WO2016171152A1 - Therapeutic agent, improving agent, and preventative agent for corneal disorders - Google Patents

Therapeutic agent, improving agent, and preventative agent for corneal disorders Download PDF

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WO2016171152A1
WO2016171152A1 PCT/JP2016/062452 JP2016062452W WO2016171152A1 WO 2016171152 A1 WO2016171152 A1 WO 2016171152A1 JP 2016062452 W JP2016062452 W JP 2016062452W WO 2016171152 A1 WO2016171152 A1 WO 2016171152A1
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agent
smoking
corneal
nicotinamide
nmn
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PCT/JP2016/062452
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French (fr)
Japanese (ja)
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明弘 樋口
一男 坪田
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学校法人 慶應義塾
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom

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  • the present invention relates to a corneal disorder therapeutic agent, ameliorating agent or prophylactic agent comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
  • Nicotinamide mononucleotide and nicotinamide riboside are intermediate metabolites of the coenzyme NAD + (nicotinamide adenine dinucleotide) that functions in the metabolic pathway, suggesting its involvement in aging and its potential application in anti-aging medicine (Non-Patent Document 1).
  • nicotinamide mononucleotide and nicotinamide riboside have not been known to be effective for the treatment, improvement or prevention of corneal disorders.
  • One of the objects of the present invention is to provide a novel therapeutic agent, ameliorating agent or preventing agent for corneal disorders.
  • the present inventor made a surprising discovery that nicotinamide mononucleotide or nicotinamide riboside is effective for the treatment, amelioration or prevention of corneal disorders. Based on this discovery, the present invention has been completed through further studies.
  • the present invention includes the following aspects: Item 1. A therapeutic agent, ameliorating agent or prophylactic agent for corneal disorder corneal injury, comprising as an active ingredient nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof. Item 2. The therapeutic agent, ameliorating agent or prophylactic agent according to Item 1, which is an eye drop. Item 3. Antioxidant potentiator for treating, ameliorating or preventing corneal disorder corneal damage, comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient. Item 4. The enhancer according to item 3, which is an eye drop. Item 5.
  • Treatment or improvement of corneal disorder comprising administering an effective amount of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof to a person in need of treatment, improvement or prevention Or prevention methods.
  • Nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for use in the treatment, amelioration or prevention of a corneal disorder.
  • Item 7 Use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for producing a medicament for treating, ameliorating or preventing a corneal disorder.
  • a novel therapeutic agent, ameliorating agent or preventing agent for corneal disorders is provided.
  • the graph which shows the measurement result of a body weight The graph which shows the measurement result of tear volume.
  • the graph which shows a fluorescence score The graph which shows the expression level of the antioxidant related gene in a NMN instillation treatment group (Smoking + 30mM NMN eye drop) by the change rate (Fold change) with respect to the smoking treatment group (Smoking).
  • the ⁇ Ct value is a value that is inversely proportional to the amount of target mRNA in the sample.
  • the present invention is a corneal disorder therapeutic agent, ameliorating agent or prophylactic agent comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
  • treatment means cure of a disease or symptom or suppression of a symptom.
  • Immprovement means improvement of a disease or symptom (partial cure) or partial suppression of a symptom.
  • prevention means preventing the onset of a disease or symptom.
  • the therapeutic agent, ameliorating agent or preventive agent of the present invention comprises nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
  • Nicotinamide mononucleotide is a compound represented by the following chemical formula.
  • Nicotinamide riboside is a compound represented by the following chemical formula.
  • Pharmacologically acceptable salts include acid addition salts and base addition salts.
  • metal salts for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
  • ammonium salts and salts with inorganic acids for example, Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, salts with inorganic acids such as phosphoric acid, etc.
  • organic acid salts eg acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid
  • salts with organic acids such as succinic acid, methanesulfonic acid, and p-toluenesulfonic acid).
  • Nicotinamide mononucleotide and nicotinamide riboside are known compounds and can be produced by known production methods.
  • the therapeutic agent, ameliorating agent or preventive agent of the present invention is intended for corneal disorders.
  • the cornea is composed of three layers of epithelium, parenchyma and endothelium from the surface side.
  • the corneal disorder includes a corneal epithelial disorder in which the corneal epithelium is damaged by a stimulus such as dust or an infection or a corneal parenchymal disorder in which the corneal stroma is damaged or clouded.
  • a corneal epithelial disorder in which the corneal epithelium is damaged by a stimulus such as dust or an infection
  • a corneal parenchymal disorder in which the corneal stroma is damaged or clouded.
  • Corneal disorders include corneal damage (Corneal injury). Corneal damage refers to a wound on the cornea located on the surface of the eyeball. Corneal damage includes traumatic corneal damage, corneal damage, corneal erosion, corneal ulcer and the like. More specifically, based on corneal damage, disease (eg, viral or bacterial infection) resulting from physical impact, mechanical impact or contact with chemicals (eg, strong alkalis). Examples include, but are not limited to, corneal damage, corneal damage caused by contact lens wearing, and corneal damage caused by surgery on the cornea (eg, LASIK surgery).
  • the disorder of the corneal epithelium may extend to the corneal stroma. In such a case, the situation becomes very dangerous for the cornea.
  • the corneal stroma is damaged, conventionally, intracorneal steroid injection or finally corneal transplantation is required, and it has been desired to be cured at the stage of corneal epithelial damage, which is less burdensome for the patient.
  • dry eye which is a pathological condition in which the amount of tear secretion decreases or the quality of tears, even if the amount is sufficient, reduces the ability to moisturize the surface of the eye is reduced. And “corneal damage”.
  • the expression level of an antioxidant-related gene encoding an antioxidant enzyme is increased by administration of the therapeutic agent, ameliorating agent or prophylactic agent of the present invention.
  • an effect of treating, improving or preventing a corneal disorder is exhibited by increasing the expression level of the gene and enhancing the antioxidant ability. Therefore, the present invention also provides an antioxidant capacity enhancer for treating, ameliorating or preventing corneal disorders, comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient. To do.
  • an antioxidant-related gene encoding an antioxidant enzyme (anti-oxidative enzyme)
  • various genes that enhance the antioxidant capacity of cells are known.
  • GST ⁇ 2 Glutathione S-transferase 2 gene
  • Gpx4 Glutathione peroxidase 4
  • Gclm Glutamate-cycteine ligase
  • Txnrd Thioredoxin reductase 1 gene and the like
  • the therapeutic agent, improver or preventive agent of the present invention can also be provided as a pharmaceutical composition for preventing and / or treating presbyopia containing the compound of the present invention as an active ingredient.
  • the therapeutic agent, ameliorating agent or preventive agent of the present invention can be used for mammals including humans (for example, humans, cows, horses, pigs, monkeys, dogs, cats, mice, rats, rabbits, goats, sheep, etc.). And preferably used for humans.
  • various dosage forms can be adopted depending on the purpose by mixing with a pharmaceutically acceptable carrier as necessary.
  • the form is not particularly limited, and examples thereof include eye drops, oral preparations, injections, suppositories, ointments, patches, and the like, and eye drops are preferable.
  • Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • the eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments and the like.
  • Such a preparation is prepared as a composition suitable for the dosage form, if necessary, as a pharmaceutically acceptable carrier, for example, an isotonic agent, a chelating agent, a stabilizer, a pH adjusting agent, a preservative, an antioxidant. , A solubilizing agent, a thickening agent, and the like, and can be produced by a method known to those skilled in the art.
  • Isotonic agents include glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol and other sugars, glycerin, polyethylene glycol, propylene glycol and other polyhydric alcohols, sodium chloride, potassium chloride, calcium chloride and other inorganic salts
  • the blending amount is preferably 0 to 5% by weight based on the total amount of the composition.
  • Chelating agents include edetates such as disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate Citric acid and the like, and the blending amount thereof is preferably 0 to 0.2% by weight based on the total amount of the composition.
  • edetates such as disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate Citric acid and the like, and the blending amount thereof is preferably 0 to 0.2% by weight based on the total amount of the composition.
  • the stabilizer examples include sodium bisulfite and the like, and the blending amount is preferably 0 to 1% by weight with respect to the total amount of the composition.
  • Examples of the pH adjuster include acids such as hydrochloric acid, carbonic acid, acetic acid and citric acid, and further alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, Examples thereof include alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, bases such as trometamol, and the like.
  • the blending amount is preferably 0 to 20% by weight based on the total amount of the composition.
  • sorbic acid potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid ester such as propyl paraoxybenzoate, butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride,
  • quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad (polydronium chloride), polyhexamethylene biguanide, chlorhexidine and the like. 0.2% by weight is preferred.
  • antioxidant examples include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like, and the blending amount is preferably 0 to 0.4% by weight with respect to the total amount of the composition.
  • solubilizers include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc., and the blending amount is based on the total amount of the composition. 0 to 3% by weight is preferred.
  • the thickening agent examples include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and the like.
  • the content is preferably 0 to 70% by weight based on the total amount of the composition.
  • the above-mentioned desired components may be sterilized purified water, physiological saline, aqueous solvents such as buffer solutions (for example, borate buffer solution, phosphate buffer solution, etc.), cottonseed oil, soybean oil, It can be carried out by dissolving or suspending in a non-aqueous solvent such as sesame oil or peanut oil, adjusting to a predetermined osmotic pressure, and performing sterilization such as filtration sterilization.
  • aqueous solvents such as buffer solutions (for example, borate buffer solution, phosphate buffer solution, etc.), cottonseed oil, soybean oil.
  • an ointment base can be included in addition to the various components described above.
  • the ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying an oil phase and an aqueous phase with a surfactant; hydroxypropyl methylcellulose, carboxymethylcellulose
  • a water-soluble base composed of polyethylene glycol or the like is preferred.
  • a hydrocarbon gel ointment base is exemplified as a specific example of the oily base, and commercially available products such as Platibase (trademark) can be used.
  • the dose of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof, which is an active ingredient of the therapeutic agent, ameliorating agent or prophylactic agent of the present invention, is determined based on the patient's body weight, age, sex, symptom, administration Usually, for adults, the active ingredient is about 0.1 ⁇ g to about 1 g per kg of body weight, about 1 ⁇ g to about 500 mg per day, about 10 ⁇ g to about 500 mg once or several times for adults. Divided into two doses. In the case of liquid eye drops, 0.01 to 50 mg / mL, preferably 0.1 to 10 mg / mL, may be instilled 1 to several drops at a time several times a day.
  • the present invention is also a method for the treatment, amelioration or prevention of corneal disorders, which requires treatment, improvement, prevention, etc. of an effective amount of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof.
  • a method comprising the step of administering to said person.
  • the present invention also provides use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for treating, ameliorating or preventing corneal disorders.
  • the present invention also provides the use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for the manufacture of a medicament for the treatment, amelioration or prevention of corneal disorders.
  • Example 1 Healing Efficacy Test Using Smoking Rats As described in WO2012 / 161112, a keratoconjunctival epithelial disorder model was prepared by the following method, and the healing effect of nicotinamide mononucleotide on keratoconjunctival epithelial disorder was evaluated.
  • a PBS solution concentration: 30 mM
  • nicotinamide mononucleotide CAS 1094-61-7
  • the damaged part of the corneal epithelium was stained with the fluorescent dye fluorescein.
  • the degree of corneal epithelial damage was determined by dividing the entire cornea into nine parts, upper, middle, lower, and left middle right, and scoring the damage for each part according to the following criteria, and obtaining the total value. Thereafter, the score values were compared between groups. In the statistical analysis, the significant difference of each group was tested using the Dunnett method. In order to make a fair evaluation, from the start of instillation to scoring of corneal epithelial disorder, the contents of the drug solution administered to each group were blinded and collated after scoring.
  • Body weight is significantly reduced by smoking treatment, but P value is 0.79 between NMN ophthalmic group (Smoking + NMN) and smoking treatment group (Smoking) (Smoking vs Smoking + NMN), significantly different (FIG. 1).
  • P-values between -smoking vs Smoking + NMN were P ⁇ 0.05, respectively.
  • Tear volume is also significantly reduced by smoking treatment, but P value is 0.80 between NMN ophthalmic group (Smoking + NMN) and smoking treatment group (Smoking) (Smoking vs Smoking + NMN) There was no significant difference (FIG. 2). This indicates that tear volume is not increased by NMN instillation.
  • Fluorescent staining score (Fluorescein score) is significantly increased by smoking treatment (Non-smoking v.s. Smoking: P ⁇ 0.005).
  • NMN ophthalmic group (Smoking + NMN) (fluorescence score average value: 2.1 ⁇ 1.0)
  • smoking treatment group (smoking score average value: 4.0 ⁇ 1.0)
  • corneal condition by NMN instillation was observed (FIG. 3).
  • the P value of the control group (Non-smoking) and the smoking treatment group (Smoking) (Non-smoking vs Smoking) is P ⁇ 0.005, and the control group (Non-smoking) and NMN ophthalmic group (Smoking + The P-value between (NMN) and (Non-smoking vs Smoking + NMN) was P> 0.05.
  • the therapeutic agent, ameliorating agent or prophylactic agent of the present invention is effective for corneal injury, particularly corneal injury.
  • Example 2 Measurement of the expression level of an antioxidant-related gene The expression level of an antioxidant-related gene in the NMN eye drop group rats in Example 1 was measured.
  • GST ⁇ 2 Glutathione S-transferase ⁇ 2
  • Gpx4 Glutathione peroxidase 4
  • Gclm Glutamate-cycteine ligase

Abstract

The invention provides a therapeutic agent, an improving agent, and a preventative agent for corneal disorders, the agents having as an active ingredient nicotinamide mononucleotide or nicotinamide riboside or a pharmaceutically acceptable salt thereof.

Description

角膜障害の治療剤、改善剤または予防剤Agents for treating, improving or preventing corneal disorders
　本出願は、２０１５年４月２０日に出願された、日本国特許出願第２０１５－０８６２５７号明細書（その開示全体が参照により本明細書中に援用される）に基づく優先権を主張する。 This application claims priority based on Japanese Patent Application No. 2015-086257, filed Apr. 20, 2015 (the entire disclosure of which is incorporated herein by reference).
　本発明は、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害の治療剤、改善剤または予防剤に関する。 The present invention relates to a corneal disorder therapeutic agent, ameliorating agent or prophylactic agent comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
　ニコチンアミドモノヌクレオチドおよびニコチンアミドリボシドは、代謝経路で機能する補酵素NAD+（ニコチンアミドアデニンジヌクレオチド）の中間代謝産物であり、老化への関与が示唆され、アンチエイジング医薬への応用が期待されている（非特許文献１）。 Nicotinamide mononucleotide and nicotinamide riboside are intermediate metabolites of the coenzyme NAD + (nicotinamide adenine dinucleotide) that functions in the metabolic pathway, suggesting its involvement in aging and its potential application in anti-aging medicine (Non-Patent Document 1).
　しかしながら、ニコチンアミドモノヌクレオチドやニコチンアミドリボシドが、角膜障害の治療、改善または予防に有効であることは知られていなかった。 However, nicotinamide mononucleotide and nicotinamide riboside have not been known to be effective for the treatment, improvement or prevention of corneal disorders.
　本発明の目的の一つは、新規な角膜障害の治療剤、改善剤または予防剤を提供することである。 One of the objects of the present invention is to provide a novel therapeutic agent, ameliorating agent or preventing agent for corneal disorders.
　本発明者は、鋭意検討の結果、ニコチンアミドモノヌクレオチドまたはニコチンアミドリボシドが、角膜障害の治療、改善または予防に有効であるとの驚くべき発見をした。本発明は、この発見に基づき、さらに検討を重ねて完成したものである。 As a result of intensive studies, the present inventor made a surprising discovery that nicotinamide mononucleotide or nicotinamide riboside is effective for the treatment, amelioration or prevention of corneal disorders. Based on this discovery, the present invention has been completed through further studies.
　すなわち、本発明は以下の態様を包含する：
　項１、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害角膜損傷の治療剤、改善剤または予防剤。
　項２、点眼薬である、項１に記載の治療剤、改善剤または予防剤。
　項３、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害角膜損傷を治療、改善または予防するための、抗酸化能増強剤。
　項４、点眼薬である、項３に記載の増強剤。
　項５、有効量のニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を、治療、改善若しくは予防を必要としている者に投与する工程を含む、角膜障害の治療、改善または予防方法。
　項６、角膜障害の治療、改善または予防に使用するための、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩。
　項７、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩の角膜障害の治療、改善または予防するための医薬を製造するための使用。 That is, the present invention includes the following aspects:
Item 1. A therapeutic agent, ameliorating agent or prophylactic agent for corneal disorder corneal injury, comprising as an active ingredient nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof.
Item 2. The therapeutic agent, ameliorating agent or prophylactic agent according to Item 1, which is an eye drop.
Item 3. Antioxidant potentiator for treating, ameliorating or preventing corneal disorder corneal damage, comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
Item 4. The enhancer according to item 3, which is an eye drop.
Item 5. Treatment or improvement of corneal disorder, comprising administering an effective amount of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof to a person in need of treatment, improvement or prevention Or prevention methods.
Item 6. Nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for use in the treatment, amelioration or prevention of a corneal disorder.
Item 7. Use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for producing a medicament for treating, ameliorating or preventing a corneal disorder.
　本発明によれば、新規な角膜障害の治療剤、改善剤または予防剤が提供される。 According to the present invention, a novel therapeutic agent, ameliorating agent or preventing agent for corneal disorders is provided.
体重の測定結果を示すグラフ。The graph which shows the measurement result of a body weight. 涙量の測定結果を示すグラフ。The graph which shows the measurement result of tear volume. 蛍光スコアを示すグラフ。The graph which shows a fluorescence score. NMN点眼処理群（Smoking + 30mM NMN eye drop）における抗酸化関連遺伝子の発現量を、喫煙処理群（Smoking）に対する変化の割合（Fold change）により示すグラフ。ΔＣｔ値は試料中の標的mRNAの量に反比例する値である。The graph which shows the expression level of the antioxidant related gene in a NMN instillation treatment group (Smoking + 30mM NMN eye drop) by the change rate (Fold change) with respect to the smoking treatment group (Smoking). The ΔCt value is a value that is inversely proportional to the amount of target mRNA in the sample.
　本発明は、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害の治療剤、改善剤または予防剤である。 The present invention is a corneal disorder therapeutic agent, ameliorating agent or prophylactic agent comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
　本明細書において、「治療」とは、疾患若しくは症状の治癒又は或いは症状の抑制を意味する。「改善」とは、疾患若しくは症状の改善（部分的な治癒）又は或いは症状の部分的な抑制を意味する。「予防」とは、疾患又は症状の発現を未然に防ぐことを意味する。 In this specification, “treatment” means cure of a disease or symptom or suppression of a symptom. “Improvement” means improvement of a disease or symptom (partial cure) or partial suppression of a symptom. “Prevention” means preventing the onset of a disease or symptom.
　本発明の治療剤、改善剤または予防剤は、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする。 The therapeutic agent, ameliorating agent or preventive agent of the present invention comprises nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
　ニコチンアミドモノヌクレオチド（Nicotinamide mononucleotide、NMN）は、下記化学式で表される化合物である。 Nicotinamide mononucleotide (NMN) is a compound represented by the following chemical formula.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　ニコチンアミドリボシド（Nicotinamide riboside）は、下記化学式で表される化合物である。 Nicotinamide riboside is a compound represented by the following chemical formula.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　薬理学的に許容される塩としては、酸付加塩及び塩基付加塩が挙げられる。具体的には、金属塩（例えば、ナトリウム塩、カリウム塩などのアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩など。）、アンモニウム塩、無機酸との塩（例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸など無機酸との塩など。）、有機酸との塩（例えば、酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸などの有機酸との塩など）が挙げられる。 Pharmacologically acceptable salts include acid addition salts and base addition salts. Specifically, metal salts (for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt), ammonium salts and salts with inorganic acids (for example, , Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, salts with inorganic acids such as phosphoric acid, etc.), organic acid salts (eg acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid) And salts with organic acids such as succinic acid, methanesulfonic acid, and p-toluenesulfonic acid).
　ニコチンアミドモノヌクレオチド及びニコチンアミドリボシドは公知の化合物であり、公知の製造方法により製造することができる。 Nicotinamide mononucleotide and nicotinamide riboside are known compounds and can be produced by known production methods.
　本発明の治療剤、改善剤または予防剤は、角膜障害（Corneal disorder）を対象とする。角膜は、表面側から上皮、実質及び内皮の三層から構成される。角膜障害は、角膜上皮がゴミなどによる刺激や感染症等の疾病により損傷を受ける角膜上皮障害、角膜実質に傷や混濁が起こる角膜実質障害を包含する。角膜がゴミなどによる刺激や微生物感染により損傷を受け、角膜障害が生じると、強い痛みを伴う。 The therapeutic agent, ameliorating agent or preventive agent of the present invention is intended for corneal disorders. The cornea is composed of three layers of epithelium, parenchyma and endothelium from the surface side. The corneal disorder includes a corneal epithelial disorder in which the corneal epithelium is damaged by a stimulus such as dust or an infection or a corneal parenchymal disorder in which the corneal stroma is damaged or clouded. When the cornea is damaged by irritation caused by dust or microbial infection, and corneal damage occurs, it is accompanied by intense pain.
　角膜障害は、角膜損傷（Corneal injury（Corneal damage））を包含する。角膜損傷とは、眼球の表面に位置する角膜の傷を意味する。角膜損傷は、外傷性の角膜障害、角膜傷害、角膜びらん、角膜潰瘍等を包含する。より具体的には、物理的な衝撃、機械的な衝撃若しくは化学薬品（例えば、強アルカリ。）への接触に起因する角膜の損傷、疾病（例えば、ウィルス性または細菌性の感染。）に基づく角膜の損傷、コンタクトレンズの装着に起因する角膜の損傷、角膜に対する手術（例えば、LASIK手術）に起因する角膜の損傷が例示されるが、これに限定されない。 Corneal disorders include corneal damage (Corneal injury). Corneal damage refers to a wound on the cornea located on the surface of the eyeball. Corneal damage includes traumatic corneal damage, corneal damage, corneal erosion, corneal ulcer and the like. More specifically, based on corneal damage, disease (eg, viral or bacterial infection) resulting from physical impact, mechanical impact or contact with chemicals (eg, strong alkalis). Examples include, but are not limited to, corneal damage, corneal damage caused by contact lens wearing, and corneal damage caused by surgery on the cornea (eg, LASIK surgery).
　角膜上皮の障害は、角膜実質に及ぶ場合がある。このような場合、角膜にとって非常に危険な状況に陥る。しかしながら角膜実質に障害が及んだ場合は、従来、角膜実質内ステロイド注射あるいは最終的に角膜移植が必要となり、患者に負担の少ない角膜上皮障害の段階で治癒させることが望ましかった。 The disorder of the corneal epithelium may extend to the corneal stroma. In such a case, the situation becomes very dangerous for the cornea. However, when the corneal stroma is damaged, conventionally, intracorneal steroid injection or finally corneal transplantation is required, and it has been desired to be cured at the stage of corneal epithelial damage, which is less burdensome for the patient.
　ただし、本発明のある態様においては、涙の分泌量が減ったり、量は十分でも涙の質が低下することによって、目の表面を潤す力が低下した病態であるドライアイは、「角膜障害」及び「角膜損傷」には含まれない。 However, in one aspect of the present invention, dry eye, which is a pathological condition in which the amount of tear secretion decreases or the quality of tears, even if the amount is sufficient, reduces the ability to moisturize the surface of the eye is reduced. And “corneal damage”.
　後述の実施例に示すように、本発明の治療剤、改善剤または予防剤の投与により、抗酸化酵素（anti-oxidative enzyme）をコードする抗酸化関連遺伝子の発現量が増大する。本発明を束縛するものではないが、当該遺伝子の発現量増大し、抗酸化能が増強されることにより、角膜障害の治療、改善または予防の効果が発揮される。従って、本発明はニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害を治療、改善または予防するための、抗酸化能増強剤をも提供する。 As shown in Examples described later, the expression level of an antioxidant-related gene encoding an antioxidant enzyme (anti-oxidative enzyme) is increased by administration of the therapeutic agent, ameliorating agent or prophylactic agent of the present invention. Although not restricting the present invention, an effect of treating, improving or preventing a corneal disorder is exhibited by increasing the expression level of the gene and enhancing the antioxidant ability. Therefore, the present invention also provides an antioxidant capacity enhancer for treating, ameliorating or preventing corneal disorders, comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient. To do.
　ここで、抗酸化酵素（anti-oxidative enzyme）をコードする抗酸化関連遺伝子としては、細胞の抗酸化能を増強する種々のものが公知である。特に限定されるものではないが、GSTμ2（Glutathione S-transferase μ2）遺伝子、Gpx4（Glutathione peroxidase 4）遺伝子、Gclm（Glutamate-cycteine ligase）遺伝子及びTxnrd（Thioredoxin reductase 1）遺伝子などが挙げられる。 Here, as an antioxidant-related gene encoding an antioxidant enzyme (anti-oxidative enzyme), various genes that enhance the antioxidant capacity of cells are known. Although not particularly limited, GSTμ2 (Glutathione S-transferase 2) gene, Gpx4 (Glutathione peroxidase 4) gene, Gclm (Glutamate-cycteine ligase) gene, Txnrd (Thioredoxin reductase 1) gene and the like can be mentioned.
　本発明の治療剤、改善剤または予防剤は、本発明の化合物を有効成分として含有する老視を予防及び／又は治療するための医薬組成物としても提供されうる。 The therapeutic agent, improver or preventive agent of the present invention can also be provided as a pharmaceutical composition for preventing and / or treating presbyopia containing the compound of the present invention as an active ingredient.
　本発明の治療剤、改善剤または予防剤は、ヒトを含む哺乳動物（例えばヒト、ウシ、ウマ、ブタ、サル、イヌ、ネコ、マウス、ラット、ウサギ、ヤギ、ヒツジ等）に用いることが可能であり、好ましくはヒトに用いられる。 The therapeutic agent, ameliorating agent or preventive agent of the present invention can be used for mammals including humans (for example, humans, cows, horses, pigs, monkeys, dogs, cats, mice, rats, rabbits, goats, sheep, etc.). And preferably used for humans.
　本発明の治療剤、改善剤または予防剤を医薬組成物として提供する場合、必要に応じて薬学的に許容される担体と配合し、目的に応じて各種の投与形態を採用可能である。該形態は特に限定されず、例えば、点眼剤、経口剤、注射剤、坐剤、軟膏剤、貼付剤等が挙げられ、点眼剤が好ましい。これらの投与形態は、各々当業者に公知慣用の製剤方法により製造できる。点眼剤は、水性点眼剤、非水性点眼剤、懸濁性点眼剤、乳濁性点眼剤、眼軟膏等のいずれでもよい。このような製剤は、投与形態に適した組成物として、必要に応じて薬学的に許容される担体、例えば等張化剤、キレート剤、安定化剤、ｐＨ調節剤、防腐剤、抗酸化剤、溶解補助剤、粘稠化剤等を配合し、当業者に公知の製剤方法により製造できる。 When providing the therapeutic agent, improver or preventive agent of the present invention as a pharmaceutical composition, various dosage forms can be adopted depending on the purpose by mixing with a pharmaceutically acceptable carrier as necessary. The form is not particularly limited, and examples thereof include eye drops, oral preparations, injections, suppositories, ointments, patches, and the like, and eye drops are preferable. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art. The eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments and the like. Such a preparation is prepared as a composition suitable for the dosage form, if necessary, as a pharmaceutically acceptable carrier, for example, an isotonic agent, a chelating agent, a stabilizer, a pH adjusting agent, a preservative, an antioxidant. , A solubilizing agent, a thickening agent, and the like, and can be produced by a method known to those skilled in the art.
　等張化剤としては、グルコース、トレハロース、ラクトース、フルクトース、マンニトール、キシリトール、ソルビトール等の糖類、グリセリン、ポリエチレングリコール、プロピレングリコール等の多価アルコール類、塩化ナトリウム、塩化カリウム、塩化カルシウム等の無機塩類等が挙げられ、その配合量は、組成物全量に対して０～５重量％が好ましい。 Isotonic agents include glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol and other sugars, glycerin, polyethylene glycol, propylene glycol and other polyhydric alcohols, sodium chloride, potassium chloride, calcium chloride and other inorganic salts The blending amount is preferably 0 to 5% by weight based on the total amount of the composition.
　キレート剤としては、エデト酸二ナトリウム、エデト酸カルシウム二ナトリウム、エデト酸三ナトリウム、エデト酸四ナトリウム、エデト酸カルシウム等のエデト酸塩類、エチレンジアミン四酢酸塩、ニトリロ三酢酸又はその塩、ヘキサメタリン酸ソーダ、クエン酸等が挙げられ、その配合量は、組成物全量に対して０～０.２重量％が好ましい。 Chelating agents include edetates such as disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate Citric acid and the like, and the blending amount thereof is preferably 0 to 0.2% by weight based on the total amount of the composition.
　安定化剤としては、亜硫酸水素ナトリウム等が挙げられ、その配合量は、組成物全量に対して０～１重量％が好ましい。 Examples of the stabilizer include sodium bisulfite and the like, and the blending amount is preferably 0 to 1% by weight with respect to the total amount of the composition.
　ｐＨ調節剤としては、塩酸、炭酸、酢酸、クエン酸等の酸が挙げられ、さらに水酸化ナトリウム、水酸化カリウムなどのアルカリ金属水酸化物、炭酸ナトリウムなどのアルカリ金属炭酸塩又は炭酸水素塩、酢酸ナトリウムなどのアルカリ金属酢酸塩、クエン酸ナトリウムなどのアルカリ金属クエン酸塩、トロメタモール等の塩基等が挙げられ、その配合量は、組成物全量に対して０～２０重量％が好ましい。 Examples of the pH adjuster include acids such as hydrochloric acid, carbonic acid, acetic acid and citric acid, and further alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, Examples thereof include alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, bases such as trometamol, and the like. The blending amount is preferably 0 to 20% by weight based on the total amount of the composition.
　防腐剤としては、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等のパラオキシ安息香酸エステル、グルコン酸クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム等の第４級アンモニウム塩、アルキルポリアミノエチルグリシン、クロロブタノール、ポリクォッド（塩化ポリドロニウム）、ポリヘキサメチレンビグアニド、クロルヘキシジン等が挙げられ、その配合量は、組成物全量に対して０～０.２重量％が好ましい。 As preservatives, sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid ester such as propyl paraoxybenzoate, butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, Examples thereof include quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad (polydronium chloride), polyhexamethylene biguanide, chlorhexidine and the like. 0.2% by weight is preferred.
　抗酸化剤としては、亜硫酸水素ナトリウム、乾燥亜硫酸ナトリウム、ピロ亜硫酸ナトリウム、濃縮混合トコフェロール等が挙げられ、その配合量は、組成物全量に対して０～０.４重量％が好ましい。 Examples of the antioxidant include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like, and the blending amount is preferably 0 to 0.4% by weight with respect to the total amount of the composition.
　溶解補助剤としては、安息香酸ナトリウム、グリセリン、Ｄ－ソルビトール、ブドウ糖、プロピレングリコール、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、Ｄ－マンニトール等が挙げられ、その配合量は、組成物全量に対して０～３重量％が好ましい。 Examples of solubilizers include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc., and the blending amount is based on the total amount of the composition. 0 to 3% by weight is preferred.
　粘稠化剤としては、ポリエチレングリコール、メチルセルロース、エチルセルロース、カルメロースナトリウム、キサンタンガム、コンドロイチン硫酸ナトリウム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール等が挙げられ、その配合量は、組成物全量に対して０～７０重量％が望ましい。 Examples of the thickening agent include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and the like. The content is preferably 0 to 70% by weight based on the total amount of the composition.
　点眼剤を調製する場合、例えば、所望の上記成分を滅菌精製水、生理食塩水、緩衝液（例えば、ホウ酸緩衝液、リン酸緩衝液など。）等の水性溶剤、又は綿実油、大豆油、ゴマ油、落花生油等の植物油等の非水性溶剤に溶解又は懸濁させ、所定の浸透圧に調整し、濾過滅菌等の滅菌処理を施すことにより行うことができる。 When preparing eye drops, for example, the above-mentioned desired components may be sterilized purified water, physiological saline, aqueous solvents such as buffer solutions (for example, borate buffer solution, phosphate buffer solution, etc.), cottonseed oil, soybean oil, It can be carried out by dissolving or suspending in a non-aqueous solvent such as sesame oil or peanut oil, adjusting to a predetermined osmotic pressure, and performing sterilization such as filtration sterilization.
　尚、眼軟膏剤を調製する場合は、前記各種の成分の他に、軟膏基剤を含むことができる。前記軟膏基剤としては、特に限定されないが、ワセリン、流動パラフィン、ポリエチレン等の油性基剤；油相と水相とを界面活性剤等により乳化させた乳剤性基剤；ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ポリエチレングリコール等からなる水溶性基剤等が好ましく挙げられる。油性基剤の具体例として炭化水素ゲル軟膏基剤が例示され、プラチベース（商標）等の市販品を使用することができる。 In addition, when preparing an eye ointment, an ointment base can be included in addition to the various components described above. The ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying an oil phase and an aqueous phase with a surfactant; hydroxypropyl methylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred. A hydrocarbon gel ointment base is exemplified as a specific example of the oily base, and commercially available products such as Platibase (trademark) can be used.
　本発明の治療剤、改善剤または予防剤の有効成分であるニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩の用量は、患者の体重、年齢、性別、症状、投与形態及び投与回数等によって異なるが、通常は成人に対して、有効成分を１日に体重１ｋｇあたり、０．１μｇ～１ｇ程度、１μｇ～５００ｍｇ程度、１０μｇ～５００ｍｇ程度を１回、又は、数回に分けて投与すればよい。また、液体点眼剤の場合は、０.０１～５０ｍｇ／ｍＬ、好ましくは０．１～１０ｍｇ／ｍＬのものを１日数回、１回に１～数滴点眼すればよい。 The dose of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof, which is an active ingredient of the therapeutic agent, ameliorating agent or prophylactic agent of the present invention, is determined based on the patient's body weight, age, sex, symptom, administration Usually, for adults, the active ingredient is about 0.1 μg to about 1 g per kg of body weight, about 1 μg to about 500 mg per day, about 10 μg to about 500 mg once or several times for adults. Divided into two doses. In the case of liquid eye drops, 0.01 to 50 mg / mL, preferably 0.1 to 10 mg / mL, may be instilled 1 to several drops at a time several times a day.
　本発明はまた、角膜障害の治療、改善または予防方法であって、有効量のニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を、治療、改善、予防等を必要としている者に投与する工程を含む方法をも提供する。 The present invention is also a method for the treatment, amelioration or prevention of corneal disorders, which requires treatment, improvement, prevention, etc. of an effective amount of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof. There is also provided a method comprising the step of administering to said person.
　本発明はまた、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩の角膜障害を治療、改善または予防するための使用をも提供する。 The present invention also provides use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for treating, ameliorating or preventing corneal disorders.
　本発明はまた、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩の角膜障害の治療、改善または予防するための医薬を製造するための使用をも提供する。 The present invention also provides the use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for the manufacture of a medicament for the treatment, amelioration or prevention of corneal disorders.
　本明細書中に引用されているすべての特許出願および文献の開示は、それらの全体が参照により本明細書に組み込まれるものとする。 The disclosures of all patent applications and documents cited in this specification are hereby incorporated by reference in their entirety.
　実施例１　喫煙ラットを用いた治癒効力試験
　WO2012/161112に記載された通り、以下に示す方法で角結膜上皮障害モデルを作製し、ニコチンアミドモノヌクレオチドの角結膜上皮障害に対する治癒効果を評価した。 Example 1 Healing Efficacy Test Using Smoking Rats As described in WO2012 / 161112, a keratoconjunctival epithelial disorder model was prepared by the following method, and the healing effect of nicotinamide mononucleotide on keratoconjunctival epithelial disorder was evaluated.
　この実験は、各個体の両眼を用い、両眼に同じ薬液を投与し、群間で比較を行った。試験群には喫煙処理及び点眼処理を施し（NMN点眼群（Smoking+NMN））、喫煙処理及び点眼処理を施さない群（Non-treatment）及び喫煙処理のみを施した群（喫煙処理群（Smoking））を、対照群とした。 In this experiment, both eyes of each individual were used, the same drug solution was administered to both eyes, and comparison was made between groups. The test group was treated with smoking and instillation (NMN instillation group (Smoking + NMN)), the group without smoking treatment and instillation treatment (Non-treatment), and the group with only smoking treatment (smoking treatment group (Smoking) )) Was taken as a control group.
　（実験方法）
　雄性Sprague-Dawley（SD）ラット（６週齢）に喫煙処理を施し、角結膜上皮障害モデルを作製した。具体的には、ラットを入れたチャンバー中にタバコ（Seven Stars）の主流煙（３００ｍＬ）を３０分毎に６回添加し、1日あたり3時間、１２日間処理することにより角結膜上皮障害を惹起した。 (experimental method)
Male Sprague-Dawley (SD) rats (6 weeks old) were treated with smoking to produce a model of keratoconjunctival epithelial disorder. Specifically, the mainstream smoke (300 mL) of tobacco (Seven Stars) was added 6 times every 30 minutes into the chamber containing the rats, and the keratoconjunctival epithelial disorder was treated by treatment for 3 hours per day for 12 days. Evoked.
　点眼条件として、ニコチンアミドモノヌクレオチド（CAS 1094-61-7）のＰＢＳ溶液（濃度：３０ｍＭ）を、それぞれ１回５μＬで喫煙処理前に１回、処理後に３回の都合１日４回、１２日間連日点眼した。 As instillation conditions, a PBS solution (concentration: 30 mM) of nicotinamide mononucleotide (CAS 1094-61-7), 5 μL each time, once before smoking treatment and 3 times after treatment for 4 times a day, 12 times Instilled every day.
　なお、動物は各群６匹（１２眼）とした。１２日後の喫煙処理後に、体重（Body weight）、涙量（Tear volume）及び蛍光染色スコアを測定した。 In addition, 6 animals (12 eyes) were used for each group. After smoking treatment 12 days later, body weight (Body weight), tear volume (Tear volume) and fluorescent staining score were measured.
　点眼終了後、角膜上皮の障害部を蛍光色素フルオレセインにて染色した。角膜上皮の障害の程度は、角膜全体を上中下及び左中右の合わせて９つの部分に分割して、各部分ごとに下記の基準で障害をスコア化し、その合計値を求めた。その後、群間においてスコア値を比較検討した。統計解析は、各群の有意差をDunnett法（Dunnett method）を用いて検定した。なお、公平な評価を行うため、点眼開始から角膜上皮障害のスコア化まで、各群に投与した薬液の内容にブラインドをかけ、スコア化後に照合した。 After completion of instillation, the damaged part of the corneal epithelium was stained with the fluorescent dye fluorescein. The degree of corneal epithelial damage was determined by dividing the entire cornea into nine parts, upper, middle, lower, and left middle right, and scoring the damage for each part according to the following criteria, and obtaining the total value. Thereafter, the score values were compared between groups. In the statistical analysis, the significant difference of each group was tested using the Dunnett method. In order to make a fair evaluation, from the start of instillation to scoring of corneal epithelial disorder, the contents of the drug solution administered to each group were blinded and collated after scoring.
　（角膜上皮のフルオレセイン染色スコア判断基準）
０：染色されない（点状蛍光なし）
１：わずかに点状蛍光がみられる
２：比較的多く点状蛍光がみられる
３：密に点状蛍光がみられる。 (Criteria for fluorescein staining score of corneal epithelium)
0: Not stained (no point fluorescence)
1: Slight point-like fluorescence is observed 2: Remarkably more point-like fluorescence is observed 3: Point-like fluorescence is densely observed
　（結果）
　結果を図１～３に示す。 (result)
The results are shown in FIGS.
　体重（Body weight）は、喫煙処理により有意に減少するものの、NMN点眼群（Smoking+NMN）と喫煙処理群(Smoking)の間（Smoking v.s. Smoking+NMN）ではP値は0.79であり、有意差がなかった（図１）。なお、対照群（Non-smoking）と喫煙処理群(Smoking)との間（Non-smoking v.s. Smoking）、及び、対照群（Non-smoking）とNMN点眼群(Smoking+NMN)との間（Non-smoking v.s. Smoking+NMN）との間のP値は、それぞれP<0.05であった。 Body weight is significantly reduced by smoking treatment, but P value is 0.79 between NMN ophthalmic group (Smoking + NMN) and smoking treatment group (Smoking) (Smoking vs Smoking + NMN), significantly different (FIG. 1). Between the control group (Non-smoking) and the smoking treatment group (Smoking) (Non-smoking vs Smoking), and between the control group (Non-smoking) and the NMN ophthalmic group (Smoking + NMN) (Non-smoking) P-values between -smoking vs Smoking + NMN) were P <0.05, respectively.
　また、涙量（Tear volume）も喫煙処理により有意に減少するものの、NMN点眼群（Smoking+NMN）と喫煙処理群(Smoking)との間（Smoking v.s. Smoking+NMN）ではP値は0.80であり、有意差がなかった（図２）。このことは、NMN点眼により涙量は増加しないことを示している。なお、対照群（Non-smoking）と喫煙処理群(Smoking)との間（Non-smoking v.s. Smoking）、及び、対照群（Non-smoking）とNMN点眼群(Smoking+NMN)との間（Non-smoking v.s. Smoking+NMN）との間のP値は、それぞれP<0.01であった。 Tear volume is also significantly reduced by smoking treatment, but P value is 0.80 between NMN ophthalmic group (Smoking + NMN) and smoking treatment group (Smoking) (Smoking vs Smoking + NMN) There was no significant difference (FIG. 2). This indicates that tear volume is not increased by NMN instillation. Between the control group (Non-smoking) and the smoking treatment group (Smoking) (Non-smoking vs Smoking), and between the control group (Non-smoking) and the NMN ophthalmic group (Smoking + NMN) (Non-smoking) -smoking の 間 vs Smoking + NMN), P <0.01 respectively.
　蛍光染色スコア（Fluorescein score）は、喫煙処理により有意に増大する（Non-smoking v.s. Smoking：P<0.005）。NMN点眼群（Smoking+NMN）（蛍光スコア平均値：2.1±1.0）では、喫煙処理群（Smoking）（蛍光スコア平均値：4.0±1.0）に比べて有意に減少した（Smoking v.s. Smoking+NMN：P<0.005）。NMN点眼による角膜状態の改善が認められた（図３）。なお、対照群（Non-smoking）と喫煙処理群(Smoking)との間（Non-smoking v.s. Smoking）のP値はP<0.005であり、対照群（Non-smoking）とNMN点眼群(Smoking+NMN)との間（Non-smoking v.s. Smoking+NMN）との間のP値はP>0.05であった。 Fluorescent staining score (Fluorescein score) is significantly increased by smoking treatment (Non-smoking v.s. Smoking: P <0.005). In the NMN ophthalmic group (Smoking + NMN) (fluorescence score average value: 2.1 ± 1.0), there was a significant decrease compared to the smoking treatment group (smoking score average value: 4.0 ± 1.0) (Smoking vs Smoking + NMN: P <0.005). Improvement of the corneal condition by NMN instillation was observed (FIG. 3). The P value of the control group (Non-smoking) and the smoking treatment group (Smoking) (Non-smoking vs Smoking) is P <0.005, and the control group (Non-smoking) and NMN ophthalmic group (Smoking + The P-value between (NMN) and (Non-smoking vs Smoking + NMN) was P> 0.05.
　蛍光染色スコアの結果から、本発明の治療剤、改善剤または予防剤が角膜障害、特に角膜損傷に対して有効であることは明らかである。 From the result of the fluorescent staining score, it is clear that the therapeutic agent, ameliorating agent or prophylactic agent of the present invention is effective for corneal injury, particularly corneal injury.
　実施例２　抗酸化関連遺伝子の発現量測定
　実施例１でのNMN点眼群ラットにおける抗酸化関連遺伝子の発現量を測定した。 Example 2 Measurement of the expression level of an antioxidant-related gene The expression level of an antioxidant-related gene in the NMN eye drop group rats in Example 1 was measured.
　（実験方法）
　NMN点眼群（Smoking+NMN）及び喫煙処理群(Smoking)ラットから角膜を摘出し、TRIzol（Life Technologies社製）を使用してtotal RNAを抽出した。TaqMan Real-time RT-PCR（Life Technologies社製）を用いた定量RT-PCR法により、GSTμ2（Glutathione S-transferase μ2）遺伝子、Gpx4（Glutathione peroxidase 4）遺伝子、Gclm（Glutamate-cycteine ligase）遺伝子及びTxnrd（Thioredoxin reductase 1）遺伝子のmRNA発現変動を測定した。 (experimental method)
The cornea was extracted from NMN ophthalmic group (Smoking + NMN) and smoking treatment group (Smoking) rats, and total RNA was extracted using TRIzol (manufactured by Life Technologies). By quantitative RT-PCR using TaqMan Real-time RT-PCR (Life Technologies), GSTμ2 (Glutathione S-transferase μ2) gene, Gpx4 (Glutathione peroxidase 4) gene, Gclm (Glutamate-cycteine ligase) gene and Changes in mRNA expression of Txnrd (Thioredoxin reductase 1) gene were measured.
　mRNA発現変動の解析は、比較Ct法（ΔCt法）により行った。 Analysis of mRNA expression fluctuation was performed by the comparative Ct method (ΔCt method).
　（結果）
　結果を図４に示す。各遺伝子のmRNA発現について、喫煙処理群（Smoking）に対するNMN点眼群（Smoking + 30mM NMN eye drop（Smoking+NMN））の倍率変化（Fold change）を示す。NMN点眼群（Smoking+NMN）において、抗酸化関連遺伝子の発現量の有意な増大が認められた。実施例１の結果と併せて、抗酸化関連遺伝子がコードする抗酸化酵素の発現増大が、角膜障害、特に角膜損傷の改善に寄与していることが示唆される。 (result)
The results are shown in FIG. About the mRNA expression of each gene, Fold change of the NMN eye drop group (Smoking + 30 mM NMN eye drop (Smoking + NMN)) with respect to the smoking treatment group (Smoking) is shown. In the NMN ophthalmic group (Smoking + NMN), a significant increase in the expression level of antioxidant-related genes was observed. Together with the results of Example 1, it is suggested that the increase in the expression of the antioxidant enzyme encoded by the antioxidant-related gene contributes to the improvement of corneal damage, particularly corneal damage.

Claims (7)

  1. 　ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害の治療剤、改善剤または予防剤。 An agent for treating, improving or preventing corneal disorders, comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
  2. 　点眼薬である、請求項１に記載の治療剤、改善剤または予防剤。 The therapeutic agent, ameliorating agent or prophylactic agent according to claim 1, which is an eye drop.
  3. 　ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を有効成分とする、角膜障害を治療、改善または予防するための、抗酸化能増強剤。 Antioxidant potentiator for treating, improving or preventing corneal disorders, comprising nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof as an active ingredient.
  4. 　点眼薬である、請求項３に記載の増強剤。 The enhancer according to claim 3, which is an eye drop.
  5. 　有効量のニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩を、治療、改善若しくは予防を必要としている者に投与する工程を含む、角膜障害の治療、改善または予防方法。 A method for treating, ameliorating or preventing corneal disorders, comprising a step of administering an effective amount of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof to a person in need of treatment, amelioration or prevention. .
  6. 　角膜障害の治療、改善または予防に使用するための、ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩。 Nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for use in the treatment, amelioration or prevention of corneal disorders.
  7. 　ニコチンアミドモノヌクレオチド若しくはニコチンアミドリボシドまたはその薬理学的に許容される塩の角膜障害の治療、改善または予防するための医薬を製造するための使用。
          Use of nicotinamide mononucleotide or nicotinamide riboside or a pharmacologically acceptable salt thereof for the manufacture of a medicament for treating, ameliorating or preventing a corneal disorder.
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WO2018052019A1 (en) * 2016-09-13 2018-03-22 めぐみ 田中 Visual function improvement agent, and method for improving visual function
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CN114007693A (en) * 2019-06-25 2022-02-01 千寿制药株式会社 Novel use of Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR)

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