WO2016171152A1 - Agent thérapeutique, agent d'amélioration, et agent de prévention pour les troubles de la cornée - Google Patents

Agent thérapeutique, agent d'amélioration, et agent de prévention pour les troubles de la cornée Download PDF

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Publication number
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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English (en)
Japanese (ja)
Inventor
明弘 樋口
一男 坪田
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学校法人 慶應義塾
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Publication of WO2016171152A1 publication Critical patent/WO2016171152A1/fr

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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

Definitions

  • 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

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Abstract

L'invention concerne un agent thérapeutique, un agent d'amélioration, et un agent de prévention pour les troubles de la cornée, lesdits agents comprenant en tant qu'ingrédient actif du nicotinamide mononucléotide ou du nicotinamide riboside ou un sel pharmaceutiquement acceptable associé.
PCT/JP2016/062452 2015-04-20 2016-04-20 Agent thérapeutique, agent d'amélioration, et agent de prévention pour les troubles de la cornée WO2016171152A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015086257A JP2018100222A (ja) 2015-04-20 2015-04-20 角膜損傷の治療剤、改善剤または予防剤
JP2015-086257 2015-04-20

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WO2016171152A1 true WO2016171152A1 (fr) 2016-10-27

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018052019A1 (fr) * 2016-09-13 2018-03-22 めぐみ 田中 Agent améliorant la fonction visuelle, et procédé d'amélioration de la fonction visuelle
CN109662973A (zh) * 2019-01-31 2019-04-23 山东省眼科研究所 烟酰胺腺嘌呤二核苷酸或其前体物质在制备治疗角膜上皮缺损的药物中的应用
WO2019181961A1 (fr) 2018-03-20 2019-09-26 三菱商事ライフサイエンス株式会社 MÉTHODE DE PRÉPARATION DE β-NMN ET COMPOSITION EN CONTENANT
CN114007693A (zh) * 2019-06-25 2022-02-01 千寿制药株式会社 烟酰胺单核苷酸(nmn)及烟酰胺核苷(nr)的新用途

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JP2008538215A (ja) * 2005-03-30 2008-10-16 サートリス ファーマシューティカルズ， インコーポレイテッド サーチュイン活性化剤による眼障害の処置
WO2014146044A1 (fr) * 2013-03-15 2014-09-18 Washington University Administration de nicotinamide mononucléotide dans le traitement d'une maladie

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JP2008538215A (ja) * 2005-03-30 2008-10-16 サートリス ファーマシューティカルズ， インコーポレイテッド サーチュイン活性化剤による眼障害の処置
WO2014146044A1 (fr) * 2013-03-15 2014-09-18 Washington University Administration de nicotinamide mononucléotide dans le traitement d'une maladie

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HIGUCHI AKIHIKO ET AL.: "Corneal damage and lacrimal gland dysfunction in a smoking rat model", FREE RADICAL BIOLOGY & MEDICINE, vol. 51, no. 12, 2011, pages 2010 - 2216, XP028117056 *
PICCIOTTO NATALIE ET AL.: "Nicotinamide mononucleotide supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness in old mice(698.10", FASEB JOURNAL, vol. 28, no. 1, 2014, pages 698.10 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018052019A1 (fr) * 2016-09-13 2018-03-22 めぐみ 田中 Agent améliorant la fonction visuelle, et procédé d'amélioration de la fonction visuelle
US10898738B2 (en) 2016-09-13 2021-01-26 Megumi Tanaka Visual function printing agent, and method for improving visual functions
WO2019181961A1 (fr) 2018-03-20 2019-09-26 三菱商事ライフサイエンス株式会社 MÉTHODE DE PRÉPARATION DE β-NMN ET COMPOSITION EN CONTENANT
CN109662973A (zh) * 2019-01-31 2019-04-23 山东省眼科研究所 烟酰胺腺嘌呤二核苷酸或其前体物质在制备治疗角膜上皮缺损的药物中的应用
CN109662973B (zh) * 2019-01-31 2021-05-18 山东省眼科研究所 烟酰胺腺嘌呤二核苷酸或其前体物质在制备治疗角膜上皮缺损的药物中的应用
CN114007693A (zh) * 2019-06-25 2022-02-01 千寿制药株式会社 烟酰胺单核苷酸(nmn)及烟酰胺核苷(nr)的新用途

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