WO2018030389A1 - Use of nad-related metabolite - Google Patents

Abstract

The present invention provides a food (particularly a supplement, a health supplement, a food for specified health uses, a food having a nutrient function, or a food having function claims) and a preparation for external application (particularly a medicine (a medicine for medical uses, an OTC), a quasi drug, a cosmetic, and a skin care product), each of which contains an NAD-related metabolite or a pharmaceutically acceptable salt or prodrug thereof. The present invention also provides a pharmaceutical composition for preventing or treating an ophthalmic disease selected from the group consisting of presbyopia, glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, chorioretinal atrophy associated with high myopia, corneal endothelial dystrophy , bullous keratopathy, cataract, retinal artery/vein occlusion, Fuchs's corneal dystrophy, bullous keratopathy, optic neuropathy and Leber's disease.

Description

Use of NAD-related metabolites

The present invention relates to the use of NAD-related metabolites.

With the spread of OA equipment, game consoles, large screen displays, smartphones, night activities or night behavior (insomnia), strong light reflection by structures such as buildings, etc., with the recent urbanization of living, The burden or load is increasing and the eyes are constantly under stress.

In such a situation, to maintain eye health, it is most preferable to reduce the burden or load as described above and to rest the eye by sleeping etc., but this is also difficult to do in practice and maintaining eye health Or some measure is needed to improve health.

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.

As supplements that are good for eye health, 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.

Also, 80% of human information is said to be obtained from the eyes, and maintaining vision is an important issue. In Japan, an aging society is imminent, and ophthalmic diseases are expected to increase. Currently, about 1.5 million visually impaired people who have difficulty in daily life are expected, and the cost of social care is estimated to be 8 trillion yen.

With aging, 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.

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. The only evidenced treatment is intraocular pressure-lowering drugs, and 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. In addition, 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.

In recent years, it has been reported that nicotinamide adenine dinucleotide (NAD) is required as a substrate for the activation of the longevity gene Sirtuin (Non-patent Document 1), and its importance is highlighted as a contact point between aging and metabolism. Since NAD decreases with age, attempts have been reported to challenge anti-aging or control of diseases such as diabetes and Alzheimer's disease by enhancing NAD in decreasing organs. Patent Document 1 describes the relationship between various age-related diseases such as weight gain and insulin sensitivity and NAD and NAD-related metabolites.

WO2014 / 146044

However, there has been no report with scientific demonstration of NAD and NAD-related metabolites as health supplements, health functional foods, or preventive drugs in the ophthalmic field. For example, 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.

Food (including beverages, specified health foods, specified health foods, supplements), over-the-counter drugs (over-the-counter drugs, OTC) for the use of NAD-related metabolites to maintain and enhance eye health and prevent eye aging And quasi-drugs and cosmetics.

Also, 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. 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. 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. 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. 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.

Item 13. 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. 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.

Item 15. 11 ~ 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 14. The pharmaceutical composition according to any one of 13.

Since 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. In addition, NAD-related metabolites are excellent in safety because they are components present in the living body.

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, and 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. In the figure, the vertical axis represents the NAD concentration, and 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 Retinal tissue cultured in medium not containing NMN, 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 graph which shows the effect of a NAMPT specific inhibitor and NMN with respect to intracellular NAD in a human corneal endothelial cell line. The graph which shows the oxidative stress protection effect of the NAD related metabolite in the immortalized human corneal endothelial cell line. The vertical axis represents the mitochondrial membrane potential. Schematic diagram illustrating each step in the mitochondrial stress assay and the addition of oligomycin, carbonylcyanide-p-trifluoromethoxyphenylhydrazone, added substances, and rotenone and antimycin A. 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 μM 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 μM NMN. (C) Graph showing oxygen consumption rate in proton leak and ATP production. In each phase, the left side is the control and the right side is the addition of 500 μM NMN. Absorbance at 450 nm of a suspension containing corneal cells (Ctrl) stored in a corneal preservation solution without addition of NMN and a suspension containing corneal cells (NMN) preserved in a corneal preservation solution with addition of NMN. Welch Two Sample t-test. Absorbance at 450 nm of a suspension containing corneal cells (Ctrl) stored in an ocular storage solution without addition of NMN and a suspension containing corneal cells (NMN) stored in an ocular storage solution added with NMN. Welch Two Sample t-test. NMN non-addition group (NMN ^-) and comparison of the NMN added group corneal thickness at ^{(NMN +) (μm),} Pre: preoperative, Post: postoperative. 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. Preferably, the subject is a human.

In this specification, “food” is a concept that broadly encompasses what can be taken orally, and includes beverages. In addition to general foods including health foods, 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.

As used herein, “food composition” refers to a composition provided as a food. When the food is a composition, “food” and “food composition” can be used interchangeably.

As used herein, “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.

As used herein, “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.

As used herein, “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. Examples of 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.

In one embodiment, 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. In another embodiment, 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.

According to the present invention, 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. Food, nutritional functional food, and functional label food), supplements, and the like. 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). The

In one embodiment, the food is a health functional food. In another embodiment, 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.

In foods, it is common to produce powders such as NAD-related metabolites or aqueous solutions, oil dispersions, suspensions, emulsions and the like.

The food or food composition containing the NAD-related metabolite or the like of the present invention (hereinafter collectively referred to as “the food 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 (body weight 60 kg) 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. In another embodiment, 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. In another embodiment, 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. In still another embodiment, 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 mg or less, 3500 mg or less, 3000 mg or less, 2500 mg or less, or 2000 mg or less It is.

The food of the present invention can be formulated by a general method as a supplement together with a carrier acceptable as food. Examples of the carrier include liquid carriers such as water, ethanol, propylene glycol, and glycerin, and solid carriers such as glucose, sucrose, dextrin, cyclodextrin, and gum arabic.

Furthermore, in 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. For example, the above intake may be taken orally by dividing it once to several times a day (for example, about 3 times).

In addition, according to the present invention, 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. (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.

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.

For external preparations such as quasi drugs and cosmetics, ointments; skin care products such as creams, milk, gels, lotions, essences, face packs, cleaning agents; foundations; lipsticks; plasters; poultices; soaps; It can be in the form of a bath preparation, but is not limited thereto.

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. In another embodiment, 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. In another embodiment, 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. In still another embodiment, 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 mg or less, 3500 mg or less, 3000 mg or less, 2500 mg or less, or 2000 mg or less It is.

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. Examples of 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.

As long as 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.

According to the present invention, 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. In another embodiment, 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. In another embodiment, 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. In still another embodiment, 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 mg or less, 3500 mg or less, 3000 mg or less, 2500 mg or less, or 2000 mg or less It is.

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. Examples of 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. .

In the pharmaceutical composition of the present invention, minerals; vitamin E, vitamin C 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. 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. In addition, 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. For example, 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. For example, 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.

For example, 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.

In addition, 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.

In one embodiment, the pharmaceutical composition of the invention increases the amount of NAD-related metabolites in the anterior aqueous humor in the subject. In particular, the pharmaceutical composition of the present invention increases the amount of NAD in anterior aqueous humor in a subject. Without being bound by theory, 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. Includes the use of drugs.

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.

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.
[1] Use of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof for maintaining ocular health, promoting ocular health, or preventing ocular aging (excluding medical practice).
[2] Foods to which NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof are added.
[3] 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.
[7] 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). The food according to any one of [1] to [6], which is a seed.
[8] 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.
[9] The food according to any one of [1] to [8] for reducing eye stress.
[10] A food composition containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof used for maintaining ocular health, promoting ocular health, or preventing ocular aging.
[11] 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.
[12] 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.
[13] The food composition according to any one of [10] to [12], wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
[14] The food composition according to any one of [10] to [12], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
[15] 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). The food composition according to any one of [10] to [14], which is a seed.
[16] The food composition according to any one of [10] to [15], wherein the amount of NAD-related metabolites in the anterior aqueous humor is increased or retinal cell death is suppressed.
[17] The food composition according to any one of [10] to [16], for reducing eye stress.
[18] Use of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof for preparing a food for use in maintaining eye health, promoting eye health, or preventing eye aging.
[19] The use according to [18], which is a beverage, supplement, health supplement, specified health food, nutritional functional food, or functional indication food.
[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.
[23] 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). The use according to any one of [1] and [18] to [22], which is a seed.
[24] The use according to any one of [1] and [18] to [23] for reducing eye stress.
[25] An external preparation containing a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[26] The external preparation according to [25], which is a quasi-drug or a cosmetic.
[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.
[28] The external preparation according to any one of [25] to [27], which increases the amount of NAD-related metabolites in anterior aqueous humor or suppresses retinal cell death.
[29] A NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutical composition for prevention or treatment of eye diseases (however, eye diseases exclude dry eye).
[30] Presbyopia, glaucoma, diabetic retinopathy, retinitis pigmentosa, addition containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof, and pharmacologically acceptable carriers. 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.
[31] Presbyopia, glaucoma, diabetic retinopathy, retinitis pigmentosa, addition containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof, and pharmacologically acceptable carriers. 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.
[32] For prevention or treatment of an eye disease selected from the group consisting of a corneal disease, a retinal disease, and an optic nerve disease, comprising a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof [27] The pharmaceutical composition according to [27].
[33] For prevention or treatment of an eye disease selected from the group consisting of a corneal disease, a retinal disease, and an optic nerve disease, comprising a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof Pharmaceutical composition.
[34] The pharmaceutical composition according to any of [29] to [33], wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
[35] The pharmaceutical composition according to any of [29] to [33], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
[36] 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). The pharmaceutical composition according to any one of [29] to [35], which is a seed.
[37] 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.
[42] 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.
[43] 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.
[44] The method according to [42], wherein the eye disease is selected from the group consisting of corneal disease, retinal disease, and optic nerve disease.
[45] The method according to any one of [42] to [44], wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
[46] The method according to any of [42] to [44], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
[47] 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). The method according to any one of [42] to [44], which is a seed.
[48] 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.
[49] 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], selected from the group consisting of venous occlusion, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber disease.
[50] The use according to [48], wherein the eye disease is selected from the group consisting of corneal disease, retinal disease, and optic nerve disease.
[51] The use according to [48], wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
[52] The use according to [48], wherein the daily intake of NAD-related metabolites is 0.1 mg to 2000 mg.
[53] 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). The use according to any one of [48] to [52], which is a seed.

The disclosures of all patent applications and documents cited in this specification are hereby incorporated by reference in their entirety.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

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.

As a result, as shown in FIG. 2, increase in corneal thickness was suppressed in the NMN administration 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) were used. After general anesthesia with 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 results are shown in FIG. 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. Four hours after cutting, 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 μL 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 μL 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.

The results are shown in FIG. In the disease group, significant cell death is induced 4 hours after amputation of the optic nerve and retinal arteriovenous vein. After cutting and isolating the retina, the viable cell rate is 20% compared to the control group (medium (1)). However, the subcutaneous administration of NMN twice the day before and on the day markedly increased the viable cell rate to 41% (medium + NMN (1)). The same effect can be reproduced by inspecting the presence or absence of NMN after incubation after tissue isolation (medium (2), medium + NMN (2)), and administration of NMN is related to NAD metabolism in the tissue. It is thought that it contributed to the increase of the product concentration and suppressed cell death.

Example 4 Examination using human corneal endothelial cell line

In a study using human corneal endothelial cell lines (B4G12, DSMZ, Germany), a specific amount of 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.

As a result, as shown in FIG. 5, the addition of NAMPT-specific inhibitor markedly decreased intracellular NAD, and the addition of NMN dramatically contributed to the increase in intracellular NAD concentration. That is, the existence of a NAMPT-dependent metabolic pathway was found.

Embodiment 5 FIG. 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.

As a result, as shown in FIG. 6, a decrease in mitochondrial membrane potential was observed in the hydrogen peroxide stress group without addition of NMN compared to the control group cultured in a medium containing neither NMN nor hydrogen peroxide. Compared with the hydrogen peroxide stress group without addition of Nm, the NMN addition group of 5uM or more was found to significantly improve the mitochondrial membrane potential. For statistical processing, one-way ANOVA and Boferroni were used.

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.

2. Method 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.

3. Results As shown in FIGS. 8A to 8C, when NMN 500 μM was added before stress loading on mitochondria, the activity of mitochondrial respiration was significantly increased compared to the case without addition, and also the increase in ATP production. Contributed. From this study, it was found that activation of NAD metabolism by NMN increases the activity of mycotondoria in lens epithelial cells and activates ATP production.

Example 7 Effect of NAD-related metabolites on corneal cell viability In this experiment, it was verified whether the addition of NAD-related metabolites would improve 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. One month later, 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. Next, it was pre-cultured in a CO ₂ incubator at 37 ° C., and the drug was added to each well. After further culturing in a CO ₂ incubator at 37 ° C. for a certain time, a CCK-8 solution was added. A color reaction was performed in a CO ₂ incubator at 37 ° C., the absorbance at 450 nm of the cells was measured with a microplate reader, and the viability of the corneal cells was calculated from the measured values.

As shown in FIG. 9, in the group of cells (NMN) stored in the corneal preservation solution to which NMN was added, 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.

The eyeballs of mice (8 years old, male ク レ Japan Claire) were collected and stored in a whole eye preservation solution (EP • II, Kaken Pharmaceutical Co., Ltd.) supplemented with NMN. Two weeks later, 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 (Dojindo Laboratories Co., Ltd.) is as described in Example 6.

As shown in FIG. 10, in the group of cells (NMN) preserved in the eyeball preservation solution to which NMN was added, cell survival was compared with the group of cells preserved in the conventional eye preservation solution to which NMN was not added (Ctrl). The rate has improved by 28%. This suggests the usefulness of NMN as an additive for the whole-eye storage solution.

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 (μm) 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.

As shown in FIG. 11, although there was no significant difference in the NMN-free group, the corneal thickness tended to increase, but in the NMN-added group, a decrease in corneal thickness was observed and the transparency of the cornea was maintained.

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. Moreover, 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.

Claims (15)

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).
2. Foods supplemented with NAD-related metabolites, pharmaceutically acceptable salts, or prodrugs thereof.
3. The food according to claim 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.
4. The food according to claim 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 claims 2 to 4, wherein the daily intake of NAD-related metabolites is 0.1 pg to 2000 mg.
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.
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.
8. An external preparation containing a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
9. The external preparation according to claim 8, which is a quasi-drug or a cosmetic.
10. The external use according to claim 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. Agent.
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.
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.
13. The pharmaceutical composition according to claim 11 or 12, wherein the daily intake of the NAD-related metabolite is 0.1 pg to 2000 mg.
14. The pharmaceutical composition according to any one of claims 11 to 13, which is a powder, granule, fine granule, tablet, pill, troche, capsule, chewable or syrup.
15. 11 ~ 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 14. The pharmaceutical composition according to any one of 13.

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