JP7090336B2 - Utilization of NAD-related metabolites - Google Patents

Description

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

With the spread of OA devices, game consoles, large screen displays, smartphones, etc., increase in night activities or night activities (sleeplessness), strong light reflection by structures such as buildings, etc. The burden or load is increasing and the eyes are constantly under stress.

In such a situation, in order to maintain the health of the eyes, it is most preferable to reduce the burden or load as described above and rest the eyes by sleeping or the like, but it is also difficult to actually do this, and maintaining the health of the eyes. Or some measures are needed to improve health.

Physical countermeasures such as blue light and cut glasses have been proposed, but as a simple and continuous countermeasure every day, a compound having an eye health maintenance or health promotion effect or an eye aging prevention effect is used. It is desirable to take it as a supplement, food, beverage, etc., or as an external preparation such as cosmetics, cream, etc.

As supplements that are good for eye health, extracts or dried products such as blueberries and grapes that contain a large amount of polyphenols, and extracts that contain lutein (carotenoid contained in green and yellow vegetables) are widely known and used. The current situation is that a single ingredient that does not contain extra ingredients requires less intake, and there are still few supplements that are highly effective.

In addition, it is said that 80% of human information can be obtained from the eyes, and maintaining vision is an important issue. In Japan, the number of ophthalmic diseases is expected to increase in the face of a super-aging society. Currently, it is estimated that there are about 1.5 million visually impaired people who have difficulty in daily life, and it is estimated that the cost of social care will be 8 trillion yen.

With aging, the optic nerve loses nerve fibers, the retinal nerve fiber layer becomes thinner, ganglion cells also drop out, 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 to be glaucoma, diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, and reticulochoroidal atrophy associated with severe myopia, all of which are a group of diseases that worsen with age. Furthermore, cataract, retinal arteriovenous / venous obstruction, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, etc. are also age-related blindness diseases.

According to the Japan Glaucoma Society's glaucoma medical treatment guide, glaucoma has characteristic changes in the optic nerve and visual field, and is a functional structural abnormality of the eye that can improve or suppress the optic nerve disorder by sufficiently lowering the intraocular pressure. It is a characteristic disease. Acute or chronically progressive glaucoma or optic neuropathy has been suggested to involve age-related changes in the optic nerve. Glaucoma is the number one cause of blindness in Japan, but the entire pathology has not yet been elucidated. The prevalence of glaucoma increases with age, with 12.7% male and 8.9% female over 80 years of age. The only treatment with evidence is intraocular pressure-lowering drugs, and the glaucoma treatments already in use include major drugs such as prostaglandin preparations, beta-receptor blockers, or carbonate dehydrogenase inhibitors, and their combinations. Agents are mentioned. More recently, the development of new therapeutic agents for glaucoma using Rock inhibitors has also been reported.

The corneal endothelium is an important cell that contributes to the transparency of the eye, but it does not have the ability to proliferate after birth in humans. In addition, the number of corneal endothelial cells decreases markedly due to aging, invasion such as cataract surgery, or Fuchs corneal endothelial degeneration. When the number of cells decreases beyond a certain threshold, the cornea becomes cloudy and presents with bullous keratopathy. Currently, there are no prophylactic or therapeutic agents that respond to the aging phenomenon symbolized by corneal endothelial cell depletion, 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 activation of the longevity gene Sirtuin (Non-Patent Document 1), and its importance as a contact point between aging and metabolism is in the limelight. 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 the 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

Nature. 2000 Feb 17; 403 (6771): 795-800

However, there have been no reports with scientific demonstration of NAD and NAD-related metabolites as dietary supplements, foods with health claims or prophylactic agents in the field of ophthalmology. For example, Patent Document 1 only shows an increase in tear volume in mice.

An object of the present invention is to utilize NAD-related metabolites for maintaining or promoting the health of the eye, or for preventing aging of the eye.

Another object of the present invention is to provide a prophylactic or therapeutic agent for various eye diseases containing NAD-related metabolites.

Foods (including beverages, specified health foods, specified health foods, supplements), over-the-counter drugs (over-the-counter drugs, OTC) for use in maintaining and promoting eye health of NAD-related metabolites or preventing eye aging. , Quasi-drugs, cosmetics, etc. can be mentioned.

In addition, preventive or therapeutic agents for eye diseases containing NAD-related metabolites, dietary supplements, foods with health claims, and supplements that correspond to the aging society are indispensable.

As a result of focusing on the profile of NAD-related metabolites in the anterior chamber water in the eye, the present inventors detected a higher concentration of NAD-related metabolites in the anterior chamber water than in plasma. Furthermore, they have found the physiological importance of these NAD-related metabolites in the eye and their usefulness as therapeutic targets for eye diseases, and have 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 cataract.

The present invention includes the subjects described in the following sections.

Item 1. Use of NAD-related metabolites, their pharmaceutically acceptable salts, or their prodrugs to maintain eye health, promote eye health, or prevent eye aging (except in medical practice).

Item 2. Foods supplemented with NAD-related metabolites, their pharmaceutically acceptable salts, or their prodrugs.

Item 3. Item 2. The food according to Item 2, which is a beverage, a supplement, a dietary supplement, a food for specified health use, a nutritionally functional food, or a food with a functional claim.

Item 4. Item 3. The food product according to Item 3, which is in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, or pastes.

Item 5. Item 2. 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 used for maintaining eye health, promoting eye health, or preventing eye aging containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof.

Item 7. Use of NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof for preparing foods 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 2. The external preparation according to Item 8, which is a quasi-drug or a cosmetic product.

Item 10. Item 2. 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 bathing agent. ..

Item 11. Old eye, glaucoma, diabetic retinitis, retinitis pigmentosa, age-related bullous keratopathy containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof and pharmacologically acceptable carriers. Select from the group consisting of symptom, retinitis pigmentosa associated with severe myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinitis pigmentosa, retinitis pigmentosa, bullous keratopathy, optic neuropathy, and Leber's disease. A pharmaceutical composition for the prevention or treatment of eye diseases.

Item 12. An eye selected from the group consisting of corneal, retinal, and optic nerve diseases containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof, and pharmacologically acceptable carriers. A pharmaceutical composition for the prevention or treatment of a disease.

Item 13. Item 6. The pharmaceutical composition according to any one of Items 11 or 12, wherein the daily intake of the NAD-related metabolite is 0.1 pg to 2000 mg.

Item 14. Item 6. The pharmaceutical composition according to any one of Items 11 to 13, which is a powder, a granule, a fine granule, a tablet, a pill, a troche, a capsule, a chewable agent, or a syrup agent.

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

Because NAD-related metabolites can ameliorate symptoms or conditions in the corneal endothelium, retina, and optic nerve, the pharmaceutical and food compositions of the invention containing NAD-related metabolites can prevent or prevent various eye diseases. It can be used for therapeutic or eye protection purposes. In addition, since NAD-related metabolites are components existing in the living body, they are also excellent in terms of safety.

Schematic diagram showing the nicotinamide adenine dinucleotide (NAD) synthesis pathway and NAD-related metabolites. Graph showing the effect of NMN administration on corneal thickness in a rabbit bullous keratopathy model. (A) is a control, and (B) is an NMN-administered group. The vertical axis shows the thickness of the cornea, and the horizontal axis shows the number of days of breeding. Each value indicates the mean ± standard deviation. Each group N = 1. The graph which shows the measured amount of NAD in the anterior aqueous humor of the old mouse and the young mouse. In the figure, the vertical axis shows the NAD concentration, and the horizontal axis shows the week or month age of the mouse. Each value indicates the mean ± standard deviation. Each group N = 3. The graph which shows the cell survival rate in a rat acute ocular ischemia model. Sham: Pseudo-operated eye retinal tissue, medium (1): Cultured medium of treated eye retinal tissue without NMN, medium + NMN (1): Treatment eye of rat treated subcutaneously with NMN the day before and on the day Retinal tissue cultured in NMN-free medium, medium (2): Treatment eye retinal tissue cultured in NMN-containing medium, medium + NMN (2): Rats subcutaneously administered NMN the day before and on the day Treatment Eye retinal tissue cultured in a medium containing NMN. Graph showing the effect of NAMPT-specific inhibitor and NMN on intracellular NAD in 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 shows the mitochondrial membrane potential. Schematic diagram illustrating each step in the mitochondrial stress assay and the addition of oligomycin, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, additives, and rotenone and antimycin A. Basal Respiration: Basic respiration, ATP Production: ATP production, Proton Leak: Proton leak, Maximum Respiration: Maximum respiration, Spare Capacity: Reserve respiration capacity, Non-mitochondrial Respitration: Non-mitochondrial respiration. (A) A graph showing the rate of oxygen consumption over time in a mitochondrial stress assay. (1) Control (without NMN addition), (2) Add 500 μM NMN. (B) A graph showing the oxygen consumption rate in basal respiration and preliminary respiration ability. 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 NMN and a suspension containing corneal cells (NMN) stored in a corneal preservation solution with NMN added. Welch Two Sample t-test. Absorbance at 450 nm of a suspension containing corneal cells (Ctrl) stored in an eyeball storage solution without NMN and a suspension containing corneal cells (NMN) stored in an eyeball storage solution with NMN added. Welch Two Sample t-test. Comparison of corneal thickness (μm) between NMN-free group (NMN-) and NMN ^- added group (NMN ⁺ ), Pre: preoperative, Post: postoperative. Each group N = 3.

The present invention is a novel use of NAD-related metabolites in the field of ophthalmology. NAD-related metabolites can be used to maintain or promote eye health, or to 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 is applied includes mammals which 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.

As used herein, the term "food" is a concept that broadly includes those that can be ingested orally, and also includes beverages. Foods include general foods including health foods, enteral nutrition foods, special purpose foods, health functional foods including specified health foods, nutritional functional foods, foods with functional claims, and the like.

As used herein, the term "food composition" refers to a composition served as a food product. When food is a composition, "food" and "food composition" can be used interchangeably.

As used herein, "NAD-related metabolite" refers to a series of compounds comprising nicotinamide as a component in the nicotinamide adenine dinucleotide (NAD) synthesis pathway, including nicotinamide mononucleotide (NMN) and nicotinamide adenine dinucleotide. (NAD), nicotinamide riboside (NR), and nicotinamide (NAM) are included.

As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable non-toxic salt, which includes salts of inorganic acids and salts of organic acids.

As used herein, the term "prodrug" refers to a compound that, when administered to a subject that is a mammal, converts it into a compound of interest under physiological conditions in vivo. Examples of prodrugs of NAD-related metabolites include alcohol and amine group acetate, formate, and benzoic acid ester derivatives of NAD-related metabolites.

The present invention relates to maintaining eye health, promoting eye health, or aging of NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof (hereinafter referred to as "NAD-related metabolites, etc."). Regarding prophylactic use (but excluding medical practice).

Maintaining eye health means maintaining the normal condition of the eye, including anterior atrioventricular water, ciliary body, Schlemm's canal, retina, crystalline lens, optic nerve, cornea (especially corneal epithelium), retina, and visual function. Or it involves maintaining these combinations.

In one embodiment, NAD-related metabolites and the like can be used for eye protection in the subject. Eye protection refers, for example, to protecting the optic nerve, cornea (particularly 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 other stresses that act as external forces on the eyes.

According to the present invention, NAD-related metabolites and the like are used not only as general foods but also as dietary supplements and health functional foods (for specified health use) for the purpose of maintaining eye health, promoting eye health, or preventing eye aging. It can be added to foods, foods with nutritional function, and foods with functional claims), supplements, and the like. Beverages are included in foods. By ingesting NAD-related metabolites in the form of food, the effects of maintaining eye health, promoting eye health, or preventing eye aging can be easily enjoyed.

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). To.

In one embodiment, the food is a health food. In another embodiment, the food is a supplement. The food of the present invention containing NAD-related metabolites and the like as an active ingredient has an effect on the type of active ingredient, maintenance of eye health, promotion of eye health, or prevention of eye aging in the packaging, container or instruction of the food. The effect and / or the method of ingestion can be displayed.

Foods are generally produced by adding powders or aqueous solutions of NAD-related metabolites, oil dispersions, suspensions, emulsions and the like.

The food or food composition containing the NAD-related metabolite of the present invention (hereinafter collectively referred to as "food of the present invention") may be in any form, for example, juice, milk, coffee beverage, tea beverage. Beverages such as, liquid foods such as soup, pasty foods such as yogurt, semi-solid foods such as jelly and gummy, solid foods such as cookies and gum, and oil-containing foods such as dressing and mayonnaise. ..

In addition, the food product of the present invention can be in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, or pastes. 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) ~ 2000mg, 1ng ~ 2000mg, 10ng ~ 2000mg, or 0.1mg ~ 2000mg. 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. 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 yet another embodiment, the daily intake of NAD-related metabolites is 0.1 pg or higher, 1 pg or higher, 10 pg or higher, 100 pg (0.1 ng) or higher, 1 ng or higher, 10 ng or higher, 0.1 mg or higher, 0.5 mg or higher. , 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 Range from either the lower limit of 900 mg or more or 1000 mg or more to the upper limit of 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. Is.

The food product of the present invention can be formulated by a general method as a supplement or the like together with a carrier that is acceptable as a food product. 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 arabic gum.

Further, the food product of the present invention is not impaired by the effects of NAD-related metabolites, that is, sugars; proteins; fats; Minerals; Vitamins such as Vitamin E, Vitamin C, Vitamin B, Vitamin A; NAD activators by alternative pathways such as resveratrol; Inhibitors of NAD degrading enzymes such as anti-NADase antibodies; Fragrances; Other pigments such as pigments Additives can be added. Any of these additives can be used as commonly used in foods.

The dosage form of the food product of the present invention may be appropriately selected depending on the subject, eye condition, and other conditions. For example, the above intake may be orally ingested once to several times a day (for example, about 3 times).

Further, according to the present invention, NAD-related metabolites, quasi-drugs thereof, or prodrugs thereof are over-the-counter drugs for the purpose of maintaining eye health, promoting eye health, or preventing eye aging. (Over-the-counter drugs, OTC), quasi-drugs, or cosmetics; in particular, they 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). Will be done.

The manufacturing method and form at the time of use are not limited, and it can be commercialized by a known method, and examples thereof include the following.

General-purpose medicines can be in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, sublingual tablets, pastes, etc. Not limited to these.

For external use such as non-medicinal products and cosmetics, ointments; creams, milks, gels, lotions, essences, face packs, cleaning agents and other skin care products; foundations; lipsticks; plasters; paps; soaps; shampoos It can be in the form of a bathing agent, but is not limited to these.

The daily intake of NAD-related metabolites in the external preparation 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. , 1ng-2000mg, 10ng-2000mg, or 0.1mg-2000mg. 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. 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 yet another embodiment, the daily intake of NAD-related metabolites is 0.1 pg or higher, 1 pg or higher, 10 pg or higher, 100 pg (0.1 ng) or higher, 1 ng or higher, 10 ng or higher, 0.1 mg or higher, 0.5 mg or higher. , 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 Range from either the lower limit of 900 mg or more or 1000 mg or more to the upper limit of 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. Is.

The external preparation of the present invention can be formulated according to a 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 water, ethanol, propylene glycol and glycerin, and solid carriers such as glucose, sucrose, dextrin, cyclodextrin and arabic gum.

The external preparations of the present invention contain minerals; Vitamin E, Vitamin C, as required, as long as they do not impair the effects of NAD-related metabolites, i.e., as long as the formulation with NAD-related metabolites does not cause unwanted interactions. Contains vitamins such as vitamin B and vitamin A; NAD activators by other routes such as resveratrol; inhibitors of NAD-degrading enzymes such as anti-NADase antibodies; nutritional components; fragrances; other additives such as pigments. be able to. As any of these additives, those generally used for external preparations can be used.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition containing a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient for preventing or treating an eye disease.

The NAD-related metabolite in the pharmaceutical composition of the present invention preferably comprises the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD), nicotinamide riboside (NR), and nicotinamide (NAM). Be selected.

The daily dose of the NAD-related metabolite in the pharmaceutical composition 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. , 100pg (0.1ng) -2000mg, 1ng-2000mg, 10ng-2000mg, or 0.1mg-2000mg. 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. 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 yet another embodiment, the daily intake of NAD-related metabolites is 0.1 pg or higher, 1 pg or higher, 10 pg or higher, 100 pg (0.1 ng) or higher, 1 ng or higher, 10 ng or higher, 0.1 mg or higher, 0.5 mg or higher. , 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 Range from either the lower limit of 900 mg or more or 1000 mg or more to the upper limit of 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. Is.

The pharmaceutical composition of the present invention can be formulated according to a 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 water, ethanol, propylene glycol and glycerin, and solid carriers such as glucose, sucrose, dextrin, cyclodextrin and arabic gum.

The pharmaceutical composition of the present invention may further appropriately contain emulsifiers, tonicity agents, buffers, solubilizing agents, preservatives, stabilizers, antioxidants and the like commonly used in formulation. ..

The pharmaceutical compositions of the present invention, as required, minerals; Vitamin E, Vitamin C, as long as they do not impair the effects of NAD-related metabolites, i.e., do not cause unfavorable interactions with NAD-related metabolites. , Vitamins such as Vitamin B and Vitamin A; NAD activators by other routes such as resveratrol; Inhibitors of NAD degrading enzymes such as anti-NADase antibodies; Nutritional components; Fragrances; Other additives such as pigments can do. Any of these additives can be used as commonly used in pharmaceutical products.

The form of the pharmaceutical composition of the present invention is not particularly limited, and is, for example, a solid state such as powder, granule, or tablet; a liquid such as a solution, a milky liquid, or a dispersed liquid; or a semi-solid such as a paste. 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 route of administration. , Chewables, syrups, etc. When it is used as a topical preparation for ophthalmology, it may be in the form of eye drops, eye wash, eye ointment, contact lens wearing solution, contact lens preservative solution, contact lens disinfectant solution, contact lens cleaning solution, multipurpose solution for contact lenses, etc. can. In addition, the pharmaceutical composition of the present invention may be used for a corneal preservation solution and a surgical perfusate.

The administration form of the pharmaceutical composition of the present invention may be appropriately selected depending on the subject, pathological condition and progress thereof, and other conditions. For example, it may be administered once to several times (for example, about 3 times) so as to be the above-mentioned daily dose.

The route of administration of the pharmaceutical composition of the present invention is not particularly limited, and for example, oral administration, ophthalmic injection, conjunctival injection, tenon sac injection, anterior atrioventricular injection, vitreous injection, intravenous administration, subcutaneous administration, intramuscular administration, and rectal administration. , Can be administered by subcutaneous injection, transdermal administration, etc.

For example, the pharmaceutical composition of the present invention comprises glaucoma (also referred to as glaucoma), glaucoma, diabetic retinitis, retinitis pigmentosa, age-related macular degeneration, retinitis pigmentosa associated with severe myopia, corneal endothelial degeneration, and bullous. It can be used for the prevention or treatment of eye diseases selected from the group consisting of keratopathy, cataract, retinitis pigmentosa, Fuchs keratopathy, bullous keratopathy, optic neuropathy, and Leber's disease. These diseases are also age-related eye diseases that worsen with age.

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, retinal choroidal atrophy associated with severe myopia, and retinal arteriovenous / venous obstruction. Optic nerve diseases include glaucoma, optic neuropathy, Leber's 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 chamber water in a subject. In particular, the pharmaceutical composition of the present invention increases the amount of NAD in the anterior chamber water in the subject. Without being bound by theory, increased amounts of NAD in the anterior chamber water act on the repair of cells or tissues, especially the cornea, ciliary body, Schlemm's canal, retina, and lens that come into contact with the anterior chamber water. It is thought to contribute to the prevention or treatment of eye diseases.

The present invention comprises the step of incorporating NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof into foods to maintain eye health, promote eye health, or age the eyes. Includes methods of making foods or food compositions for prevention.

The present invention also relates to NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof in the manufacture of foods or food compositions having the effects of maintaining eye health, promoting eye health, or preventing eye aging. Also includes the use of drugs.

Details of the NAD-related metabolites, the amount to be blended in the food, and the composition of the food or the food composition are as described above with respect to the food of the present invention.

The invention also includes methods for the prevention and / or treatment of eye diseases, comprising administering to a subject an effective amount of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The invention also includes the use of NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof for the prevention and / or treatment of eye diseases in a subject.

Details of the NAD-related metabolite and the dose to the subject are as described above with respect to the pharmaceutical composition of the present invention.

The invention also includes:
[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 to which NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof have been added.
[3] The food according to [2], which is a beverage, a supplement, a dietary supplement, a food for specified health use, a nutritionally functional food, or a food with a functional claim.
[4] The food according to [2] or [3] in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, or pastes.
[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 the seeds [1] to [6].
[8] The food according to any one of [1] to [7], which increases the amount of NAD-related metabolites in the anterior chamber water or suppresses cell death in the retina.
[9] The food according to any one of [1] to [8] for reducing eye stress.
[10] A food composition containing a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof, used for maintaining eye health, promoting eye health, or preventing eye aging.
[11] The food composition according to [10], which is a beverage, a supplement, a dietary supplement, a food for specified health use, a nutritionally functional food, or a food with a functional claim.
[12] The food composition according to [10] or [11], which is in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, or pastes. thing.
[13] The food composition according to any one of [10] to [12], wherein the daily intake of the NAD-related metabolite 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 the NAD-related metabolite 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 the seeds [10] to [14].
[16] The food composition according to any one of [10] to [15], which increases the amount of NAD-related metabolites in the anterior chamber water or suppresses cell death of the retina.
[17] The food composition according to any one of [10] to [16] for reducing eye stress.
[18] Use of NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof for preparing foods used for maintaining eye health, promoting eye health, or preventing eye aging.
[19] The use according to [18], which is a beverage, a supplement, a dietary supplement, a food for specified health use, a nutritionally functional food, or a food with a functional claim.
[20] The use according to [18] or [19], which is in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, or pastes.
[21] The use according to any one of [18] to [20], wherein the daily intake of the NAD-related metabolite 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). Use according to any one of the species [1] and [18] to [22].
[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 product.
[27] In the form of ointments, creams, milks, gels, lotions, essences, face packs, foundations, lipsticks, plasters, poultices, powders, soaps, shampoos, cleansers, or baths [25] or [26] ] The external preparation described in.
[28] The external preparation according to any one of [25] to [27], which increases the amount of NAD-related metabolites in the anterior chamber water or suppresses cell death in the retina.
[29] NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof and pharmaceutical compositions for the prevention or treatment of eye diseases (excluding dry eye for eye diseases).
[30] NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof, including old eyes, glaucoma, diabetic retinitis, retinitis pigmentosa, addition. Consists of age-yellow spot degeneration, retinitis pigmentosa associated with severe myopia, bullous keratopathy, bullous keratopathy, glaucoma, retinitis pigmentosa, Fuchs keratopathy, bullous keratopathy, optic neuropathy, and Leber's disease The pharmaceutical composition according to [29] for the prevention or treatment of eye diseases selected from the group.
[31] NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof, and a bleeding eye, glaucoma, diabetic retinitis, retinitis pigmentosa, addition containing a pharmacologically acceptable carrier. Consists of age-yellow spot degeneration, retinitis pigmentosa associated with severe myopia, bullous keratopathy, bullous keratopathy, glaucoma, retinitis pigmentosa, Fuchs keratopathy, bullous keratopathy, optic neuropathy, and Leber's disease A pharmaceutical composition for the prevention or treatment of eye diseases selected from the group.
[32] For the prevention or treatment of eye diseases selected from the group consisting of corneal diseases, retinal diseases, and optic nerve diseases containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof. The pharmaceutical composition according to [27].
[33] For the prevention or treatment of eye diseases selected from the group consisting of corneal diseases, retinal diseases, and optic nerve diseases containing NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof. Pharmaceutical composition.
[34] The pharmaceutical composition according to any one of [29] to [33], wherein the daily intake of the NAD-related metabolite is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
[35] The pharmaceutical composition according to any one of [29] to [33], wherein the daily intake of the NAD-related metabolite is 0.1 mg to 2000 mg.
[36] 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 pharmaceutical composition according to any one of the species [29] to [35].
[37] The pharmaceutical composition according to any one of [29] to [36], which is a powder, a granule, a fine granule, a tablet, a pill, a troche, a capsule, a chewable agent, or a syrup.
[38] In the form of eye drops, eye wash, eye ointment, contact lens wearing solution, contact lens preservative solution, contact lens disinfectant solution, contact lens cleaning solution, multipurpose solution for contact lenses, corneal preservation solution, or perfusate during surgery. The pharmaceutical composition according to any one of [29] to [37].
[39] The pharmaceutical composition according to any one of [29] to [38], which increases the amount of NAD-related metabolites in the anterior chamber water or suppresses cell death in the retina.
[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 eye disease, which comprises administering to a subject an effective amount of a NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[43] The eye diseases include senile eye, glaucoma, diabetic retinitis, retinitis pigmentosa, age-related macular degeneration, retinitis pigmentosa associated with severe myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinitis pigmentosa. 42. The method according to [42], which is selected from the group consisting of venous obstruction, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber's 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 the NAD-related metabolite is 0.1 pg to 2000 mg, preferably 0.1 ng to 2000 mg.
[46] The method according to any one of [42] to [44], wherein the daily intake of the NAD-related metabolite 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 the species [42] to [44].
[48] Use of NAD-related metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof for the prevention and / or treatment of eye diseases in a subject.
[49] The eye diseases include old eyes, glaucoma, diabetic retinitis, retinitis pigmentosa, age-related macular degeneration, retinitis pigmentosa associated with severe myopia, corneal endothelial degeneration, bullous keratopathy, cataract, retinitis pigmentosa. The use according to [48] selected from the group consisting of venous obstruction, Fuchs corneal degeneration, bullous keratopathy, optic neuropathy, and Leber's 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] 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). Use according to any one of the species [48] to [52].

All patent applications and literature disclosures cited herein are incorporated herein by reference in their entirety.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1. Effect of NAD-related metabolites on corneal thickness in rabbit bullous keratopathy model Rabbit bullous keratopathy model (New Zealand White rabbit: 12 weeks old) in 2 groups of 3 each (control and bullous keratopathy model) NMN was instilled (500uM, dissolved in physiological saline) from the start date of the experiment (first measurement of corneal thickness), and the corneal thickness measurement was measured on the day of NMN administration and 7 days later. The group containing only physiological saline without administration of NMN was used as the control group.

As a result, as shown in FIG. 2, the increase in corneal thickness was suppressed in the NMN-administered group.

Example 2. Analysis of NAD-related metabolites in anterior aqueous humor
C57BL6J / Jcl mice (12-week-old young individuals, 18-month-old elderly individuals) were used. After general anesthesia with mixed anesthesia (somnopentyl xylazine), anterior chamber water was immediately collected using a 29G syringe, and NAD among NAD-related metabolites in the anterior chamber water was measured using HPLC.

The results are shown in FIG. It was found that the concentration of NAD + in the anterior chamber water tended to decrease by about 60% in the elderly individuals compared with the young individuals when comparing the young individuals and the elderly 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 saline) was subcutaneously administered, and 30 minutes before the treatment, NMN was administered again at the same concentration. Rats were anesthetized with pentobarbital (64.8 mg / kg) and then anesthetized with eye drops using Benokiseal (Santen Pharmaceutical Co., Ltd.). The dorsal conjunctiva was then incised and the optic nerve and central retinal arteries and veins in the orbit were amputated. Pseudo-surgery was limited to conjunctival incision. Four hours after the amputation, the carotid artery was incised under pentobarbital overanesthesia, and then blood was exsanguinated and sacrificed. The retina was then isolated and immersed in the wells of a 96-well plate containing 100 μL of Neurobasal medium or nicotinamide-free medium (added to either of these media to a final concentration of 0.5 mM if NMN was added). After that, 10 μL of WST-8 (Dojin Kagaku) was added. After incubation at 37 ° C. under 5% CO ₂ for 1 hour, the absorbance (450 nm) of the culture supernatant was measured with a microplate reader to calculate the ratio of treated eyes to simulated surgical eyes.

The results are shown in FIG. In the disease group, marked cell death is induced 4 hours after amputation of the optic nerve and retinal arteries and veins. After cutting and isolating the retina, the viable cell rate is 20% when compared with the control group (medium (1)). However, two subcutaneous doses of NMN on the previous day and the day markedly increased the viable cell rate, which was approximately doubled to 41% (medium + NMN (1)). The same effect can be reproduced by verifying the presence or absence of NMN added after incubation after tissue isolation (medium (2), medium + NMN (2)), and administration of NMN is related to NAD metabolism in the tissue. It is presumed that it contributed to the increase in product concentration and suppressed cell death.

Example 4. Examination using human corneal endothelial cell line

In a study using a human corneal endothelial cell line (B4G12, DSMZ, Germany), a certain amount of a specific inhibitor of NAD synthesis rate-determining enzyme NAMPT and NMN were added based on a nicotinamide-free medium, and the cells were recovered after 48 hours. , The amount of intracellular NAD was analyzed by HPLC.

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

Example 5. Measurement of mitochondrial membrane potential
Immortalized human corneal endothelial cell lines (B4G12, DSMZ, Germany) were seeded on 96-well plates (Corning, NY, USA) and cultured until confluent. Cell Meter® JC-10 Mitochondrial Membrane Potential Assay Kit (AAT Bioquest, Inc) was used to measure the mitochondrial membrane potential.

As a result, as shown in FIG. 6, in the hydrogen peroxide stress group to which NMN was not added, a decrease in mitochondrial membrane potential was observed as compared with the control group cultured in a medium containing neither NMN nor hydrogen peroxide. It was found that the mitochondrial membrane potential was significantly improved in the NMN-added group of 5 uM or more as compared with the hydrogen peroxide stress group in which the hydrogen peroxide was not added. For statistical processing, one way ANOVA and Boferroni were used.

Example 6. Metabolic analysis of lens epithelial cell line 1. Metabolic analysis of lens epithelial cell line Since oxygen is used for electron transport chain and oxidative phosphorylation, mitochondrial activity can be analyzed by using the oxygen consumption rate (OCR) index.

2. 2. Method As the lens epithelial cell line, a cell line established by RIKEN was used. Mitochondrial respiration was measured using the XF Cell Mito Stress Test Kit at 37 ° C with an extracellular Fux analyzer (XFe24; Seahorse Bioscience) according to the manufacturer's recommended protocol.

The mitochondrial stress assay begins with a set of three basic records in a glucose-supplemented medium in which the crystalline epithelial cell line is cultured, followed by 0.5 uM oligomycin (ATP synthase inhibitor), 1uM carbonyl cyanide-p-trifluoro. A total of 12 oxygens, each with 3 consecutive recordings after addition of methoxyphenyl hydrazone (FCCP, ETC conjugate) and 1uM rotenone (Rot, ETC inhibitor) with 1uM antimycin A (AA, ETC inhibitor). Consists of concentration measurement.

Mitochondrial respiration was quantified by measuring changes in oxygen concentration in extracellular medium and described as oxygen consumption rate (OCR; pmole / min) to assess mitochondrial function. See FIG. 7 for each step of the mitochondrial stress assay and the timing of compound addition.

3. 3. Results As shown in FIGS. 8A to 8C, when NMN 500 μM was added before stress loading on mitochondria, mitochondrial respiration activity was significantly increased and ATP production was also increased as compared with no addition. 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, we examined whether the addition of NAD-related metabolites improves the survival rate of corneal cells. The cornea was excised from a primate marmoset (5 years old, male) and stored in an NMN-added corneal preservation solution (Optisol GS®, manufactured by Bausch + Lomb). After one month, the survival rate of corneal cells was calculated using the Cell Counting Kit-8 Kit (Dojin Kagaku Kenkyusho Co., Ltd.). Specifically, a cell suspension prepared at 5000 cells / well of corneal cells was inoculated into wells of a microplate by 100 ul each. The drug was then precultured in a 37 ° C CO ₂ incubator and the drug was added to each well. After further culturing in a CO ₂ incubator at 37 ° C. for a certain period of time, a CCK-8 solution was added. A color reaction was performed in a CO ₂ incubator at 37 ° C, the absorbance of the cells at 450 nm was measured with a microplate reader, and the survival rate of the corneal cells was calculated from the measured values.

As shown in FIG. 9, the group of cells stored in the corneal preservation solution supplemented with NMN (NMN) was compared with the group of cells stored in the conventional corneal preservation solution not added NMN (Ctrl), and the cells survived. The rate has improved by 26%. This suggests the usefulness of NMN as an additive for the corneal preservation solution.

Example 8: Effect of NAD-related metabolites on the survival rate of eye tissue In this experiment, it was verified whether or not the addition of NAD-related metabolites improved the survival rate of eye tissue.

The eyeballs of mice (8 years old, male Claire Japan) were collected and stored in an NMN-added whole eyeball preservation solution (EP / II, Kaken Pharmaceutical Co., Ltd.). Two weeks later, cell viability was calculated using the Cell Counting Kit-8 kit (Dojindo) and compared to controls. The method for calculating the cell viability using the Cell Counting Kit-8 Kit (Dojin Kagaku Kenkyusho Co., Ltd.) is as described in Example 6.

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

Example 9. Verification of usefulness as an eye surgery perfusate
15 minutes intraoperative perforation of the anterior chamber of a rabbit (New Zealand White rabbit: 12 weeks old) with saline perfusate (NMN-free group) or NMN-added perfusate (NMN-added group). A simulated model of cataract surgery was used. The corneal thickness (μm) on the day after surgery was compared with that before surgery. Student's t-test and paired t-test were used for statistical analysis of the data, and p <0.05 was judged to be significantly different.

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 the 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 eye health, promoting eye health, or preventing eye aging. be able to. In addition, the pharmaceutical composition of the present invention containing a 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 (16)

At least one NAD-related metabolite selected from the group consisting of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), a pharmaceutically acceptable salt thereof, or a hydroxyl group thereof is acetic acid, formic acid, or Increased amounts of NAD-related metabolites in the anterior chamber water of prodrug, a compound esterified with benzoic acid , increased survival of corneal cells, increased mitochondrial membrane potential of corneal endothelial cells, or of crystalline epithelial cells Use for increased mitochondrial activity (except medical practice). A NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a hydroxyl group thereof, which is at least one selected from the group consisting of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), is acetic acid, formic acid, or. Increased amount of NAD-related metabolites in anterior chamber water, increased viability of corneal cells, increased mitochondrial membrane potential of corneal endothelial cells, or crystalline body to which prodrug, a compound esterified with benzoic acid, was added. Food for increased mitochondrial activity of epithelial cells. The food according to claim 2, which is a beverage, a supplement, a dietary supplement, a food for specified health use, a nutritionally functional food, or a food with a functional claim. The food according to claim 3, which is in the form of tablets, hard capsules, soft capsules, seamless capsules, powders, fine granules, granules, chewables, gummies, jellies, liquids (drinks), troches, or pastes. The food according to any one of claims 2 to 4, wherein the daily intake of the NAD-related metabolite is 0.1 pg to 2000 mg. The food according to any one of claims 2 to 5, wherein the NAD-related metabolite is nicotinamide mononucleotide (NMN). Prepare foods to be used to increase the amount of NAD-related metabolites in anterior chamber water, improve the viability of corneal cells, increase the mitochondrial potential of corneal endothelial cells, or increase the activity of mitochondria of crystalline epithelial cells. NAD-related metabolites, pharmaceutically acceptable salts thereof, or hydroxyl groups thereof, which are at least one selected from the group consisting of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), are acetic acid . Use of prodrugs, compounds esterified with formic acid, or benzoic acid . A NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a hydroxyl group thereof, which is at least one selected from the group consisting of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), is acetic acid, formic acid, or. Increased amount of NAD-related metabolites in anterior chamber water, increased viability of corneal cells, increased mitochondrial membrane potential of corneal endothelial cells, or crystalline body containing prodrug, a compound esterified with benzoic acid . An external preparation for increasing the activity of mitochondria in epithelial cells. The external preparation according to claim 8, which is a quasi-drug or a cosmetic product. 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 bathing agent. Agent. The external preparation according to any one of claims 8 to 10, wherein the NAD-related metabolite is nicotinamide mononucleotide (NMN). A NAD-related metabolite, a pharmaceutically acceptable salt thereof, or a hydroxyl group thereof, which is at least one selected from the group consisting of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), is acetic acid, formic acid, or. Increased amount of NAD-related metabolites in anterior chamber water, improved corneal cell viability, corneal endothelium, containing prodrug, a compound esterified with benzoic acid , and a pharmacologically acceptable carrier. A pharmaceutical composition for increasing the mitochondrial membrane potential of cells, or increasing the activity of mitochondria of crystalline epithelial cells. The pharmaceutical composition according to claim 12, wherein the daily intake of the NAD-related metabolite is 0.1 pg to 2000 mg. The pharmaceutical composition according to claim 12 or 13 , which is a powder, a granule, a fine granule, a tablet, a pill, a troche, a capsule, a chewable agent, or a syrup agent. 12 Or the pharmaceutical composition according to 13 . The pharmaceutical composition according to any one of claims 12 to 15 , wherein the NAD-related metabolite is nicotinamide mononucleotide (NMN).

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