosmetic.
  • Item 10 The external preparation according to item 8 or 9, which is in the form of an ointment, cream, milk, gel, lotion, essence, face pack, foundation, lipstick, plaster, poultice, powder, soap, shampoo, detergent, or bath preparation. .
  • Item 11 Presbyopia, glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof, and pharmacologically acceptable carriers Selected from the group consisting of chorioretinal atrophy with severe myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinal arteriovenous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber disease A pharmaceutical composition for preventing or treating an eye disease.
  • Item 12 An eye selected from the group consisting of corneal diseases, retinal diseases, and optic nerve diseases, comprising a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmacologically acceptable carrier.
  • a pharmaceutical composition for prevention or treatment of a disease comprising a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmacologically acceptable carrier.
  • Item 13 The pharmaceutical composition according to any one of Items 11 and 12, wherein the daily intake of the NAD-related metabolite is 0.1 pg to 2000 mg.
  • Item 14 The pharmaceutical composition according to any one of Items 11 to 13, which is a powder, granule, fine granule, tablet, pill, troche, capsule, chewable or syrup.
  • NAD-related metabolites can ameliorate symptoms or conditions in the corneal endothelium, retina, and optic nerve
  • the pharmaceutical and food compositions of the present invention containing NAD-related metabolites can prevent or prevent various eye diseases. It can be used for the purpose of treatment or eye protection.
  • NAD-related metabolites are excellent in safety because they are components present in the living body.
  • FIG. 1 Schematic showing the nicotinamide adenine dinucleotide (NAD) synthesis pathway and NAD-related metabolites.
  • the graph which shows the effect of NMN administration with respect to the cornea thickness in a rabbit bullous keratopathy model.
  • A is a control
  • B is an NMN administration group.
  • the vertical axis represents corneal thickness
  • the horizontal axis represents the number of breeding days.
  • Each value represents an average value ⁇ standard deviation.
  • Each group N 1.
  • the graph which shows the measurement amount of NAD in the anterior aqueous humor of an old mouse and a young mouse.
  • the vertical axis represents the NAD concentration
  • the horizontal axis represents the age or age of the mouse.
  • Each value represents an average value ⁇ standard deviation.
  • Each group N 3. The graph which shows the cell survival rate in a rat acute eye ischemia model.
  • Sham retinal tissue of sham-operated eye
  • medium (1) retinal tissue of treated eye cultured in medium not containing NMN
  • medium + NMN (1) treatment eye of rat administered NMN subcutaneously the day before and on the day
  • medium (2) retinal tissue of treated eye cultured in medium containing NMN
  • medium + NMN (2) rats administered NMN subcutaneously on the day before and after the day
  • the retinal tissue of the treated eye is cultured in a medium containing NMN.
  • the vertical axis represents the mitochondrial membrane potential.
  • Basal Respiration Basal respiration
  • ATP Production ATP production
  • Proton Leak Proton leak
  • Maximal Respiration Maximum respiration
  • Spare Capacity Prerespiratory capacity
  • Non-mitochondrial Respitration Non-mitochondrial respiration.
  • A A graph showing the oxygen consumption rate over time in the mitochondrial stress assay. (1) Control (without NMN addition), (2) 500 ⁇ M NMN added.
  • B The graph which shows the oxygen consumption rate in a basal respiration and a preliminary respiratory capacity. In each phase, the left side is the control and the right side is the addition of 500 ⁇ M NMN.
  • C Graph showing oxygen consumption rate in proton leak and ATP production.
  • the left side is the control and the right side is the addition of 500 ⁇ M NMN.
  • Each group N 3.
  • the present invention is a novel use of NAD-related metabolites in the ophthalmic field.
  • NAD-related metabolites can be used to maintain or enhance eye health or prevent eye aging.
  • NAD-related metabolites can also be used in pharmaceutical applications to prevent or treat certain ophthalmic diseases.
  • the subject to which the food, external preparation, and pharmaceutical composition of the present invention are applied includes mammals that are human or non-human animals.
  • Non-human animals include rats, mice, guinea pigs, monkeys, rabbits, dogs, cats, horses, pigs, cows and the like.
  • the subject is a human.
  • food is a concept that broadly encompasses what can be taken orally, and includes beverages.
  • foods include enteral nutritional foods, special purpose foods, health functional foods including foods for specified health use, nutritional functional foods, functional labeling foods, and the like.
  • food composition refers to a composition provided as a food.
  • food and “food composition” can be used interchangeably.
  • NAD-related metabolite refers to a series of compounds having nicotinamide as a component in the nicotinamide adenine dinucleotide (NAD) synthesis pathway, nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM) are included.
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable non-toxic salt, and the salt includes a salt of an inorganic acid and a salt of an organic acid.
  • prodrug refers to a compound that converts to a target compound under physiological conditions in vivo when administered to a subject that is a mammal.
  • prodrugs of NAD related metabolites include alcohol, amine group acetate, formate, benzoate derivatives of NAD related metabolites.
  • the present invention relates to maintaining eye health, promoting eye health, or aging of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof (hereinafter referred to as “NAD-related metabolite, etc.”). Regarding prevention use (except medical practice).
  • Maintaining eye health is maintaining the normal state of the eye, including anterior chamber water, ciliary body, Schlemm's canal, retina, lens, optic nerve, cornea (especially corneal epithelium), retina, visual function, Or maintaining these combinations is included.
  • NAD-related metabolites and the like can be used for eye protection in a subject.
  • Eye protection refers to, for example, protecting the optic nerve, cornea (particularly the corneal epithelium), retina, or a combination thereof in a subject from damage or the like.
  • NAD-related metabolites and the like can be used to reduce eye stress. Examples of stress include chemical substances, ultraviolet rays, and the like that act as external forces on the eyes.
  • NAD-related metabolites and the like are used not only for general foods but also for health supplements, health functional foods (for specified health use) for the purpose of maintaining eye health, promoting eye health, or preventing eye aging.
  • the food includes beverages. Taking NAD-related metabolites and the like in the form of food can easily enjoy the effects of maintaining eye health, promoting eye health, or preventing eye aging.
  • the NAD-related metabolite in the food of the present invention is preferably selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • the food is a health functional food.
  • the food product is a supplement.
  • the food of the present invention containing an NAD-related metabolite or the like as an active ingredient has an effect on the type of active ingredient in the food, packaging or container of the food, maintenance of eye health, promotion of eye health, or prevention of eye aging. The effect and / or method of intake can be displayed.
  • the food or food composition containing the NAD-related metabolite or the like of the present invention may be in any form, for example, juice, milk, coffee drink, tea drink It may be in the form of beverages such as soups, liquid foods such as soups, pasty foods such as yogurt, semi-solid foods such as jelly and gummi, solid foods such as cookies and gums, and fat-containing foods such as doughlessings and mayonnaise. .
  • the food of the present invention can be in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewable, gummy, jelly, liquid (drink), troches, or pastes. It is not limited.
  • the daily intake of NAD-related metabolites in the food of the present invention per adult is not particularly limited, but in one embodiment 0.1 pg to 2000 mg, 1 pg to 2000 mg, 10 pg to 2000 mg, 100 pg (0.1 ng) to 2000 mg, 1 ng to 2000 mg, 10 ng to 2000 mg, or 0.1 mg to 2000 mg.
  • the lower limit is 0.1 pg or more, 1 pg or more, 10 pg or more, 100 pg (0.1 ng) or more, 1 ng or more, 10 ng or more, 0.1 mg or more, 0.5 mg or more, 1 mg or more, 5 mg or more, 10 mg or more, 20 mg
  • these are 30 mg or more, 40 mg or more, 50 mg or more, 100 mg or more, 150 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg or more, 900 mg or more, or 1000 mg or more.
  • the upper limit is 5000 mg or less, 4500 mg or less, 4000 mg or less, 3500 mg or less, 3000 mg or less, 2500 mg or less, or 2000 mg or less.
  • the daily intake of NAD-related metabolites is 0.1 pg or more, 1 pg or more, 10 pg or more, 100 pg (0.1 ng) or more, 1 ng or more, 10 ng or more, 0.1 mg or more, 0.5 mg or more 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 100 mg or more, 150 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg Above, the range from any of the lower limits up to 900 mg or more, or up to 1000 mg or more, to any of the above upper limits up to 5000 mg or less, 4500 mg or less, 4000
  • the food of the present invention can be formulated by a general method as a supplement together with a carrier acceptable as food.
  • a carrier acceptable as food examples include liquid carriers such as water, ethanol, propylene glycol, and glycerin, and solid carriers such as glucose, sucrose, dextrin, cyclodextrin, and gum arabic.
  • the food of the present invention as long as it does not impair the effects of the NAD-related metabolites, that is, does not cause an unfavorable interaction by blending with the NAD-related metabolites, sugars; proteins; fats; Minerals; vitamins such as vitamin E, vitamin C, vitamin B, and vitamin A; NAD activators such as resveratrol; NAD-degrading enzyme inhibitors such as anti-NADase antibodies; fragrances; Additives can be blended. Any of these additives commonly used in foods can be used.
  • the dosage form of the food of the present invention may be appropriately selected depending on the subject, eye condition, and other conditions.
  • the above intake may be taken orally by dividing it once to several times a day (for example, about 3 times).
  • a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof is used for the purpose of maintaining ocular health, promoting ocular health, or preventing ocular aging.
  • OTC Over-the-counter drugs, OTC
  • quasi-drugs, or cosmetics in particular, it can also be added to over-the-counter drugs, quasi drugs, or cosmetics.
  • the NAD-related metabolite in the external preparation of the present invention is preferably selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM). Is done.
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • the production method and form at the time of use are not limited and can be commercialized by a known method. For example, the following can be mentioned.
  • Generic drugs can be in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewable, gummy, jelly, liquid (drink), troches, sublingual tablets, pastes, It is not limited to these.
  • the daily intake per adult of NAD-related metabolites in the external preparation of the present invention is not particularly limited, but in one embodiment, 0.1 pg to 2000 mg, 1 pg to 2000 mg, 10 pg to 2000 mg, 100 pg (0.1 ng) to 2000 mg 1 ng to 2000 mg, 10 ng to 2000 mg, or 0.1 mg to 2000 mg.
  • the lower limit is 0.1 pg or more, 1 pg or more, 10 pg or more, 100 pg (0.1 ng) or more, 1 ng or more, 10 ng or more, 0.1 mg or more, 0.5 mg or more, 1 mg or more, 5 mg or more, 10 mg or more, 20 mg
  • these are 30 mg or more, 40 mg or more, 50 mg or more, 100 mg or more, 150 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg or more, 900 mg or more, or 1000 mg or more.
  • the upper limit is 5000 mg or less, 4500 mg or less, 4000 mg or less, 3500 mg or less, 3000 mg or less, 2500 mg or less, or 2000 mg or less.
  • the daily intake of NAD-related metabolites is 0.1 pg or more, 1 pg or more, 10 pg or more, 100 pg (0.1 ng) or more, 1 ng or more, 10 ng or more, 0.1 mg or more, 0.5 mg or more 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 100 mg or more, 150 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg Above, the range from any of the lower limits up to 900 mg or more, or up to 1000 mg or more, to any of the above upper limits up to 5000 mg or less, 4500 mg or less, 4000
  • the external preparation of the present invention can be formulated according to the purpose by a general method together with a pharmacologically acceptable carrier.
  • the carrier is also referred to as a diluent or excipient.
  • the carrier include liquid carriers such as brine, ethanol, propylene glycol and glycerin, and solid carriers such as glucose, sucrose, dextrin, cyclodextrin and gum arabic.
  • the external preparation of the present invention does not impair the effects of NAD-related metabolites, that is, does not cause an unfavorable interaction with the NAD-related metabolites, minerals; vitamin E, vitamin C, Vitamins such as vitamin B and vitamin A; NAD activators of alternative pathways such as resveratrol; inhibitors of NAD degrading enzymes such as anti-NADase antibodies; nutritional ingredients; flavors; other additives such as pigments be able to. Any of these additives that are generally used for external preparations can be used.
  • a pharmaceutical composition containing an NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient for preventing or treating an eye disease can be provided.
  • the NAD-related metabolite in the pharmaceutical composition of the present invention is preferably from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM). Selected.
  • the daily dose per one adult (body weight 60 kg) of the NAD-related metabolite in the pharmaceutical composition of the present invention is not particularly limited, but in one embodiment, 0.1 pg to 2000 mg, 1 pg to 2000 mg, 10 pg to 2000 mg 100 pg (0.1 ng) to 2000 mg, 1 ng to 2000 mg, 10 ng to 2000 mg, or 0.1 mg to 2000 mg.
  • the lower limit is 0.1 pg or more, 1 pg or more, 10 pg or more, 100 pg (0.1 ng) or more, 1 ng or more, 10 ng or more, 0.1 mg or more, 0.5 mg or more, 1 mg or more, 5 mg or more, 10 mg or more, 20 mg
  • these are 30 mg or more, 40 mg or more, 50 mg or more, 100 mg or more, 150 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg or more, 900 mg or more, or 1000 mg or more.
  • the upper limit is 5000 mg or less, 4500 mg or less, 4000 mg or less, 3500 mg or less, 3000 mg or less, 2500 mg or less, or 2000 mg or less.
  • the daily intake of NAD-related metabolites is 0.1 pg or more, 1 pg or more, 10 pg or more, 100 pg (0.1 ng) or more, 1 ng or more, 10 ng or more, 0.1 mg or more, 0.5 mg or more 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 100 mg or more, 150 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg Above, the range from any of the lower limits up to 900 mg or more, or up to 1000 mg or more, to any of the above upper limits up to 5000 mg or less, 4500 mg or less, 4000
  • the pharmaceutical composition of the present invention can be formulated according to the purpose by a general method together with a pharmacologically acceptable carrier.
  • the carrier is also referred to as a diluent or excipient.
  • the carrier include liquid carriers such as brine, ethanol, propylene glycol and glycerin, and solid carriers such as glucose, sucrose, dextrin, cyclodextrin and gum arabic.
  • the pharmaceutical composition of the present invention can further be appropriately mixed with emulsifiers, isotonic agents, buffers, solubilizers, preservatives, stabilizers, antioxidants and the like that are generally used in formulation. .
  • minerals are optionally added as long as they do not impair the effects of NAD-related metabolites, that is, do not cause undesirable interactions with the NAD-related metabolites.
  • Vitamins such as vitamin B and vitamin A; NAD activators of alternative pathways such as resveratrol; inhibitors of NAD-degrading enzymes such as anti-NADase antibodies; nutritional ingredients; flavors; other additives such as pigments can do. Any of these additives commonly used in pharmaceuticals can be used.
  • the form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include solid forms such as powder, granules, and tablets; liquid forms such as solutions, emulsions, and dispersions; or semisolid forms such as pastes. It can be prepared in any form.
  • Specific dosage forms of the pharmaceutical composition of the present invention include powders, granules, fine granules, tablets, pills, troches, capsules (including soft capsules and hard capsules) depending on the administration method and administration route. , Chewables, syrups and the like.
  • it When it is used as an ophthalmic topical preparation, it may be in the form of eye drops, eye wash, eye ointment, contact lens mounting solution, contact lens preserving solution, contact lens disinfecting solution, contact lens cleaning solution, contact lens multipurpose solution, etc. it can.
  • the pharmaceutical composition of the present invention may be used in a corneal preservation solution and a surgical perfusion solution.
  • the dosage form of the pharmaceutical composition of the present invention may be appropriately selected depending on the subject, the disease state and its progress, and other conditions.
  • the dose may be divided into once to several times (for example, about 3 times) so as to obtain the above-mentioned daily dose.
  • the administration route of the pharmaceutical composition of the present invention is not particularly limited.
  • oral administration eye drop, conjunctival injection, tenon sac injection, intra-anterior injection, vitreous injection, intravenous administration, subcutaneous administration, intramuscular administration, rectal administration It can be administered by subcutaneous injection, transdermal administration and the like.
  • the pharmaceutical composition of the present invention has presbyopia (also referred to as presbyopia), glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, recurrent choroidal atrophy associated with high myopia, corneal endothelial degeneration, vesicular It can be used for the prevention or treatment of eye diseases selected from the group consisting of keratopathy, cataracts, retinal arteriovenous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber disease. These diseases are also age-related eye diseases that worsen with aging.
  • the pharmaceutical composition of the present invention can be used for the prevention or treatment of eye diseases selected from the group consisting of corneal diseases, retinal diseases, and optic nerve diseases.
  • Corneal diseases include corneal endothelial degeneration, Fuchs corneal degeneration, bullous keratopathy and the like.
  • Retinal diseases include diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, retina choroidal atrophy associated with high myopia, retinal movement / venous occlusion, and the like.
  • Optic nerve diseases include glaucoma, optic neuropathy, Leber disease and the like.
  • the disease to which the pharmaceutical composition of the present invention is applied is excluded when the eye disease is dry eye.
  • the pharmaceutical composition of the invention increases the amount of NAD-related metabolites in the anterior aqueous humor in the subject.
  • the pharmaceutical composition of the present invention increases the amount of NAD in anterior aqueous humor in a subject.
  • an increase in the amount of NAD in the anterior aqueous humor affects the repair of cells or tissues, especially the cornea, ciliary body, Schlemm's canal, retina, and lens that contact the anterior aqueous humor, It is thought to contribute to the prevention or treatment of eye diseases.
  • the present invention includes maintaining an eye health, enhancing an eye health, or aging an eye, comprising the step of formulating a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof in a food.
  • a method for producing a food or food composition for prevention is included.
  • the present invention also relates to a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof in the manufacture of a food or a food composition having an effect of maintaining ocular health, promoting ocular health, or preventing ocular aging.
  • a NAD-related metabolite a pharmaceutically acceptable salt thereof, or a prodrug thereof in the manufacture of a food or a food composition having an effect of maintaining ocular health, promoting ocular health, or preventing ocular aging.
  • the details of the NAD-related metabolites, the blending amount in the food, and the composition of the food or food composition are as described above for the food of the present invention.
  • the present invention also includes a method for preventing and / or treating an ocular disease, comprising administering an effective amount of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof to a subject.
  • the present invention also includes the use of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof for the prevention and / or treatment of an eye disease in a subject.
  • NAD-related metabolite The details of the NAD-related metabolite and the dose to the subject are as described above for the pharmaceutical composition of the present invention.
  • the present invention also includes the following.
  • the food according to [2] which is a beverage, a supplement, a health supplement, a food for specified health use, a nutritional functional food, or a functional indication food.
  • [4] The food according to [2] or [3], which is in the form of a tablet, hard capsule, soft capsule, seamless capsule, powder, fine granule, granule, chewable, gummy, jelly, liquid (drink), troche, or paste.
  • [5] The food according to any one of [2] to [4], wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
  • [6] The food according to any one of [2] to [4], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
  • the NAD-related metabolite is at least one selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • the food according to any one of [1] to [6] which is a seed.
  • the food according to any one of [1] to [7] wherein the amount of NAD-related metabolites in the anterior aqueous humor is increased or retinal cell death is suppressed.
  • the food composition according to [10] which is a beverage, a supplement, a health supplement, a food for specified health use, a nutritional functional food, or a functional labeling food.
  • the food composition according to [10] or [11] which is in the form of a tablet, hard capsule, soft capsule, seamless capsule, powder, fine granule, granule, chewable, gummy, jelly, liquid (drink), troche, or paste object.
  • the NAD-related metabolite is at least one selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • [20] The use according to [18] or [19], which is in the form of a tablet, hard capsule, soft capsule, seamless capsule, powder, fine granule, granule, chewable, gummy, jelly, liquid (drink), troche, or paste.
  • [21] The use according to any of [18] to [20], wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
  • [22] The use according to any one of [18] to [20], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
  • the NAD-related metabolite is at least one selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • [27] In the form of an ointment, cream, milk, gel, lotion, essence, face pack, foundation, lipstick, plaster, poultice, powder, soap, shampoo, detergent, or bath preparation [25] or [26 ] The external preparation as described in.
  • Age-related macular degeneration, recurrent choroidal atrophy with severe myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinal arteriovenous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber disease The pharmaceutical composition according to [29] for prevention or treatment of an eye disease selected from the group.
  • Age-related macular degeneration, recurrent choroidal atrophy with severe myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinal arteriovenous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber disease A pharmaceutical composition for the prevention or treatment of an eye disease selected from the group.
  • NAD-related metabolites selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • the pharmaceutical composition according to any one of [29] to [35] which is a seed.
  • the pharmaceutical composition according to any of [29] to [36] which is a powder, granule, fine granule, tablet, pill, troche, capsule, chewable or syrup.
  • [38] In the form of eye drops, eye wash, eye ointment, contact lens mounting solution, contact lens preserving solution, contact lens disinfecting solution, contact lens cleaning solution, contact lens multipurpose solution, corneal preserving solution, or perfusion solution during surgery A pharmaceutical composition according to any one of [29] to [37]. [39] The pharmaceutical composition according to any one of [29] to [38], wherein the amount of NAD-related metabolites in the anterior aqueous humor is increased or retinal cell death is suppressed. [40] The pharmaceutical composition according to any one of [29] to [38] for reducing eye stress. [41] The pharmaceutical composition according to any one of [29] to [38] for improving the survival rate of eye cells or eye tissues.
  • a method for preventing and / or treating an ophthalmic disease comprising administering an effective amount of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof to a subject.
  • the eye diseases are presbyopia, glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, retina choroidal atrophy associated with high myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinal movement /
  • the method of [42] selected from the group consisting of venous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber disease.
  • the NAD-related metabolite is at least one selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • NNN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • the method according to any one of [42] to [44], which is a seed.
  • Use of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof for the prevention and / or treatment of an eye disease in a subject.
  • the eye disease is presbyopia, glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, retina choroidal atrophy associated with high myopia, corneal endothelial degeneration, bullous keratopathy, cataracts, retinal movement /
  • the use according to [48], wherein the eye disease is selected from the group consisting of corneal disease, retinal disease, and optic nerve disease.
  • NAD-related metabolites are 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
  • the use according to [48], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
  • At least one NAD-related metabolite selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM).
  • NNMN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • NAM nicotinamide
  • Example 1 Effects of NAD-related metabolites on corneal thickness in rabbit bullous keratopathy model Rabbit bullous keratosis model (New Zealand White rabbit: 12 weeks old) was divided into 2 groups of 3 each (control and bullous keratopathy model) Separately, NMN was instilled from the start date of the experiment (first measurement of corneal thickness) (500 uM, dissolved in physiological saline), and the measurement of corneal thickness was measured on the day and 7 days after NMN administration. A group containing only saline without NMN was used as a control group.
  • Example 2 Analysis of NAD-related metabolites in anterior aqueous humor
  • C57BL6J / Jcl mice young individuals 12 weeks old, elderly individuals 18 months old
  • mixed anesthesia somnopentyl / xylalazine
  • anterior aqueous humor was quickly collected using a 29G syringe, and NAD was measured among NAD-related metabolites in the anterior aqueous humor using HPLC.
  • the concentration of NAD + in the anterior aqueous humor was found to be about 60% lower in the anterior aqueous humor than in the younger individuals when comparing the younger and older individuals.
  • Example 3 Efficacy of NAD-related metabolites in rat ocular ischemia and optic neuropathy models Wistar rats (7 weeks old, male) were used. The day before the treatment (about 16 hours before), NMN (100 mg / kg, dissolved in physiological saline) was subcutaneously administered, and NMN was again administered at the same concentration 30 minutes before the treatment. Rats were anesthetized with pentobarbital (64.8 mg / kg) and then anesthetized with Benoxeal (Santen Pharmaceutical). Thereafter, the dorsal conjunctiva was incised to cut the optic nerve and central retinal arteriovenous in the orbit. Sham operation was conjunctival incision only.
  • the carotid artery was dissected under pentobarbital overanesthesia, then exsanguinated and sacrificed.
  • the retina was then isolated and immersed in a well of a 96-well plate containing 100 ⁇ L of Neurobasal medium or nicotinamide-free medium (added to either of these mediums to a final concentration of 0.5 mM if NMN was added). Thereafter, 10 ⁇ L of WST-8 (Dojin Chemical) was added. After 1 hour of incubation at 37 ° C. and 5% CO 2 , the absorbance (450 nm) of the culture supernatant was measured with a microplate reader, and the ratio of treated eyes to sham-operated eyes was calculated.
  • NAD synthesis rate-limiting enzyme NAMPT and NMN were added based on a nicotinamide-free medium, and the cells were collected 48 hours later. The amount of NAD in the cells was analyzed by HPLC.
  • Embodiment 5 Measurement of mitochondrial membrane potential Immortalized human corneal endothelial cell line (B4G12, DSMZ, Germany) was seeded in a 96-well plate (Corning, NY, USA) and cultured until confluent. The medium was replaced with HESFM basal medium containing hydrogen peroxide (Wako) 100 uM to which various NMN concentrations were added, and further cultured for 12 hours. Then, the Cell Meter (registered trademark) JC-10 mitochondrial membrane potential assay kit (AAT Bioquest, Inc) was used to measure mitochondrial membrane potential.
  • HESFM basal medium containing hydrogen peroxide (Wako) 100 uM to which various NMN concentrations were added, and further cultured for 12 hours.
  • the Cell Meter registered trademark
  • JC-10 mitochondrial membrane potential assay kit AAT Bioquest, Inc
  • Example 6 Metabolic analysis of lens epithelial cell lines Metabolism analysis of lens epithelial cell line Since oxygen is used for electron transport system and oxidative phosphorylation, mitochondrial activity can be analyzed by using oxygen consumption rate (OCR) index.
  • OCR oxygen consumption rate
  • the lens epithelial cell line used was a cell line established by RIKEN. Mitochondrial respiration was measured at 37 ° C. with an extracellular Fux analyzer (XFe24; Seahorse Bioscience) using the XF Cell Mito Stress Test Kit according to the manufacturer's recommended protocol.
  • the mitochondrial stress assay begins with a set of three basic records in medium supplemented with glucose cultured lens epithelial cell lines, followed by 0.5 uM oligomycin (ATP synthase inhibitor), 1 uM carbonyl cyanide-p-trifluoro. A total of 12 oxygens, each followed by 3 recordings after adding methoxyphenylhydrazone (FCCP, ETC conjugate) and 1 uM rotenone (Rot, ETC inhibitor) with 1 uM antimycin A (AA, ETC inhibitor) Consists of concentration measurement.
  • Mitochondrial respiration was quantified by measuring changes in oxygen concentration in the extracellular medium, and expressed as oxygen consumption rate (OCR; pmole / min) to evaluate mitochondrial function. See FIG. 7 for the stages of the mitochondrial stress assay and the timing of compound addition.
  • Example 7 Effect of NAD-related metabolites on corneal cell viability
  • the cornea was excised from a primate marmoset (5 years old, male) and stored in a corneal preservation solution (Optisol GS (registered trademark), manufactured by Bosch Lomm) supplemented with NMN.
  • Optisol GS registered trademark
  • the survival rate of corneal cells was calculated using Cell Counting Kit-8 kit (Dojindo Laboratories). Specifically, 100 ul of a cell suspension prepared with corneal cells at 5000 cells / well was seeded in wells of a microplate.
  • the cell survival was compared with the group of cells (Ctrl) stored in the conventional corneal preservation solution to which NMN was not added.
  • the rate has improved by 26%. This suggests the usefulness of NMN as a corneal preservation solution.
  • Example 8 Effect of NAD-related metabolites on ocular tissue survival rate In this experiment, it was verified whether the addition of NAD-related metabolites improves the ocular tissue survival rate.
  • mice 8 years old, male ⁇ ⁇ Japan Marie
  • a whole eye preservation solution EP • II, Kaken Pharmaceutical Co., Ltd.
  • cell viability was calculated using Cell Counting Kit-8 kit (Dojindo) and compared with control.
  • the calculation method of the cell viability using the Cell Counting Kit-8 kit is as described in Example 6.
  • Example 9 Verification of usefulness as ophthalmic surgery perfusate Rinse (New Zealand White rabbit: 12 weeks old) in the anterior chamber with saline perfusion solution (NMN-free group) or NMN-added perfusion solution (NMN-added group) for 15 minutes during operation.
  • the simulated cataract surgery model was used.
  • the corneal thickness ( ⁇ m) on the day after surgery was compared with the corneal thickness before surgery.
  • Student's t-test and paired t-test were used for statistical analysis of data, and p ⁇ 0.05 was judged to be significant.
  • the food or external preparation of the present invention containing a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof is effectively used for maintaining ocular health, promoting ocular health, or preventing ocular aging. be able to.
  • the pharmaceutical composition of the present invention containing an NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient can effectively prevent or treat an eye disease.

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Abstract

La présente invention concerne un aliment (en particulier un supplément, un supplément diététique, un aliment pour des utilisations de santé spécifiées, un aliment ayant une fonction nutritive, ou un aliment ayant des allégations fonctionnelles) et une préparation pour application externe (en particulier un médicament - un médicament pour des utilisations médicales, un médicament en vente libre - un quasi-médicament, un produit cosmétique et un produit de soin de la peau), chacun contenant un métabolite associé à NAD ou un sel ou un promédicament pharmaceutiquement acceptable de celui-ci. La présente invention concerne également une composition pharmaceutique destinée à prévenir ou à traiter une maladie ophtalmique choisie dans le groupe constitué de la presbytie, du glaucome, de la rétinopathie diabétique, de la rétinite pigmentaire, de la dégénérescence maculaire liée à l'âge, de l'atrophie choriorétinienne associée à une forte myopie, de la dystrophie endothéliale cornéenne, de la kératopathie bulleuse, de la cataracte, de l'occlusion artérielle/veineuse rétinienne, de la dystrophie cornéenne de Fuchs, de la neuropathie optique et la maladie de Leber.
PCT/JP2017/028727 2016-08-08 2017-08-08 Utilisation d'un métabolite associé à nad Ceased WO2018030389A1 (fr)

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WO2025086358A1 (fr) * 2023-10-26 2025-05-01 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) Perfusat pour chirurgie intraoculaire contenant du nicotinamide, son procédé de préparation et son utilisation

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US12290497B2 (en) 2018-12-18 2025-05-06 Santen Pharmaceutical Co., Ltd. Agent containing 4-phenylbutyrate, for preventing or treating presbyopia
CN109662973A (zh) * 2019-01-31 2019-04-23 山东省眼科研究所 烟酰胺腺嘌呤二核苷酸或其前体物质在制备治疗角膜上皮缺损的药物中的应用
CN109662973B (zh) * 2019-01-31 2021-05-18 山东省眼科研究所 烟酰胺腺嘌呤二核苷酸或其前体物质在制备治疗角膜上皮缺损的药物中的应用
JP2022085975A (ja) * 2020-11-30 2022-06-09 日清ファルマ株式会社 β－ニコチンアミドモノヌクレオチド含有製剤
JP7553335B2 (ja) 2020-11-30 2024-09-18 日清ファルマ株式会社 β－ニコチンアミドモノヌクレオチド含有製剤
WO2025086358A1 (fr) * 2023-10-26 2025-05-01 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) Perfusat pour chirurgie intraoculaire contenant du nicotinamide, son procédé de préparation et son utilisation

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