WO2020262497A1 - ニコチンアミドモノヌクレオチド（ｎｍｎ）およびニコチンアミドリボシド（ｎｒ）の新規用途 - Google Patents

ニコチンアミドモノヌクレオチド（ｎｍｎ）およびニコチンアミドリボシド（ｎｒ）の新規用途 Download PDF

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WO2020262497A1
WO2020262497A1 PCT/JP2020/024916 JP2020024916W WO2020262497A1 WO 2020262497 A1 WO2020262497 A1 WO 2020262497A1 JP 2020024916 W JP2020024916 W JP 2020024916W WO 2020262497 A1 WO2020262497 A1 WO 2020262497A1
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Prior art keywords
meibomian gland
meibomian
nmn
composition
item
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PCT/JP2020/024916
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English (en)
French (fr)
Japanese (ja)
Inventor
雅夫 土居
毅 中嶋
麻実子 町田
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Senju Pharmaceutical Co Ltd
Kyoto University NUC
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Senju Pharmaceutical Co Ltd
Kyoto University NUC
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Application filed by Senju Pharmaceutical Co Ltd, Kyoto University NUC filed Critical Senju Pharmaceutical Co Ltd
Priority to JP2021527709A priority Critical patent/JP7572007B2/ja
Priority to EP20832373.3A priority patent/EP3991795B1/en
Priority to ES20832373T priority patent/ES2989969T3/es
Priority to US17/621,114 priority patent/US20220370484A1/en
Priority to CN202080047245.3A priority patent/CN114007693B/zh
Priority to PL20832373.3T priority patent/PL3991795T3/pl
Publication of WO2020262497A1 publication Critical patent/WO2020262497A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present disclosure relates to novel uses of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • it relates to a composition comprising NMN or NR for treating or preventing a disease, disorder or condition associated with the activity of Hsd3b6 or its homologs, or methods using it.
  • the present disclosure relates to a composition comprising NMN or NR for improving the function of the meibomian glands, or methods using the same.
  • NMN nicotinamide mononucleotide
  • NAMPT nicotinamide phosphoribosyl transferase
  • NAD + oxidized nicotinamide adenine dinucleotide
  • NR nicotinamide riboside
  • nicotinamide mononucleotide NPN
  • NR nicotinamide riboside
  • Improving the activity of Hsd3b6 or its homologs may provide treatment or prevention of diseases, disorders or conditions associated with the activity of Hsd3b6 or its homologs.
  • the present disclosure provides, among other things, the use of nicotinamide mononucleotides (NMNs) and / or nicotinamide ribosides (NR), or compositions containing them, to improve the function of the meibomian glands.
  • the composition may be characterized by being administered to the eye of the subject. Improvements in the function of the meibomian glands include, for example, increasing the number of acinar cells in the meibomian glands or increasing lipid secretion from the meibomian glands.
  • compositions may be provided for the treatment or prevention of diseases associated with meibomian gland dysfunction.
  • compositions of the present disclosure are capable of ameliorating meibomian gland tissue atrophy and enhancing the activity of steroid synthases that affect lipids secreted by the meibomian glands. It is also understood that the compositions of the present disclosure can normalize the lipid composition secreted by the meibomian glands and thus the lipids in the meibomian glands. In addition, the compositions of the present disclosure can promote testosterone production, which is known to promote meibomian gland lipid production. Since sex hormones such as testosterone affect the lipid production of meibomian glands, it is understood that the compositions of the present disclosure can normalize the lipid component composition in meibomian gland tissue.
  • (Item A1) A composition comprising nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) for improving the activity of Hsd3b6 or its homologue.
  • (Item A1-2) A composition comprising nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) for treating or preventing a disease, disorder or condition associated with the activity of Hsd3b6 or its homologue.
  • (Item A1-3) Diseases related to the activity of Hsd3b6 or its homologs include mybome gland dysfunction, diseases due to decreased steroid hormones (eg, testosterone and estrogen), menopause, osteoporosis, lifestyle-related diseases, and aging.
  • the composition according to any one of the above items selected from the group consisting of hypogonadism and myocardial infarction.
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • composition according to any one of the above items for the treatment or prevention of diseases associated with meibomian gland dysfunction. (Item A6-1) A composition for treating or preventing meibomian gland dysfunction, which comprises nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR).
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • meibomian gland dysfunction is associated with an inflammatory disease.
  • the inflammatory disease comprises at least one selected from the group consisting of meibomian glanditis, (punctate) superficial keratitis, and blepharitis.
  • the meibomian gland dysfunction is accompanied by excessive accumulation of lipids in the conduit.
  • the diseases associated with meibomian gland dysfunction are meibomian gland inflammation, posterior blepharitis, keratitis, conjunctivitis, meibomian gland inflammation, keratoconjunctivitis epithelium, ocular herbitis, Sjogren's syndrome, Stevens-Johnson syndrome, transplantation.
  • GVHD one-to-one host disease
  • (Item B1) A method for improving the activity of Hsd3b6 or its homologue of a subject, or treating or preventing a disease, disorder or symptom associated with the activity of Hsd3b6 or its homologue.
  • (Item B2) The method according to item B1, which comprises the step of administering nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) to the subject.
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • the method according to item B1 or B2 further comprising the step of measuring the activity of Hsd3b6 or a homolog thereof of the subject.
  • (Item B4) The item according to any one of items B1 to B3, which comprises a step of measuring the activity of Hsd3b6 or its homologue of the subject and administering NMN and / or NR when the activity is reduced.
  • Method. (Item C1) A method for improving the function of a subject's meibomian glands or treating or preventing a disease, disorder or symptom associated with meibomian gland dysfunction.
  • item C2 The method according to item C1, which comprises the step of administering nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) to the subject.
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • (Item C3) The method according to item C1 or C2, further comprising a step of confirming the meibomian gland function of the subject.
  • (Item C4) The method according to any one of items C1 to C3, which comprises a step of confirming the meibomian gland function of the subject and administering NMN and / or NR when the function is deteriorated.
  • (Item C5) The meibomian gland function is confirmed by slit lamp examination, Meibography, Confocal microscopy, DR-1, myboline, mybometry, Lipid chemistry, evaporation amount, BUT, or subjective symptom questionnaire, in item C4. The method described.
  • the diseases, disorders or symptoms associated with meibomian gland dysfunction include meibomian gland inflammation, posterior blepharitis, keratitis, conjunctivitis, meibomian gland inflammation, keratoconjunctival epithelial disease, meibomian gland, Sjogren's syndrome, Stevens- The method according to any of items C1 to C5, selected from the group consisting of Johnson syndrome, implant-to-host disease (GVHD), and visual dysfunction. (Item C7) The method according to any one of items C1 to C6 for increasing the number of acinar cells of the meibomian gland.
  • (Item C8) The method according to any one of items C1 to C6 for increasing lipid secretion from the meibomian glands.
  • (Item C9) The method according to any one of items C1 to C6 for enhancing testosterone production in the meibomian glands.
  • (Item D1) Use of nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) to produce compositions that improve the function of meibomian glands.
  • (Item D2) The use according to item D1, wherein the composition is for increasing the number of acinar cells in the meibomian gland.
  • item D4 The use according to any one of items D1 to D3, wherein the composition is for the treatment or prevention of a disease associated with meibomian gland dysfunction.
  • the diseases associated with meibomian gland dysfunction include meibomian gland inflammation, posterior blepharitis, keratitis, conjunctivitis, meibomian gland inflammation, keratoconjunctivitis epithelium, ocular herbitis, Sjogren's syndrome, Stevens-Johnson syndrome, and transplantation.
  • the use according to D4 selected from the group consisting of one-to-one host disease (GVHD) and visual dysfunction.
  • Item D6 The use according to any one of items D1 to D5, wherein the composition is for enhancing testosterone production in the meibomian glands.
  • Item E1 Use of nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) to produce compositions that treat or prevent meibomian gland dysfunction.
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • Item E3 The use according to item E1, wherein the meibomian gland dysfunction is associated with an inflammatory disease.
  • Nicotinamide mononucleotide (NMN) and for use in the treatment or prevention of diseases, disorders or conditions associated with the activity of Hsd3b6 or its homologs in a subject or related to the activity of Hsd3b6 or its homologs. / Or nicotinamide riboside (NR).
  • Nicotinamide mononucleotide (NMN) and / or nicotinamide riboside for use in improving the function of the meibomian glands or in the treatment or prevention of diseases, disorders or conditions associated with meibomian gland dysfunction. (NR).
  • the diseases, disorders or symptoms associated with meibomian gland dysfunction include meibomian gland inflammation, posterior blepharitis, keratitis, conjunctivitis, meibomian gland inflammation, keratoconjunctivitis, ocular blepharitis, Sjogren's syndrome, Stevens- The nicotine meibomian mononucleotide (NMN) and / or nicotine meibomian gland (NR) according to item G1, selected from the group consisting of Johnson syndrome, implant vs. host disease (GVHD), and visual dysfunction.
  • NPN nicotine meibomian mononucleotide
  • NR nicotine meibomian gland
  • (Item H1) A composition for enhancing testosterone production in the meibomian glands, which comprises nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR).
  • (Item H2) The composition according to item H1, wherein the composition is administered to the eye of a subject.
  • (Item I1) A method for enhancing testosterone production in a subject's meibomian glands.
  • (Item I2) The method according to item I1, which comprises the step of administering nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) to the subject.
  • the present disclosure provides a composition for ameliorating the activity of Hsd3b6 or its homologue, or treating or preventing a disease, disorder or condition associated with the activity of Hsd3b6 or its homologue, or a method thereof.
  • the present disclosure may provide compositions for improving the function of the meibomian glands, or methods thereof.
  • FIG. 1 is a diagram showing atrophy of meibomian gland tissue with aging.
  • the left and middle are stained eyelid photographs of 6-month-old and 24-month-old mice, respectively, and the right is a bar graph comparing the average stained areas of 6-month-old and 24-month-old mice.
  • FIG. 2 is a diagram showing changes in meibomian gland tissue (size of meibomian glands and number of secretory ducts) in 2-month-old mice in which Hsd3b6 was knocked out (KO).
  • the upper row shows the results in male mice and the lower row shows the results in female mice.
  • FIG. 1 is a diagram showing atrophy of meibomian gland tissue with aging.
  • the left and middle are stained eyelid photographs of 6-month-old and 24-month-old mice, respectively, and the right is a bar graph comparing the average stained areas of 6-month-old and 24-month-old mice.
  • FIG. 2 is a diagram showing changes in meibomian gland tissue (size of me
  • FIG. 3 is a diagram showing changes in Hsd3b6 enzyme activity in meibomian glands and cell proliferation activity of meibomian gland basal cells by instillation of NMN or NR for 2 weeks in 1.5-year-old wild-type mice.
  • FIG. 4 is a diagram showing the effect of NMN or NR on meibomian gland tissue by instillation of NMN or NR in 1.75 year old wild-type mice for 3 months. It is a graph which shows the typical stained photograph of the eyelid of the left eye (untreated) and the right eye (eye drop), and the stained area (right eye / left eye) in each individual.
  • FIG. 5 shows the testosterone content in meibomian gland tissue after gonadectomy and sham surgery in wild-type (WT) and Hsd3b6 knockout (KO) 2-month-old male mice.
  • the term "subject” refers to a subject to which a medicament or method for the treatment and prevention of the present disclosure is administered (transplanted), and the subject is a mammal (eg, human, mouse, rat, hamster, etc.). Rabbits, cats, dogs, cows, horses, sheep, monkeys, etc.) are mentioned, but primates are preferable, and humans are particularly preferable.
  • treatment means the cure of a disease or symptom or the suppression of a symptom.
  • “Prophylaxis” means to prevent the onset of a disease or symptom, and the concept also includes delaying the onset of the disease or symptom or minimizing the onset of the disease or symptom. Included.
  • a “derivative” is a compound whose core structure is the same as or similar to that of the parent compound, but which has a chemical or physical modification such as a different functional group or an additional functional group. Point to. The derivative has the same or similar biological activity as the parent compound.
  • the term "pharmaceutically acceptable salt” refers to a relatively non-toxic inorganic or organic acid addition salt of a compound of the present disclosure. These salts allow the compound to be reacted temporarily during the final isolation and purification of the compound, or the compound purified in its free base form separately with a suitable organic or inorganic acid, and so on. It can be prepared by isolating the salt formed.
  • Pharmaceutically acceptable basic salts of the compounds of the present disclosure include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt and triethylamine.
  • Aliphatic amine salts such as salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, meglumine salts, diethanolamine salts or ethylenediamine salts; aralkylamines such as N, N-dibenzylethylenediamine and venetamine salts.
  • Heterocyclic aromatic amine salts such as pyridine salt, picolin salt, quinoline salt, isoquinolin salt; tetramethylammonium salt, tetraethylamonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctyl Tertiary ammonium salts such as ammonium salt and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt can be mentioned.
  • Pharmaceutically acceptable acidic salts of the compounds of the present disclosure include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogen carbonates, perchlorates; acetates, Organic acid salts such as propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate; methanesulfonate, ISEthionate, benzenesulfonate, p. -Sulfates such as toluene sulfonates; acidic amino acid salts such as aspartate and glutamate can be mentioned.
  • inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogen carbonates, perchlorates
  • acetates Organic acid salts such as propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate
  • solvate means a solvate of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, for example, a solvate with an organic solvent (eg, alcohol (ethanol, etc.)). Includes Japanese products), hydrates, etc. When forming a hydrate, it may be coordinated with any number of water molecules. Examples of the hydrate include monohydrate, dihydrate and the like.
  • homolog refers to a protein or gene having an amino acid sequence or base sequence derived from a common ancestor. If certain homologs are due to speciation, they are called orthologs. In addition, homologs newly generated by gene duplication in a certain species are called paralogs.
  • Nicotinamide mononucleotide has the following structure It is a compound having, and is a nucleotide derived from ribose and nicotinamide. It is known as a biochemical precursor of NAD + (nicotinamide adenine dinucleotide).
  • Nicotinamide riboside has the following structure It is a compound having, and is a conjugate of ribose and nicotinamide. It can also be said that nucleotides are replaced with ribose in NMN.
  • a composition comprising NMN and / or NR, or a method comprising using (eg, administering) NMN and / or NR may be provided.
  • NMN and / or NR may be used as derivatives thereof and / or as pharmaceutically acceptable salts thereof.
  • NMN and NR can improve Hsd3b6 enzymatic activity (or homologs thereof, eg, HSD3B1 enzymatic activity).
  • NMN and NR can restore meibomian gland tissue.
  • the composition may comprise NMN.
  • the composition may comprise NR.
  • NMN and / or NR may be used in combination with additional active ingredients.
  • Further active ingredients include, but are not limited to, anti-inflammatory agents, antibacterial agents, nutritional agents, antioxidants and the like.
  • compositions or methods for improving the activity of Hsd3b6 or its homologs by NMN and NR can be provided.
  • Hsd3b6 is directly regulated by the circadian clock and the product of this gene is an important component of the aldosterone production pathway.
  • compositions or methods for treating or preventing diseases, disorders or conditions associated with the activity of Hsd3b6 or its homologs may be provided.
  • Diseases associated with the activity of Hsd3b6 or its homologs include mybome gland dysfunction, diseases due to decreased steroid hormones (eg, testosterone and estrogen), menopause, osteoporosis, lifestyle-related diseases, age-related hypogonadism and myocardium. Examples include, but are not limited to, infarcts.
  • the present disclosure may provide compositions or methods for improving the function of meibomian glands by NMN and NR.
  • the meibomian gland is one of the sebaceous glands on the edge of the eyelid, which prevents the tear film of the eye from evaporating, prevents tears from spilling onto the cheeks, and keeps the closed eyelid airtight. Secretes oily substances (sebaceous glands) with.
  • the meibomian glands are also referred to as tarsal glands.
  • Meibomian gland dysfunction is a condition in which its function is diffusely abnormal and is defined as accompanied by chronic eye discomfort, which is caused by degeneration of meibomian lipids, stagnation / chronic infection, and inflammatory conduit epithelium. It is said to be hyperkeratotic.
  • NMN and NR can restore Hsd3b6 activity in the meibomian glands and increase the size of the meibomian glands. Improvements in meibomian gland function include, for example, increasing the number of meibomian gland cell counts, increasing lipid secretion from the meibomian glands, or treating or preventing diseases associated with meibomian gland dysfunction. Can be mentioned.
  • compositions or methods may be provided for the treatment or prevention of diseases associated with meibomian gland dysfunction due to NMN and NR.
  • a composition for treating or preventing meibomian gland dysfunction comprising nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR) may be provided.
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • Meibomian gland dysfunction can be accompanied by decreased meibomian gland secretion.
  • Meibomian gland dysfunction can be associated with inflammatory disease.
  • Inflammatory diseases include, for example, at least one selected from the group consisting of meibomian glands, (punctate) superficial keratitis, and blepharitis.
  • Meibomian gland dysfunction can be associated with intraductal lipid over-accumulation. Meibomian gland dysfunction can be accompanied by eye discomfort, foreign body sensation, and / or oppressive sensation.
  • Diseases associated with meibomian gland dysfunction include, for example, meibomian adenitis, posterior blepharitis, keratitis, conjunctivitis, meibomian gland keratoconjunctivitis, visual dysfunction, androgen deficiency, atopic dermatitis, prostatic hypertrophy, eye Blepharitis, discoid lupus (eritematodes), Ectodermaldysplasia syndrome (non-sweat epidermal necrolysis), bone marrow transplantation, hypertension, menopause, Parkinson's disease, psoriasis vulgaris, Rosacea (drinking), Schegren's syndrome, Stevens-Johnson syndrome , Addictive epidermal necrolysis, Tuner syndrome, graf
  • compositions or methods for normalizing the lipid composition secreted by the meibomian glands and normalizing the lipids in the meibomian glands may be provided.
  • the composition of the present disclosure has an effect of improving meibomian gland tissue atrophy and can enhance the activity of steroid synthase that affects lipids secreted from meibomian glands, and thus contributes to normalization of lipids in meibomian glands. Is understood.
  • the method for measuring the lipid component in the meibomian gland is not particularly limited, and various methods well known in the art can be adopted as long as the lipid component in the meibomian gland can be evaluated.
  • the composition of the present disclosure can promote testosterone production, which is known to promote meibomian gland lipid production, by increasing Hsd3b6 enzyme activity. Since sex hormones such as testosterone affect meibomian gland lipid production, the compositions of the present disclosure promote the production of testosterone-containing sex hormones through enhanced Hsd3b6 enzyme activity to form a lipid component composition in meibomian gland tissue. It is understood that it contributes to the normalization of.
  • compositions of the present disclosure can be formulated into suitable dosage forms.
  • the compositions in the present disclosure may be provided as ophthalmic injections, ophthalmic ointments, eye drops or ophthalmic perfusates when they are ophthalmic compositions.
  • the composition can be formulated in any dosage form such as aerosols, solutions, extracts, elixirs, capsules, granules, pills, ointments, powders, tablets, solutions, suspensions, emulsions and the like.
  • the composition may contain any pharmaceutically acceptable additives and / or excipients known in the art.
  • Additives include, but are not limited to, tonicity modifiers, buffers, preservatives, cosolvents, and thickeners.
  • an ophthalmic composition may be provided in the form of a solution in which the active ingredient is dissolved in an aqueous solvent (eg, water).
  • compositions of the present disclosure can be administered by any suitable route determined by those skilled in the art, including but not limited to ocular injection, topical application (including application to the eye), eye drops, intravenous. It can be formulated to be suitable for administration by a route of administration selected from injection, infusion, oral, parenteral, transdermal and the like.
  • the tonicity agent examples include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol and sorbitol, polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol, and inorganic salts such as sodium chloride, potassium chloride and calcium chloride. Etc., and the blending amount thereof is preferably 0 to 5% by weight based on the total amount of the composition.
  • the chelating agent examples include edetates such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, ethylenediaminetetraacetic acid salt, nitrilotriacetic acid or a salt thereof, and sodium hexametaphosphate.
  • edetates such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, ethylenediaminetetraacetic acid salt, nitrilotriacetic acid or a salt thereof, and 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 thereof is preferably 0 to 1% by weight based on the total amount of the composition.
  • Examples of the pH adjusting agent include acids such as hydrochloric acid, carbonic acid, acetic acid and citric acid, as well as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, and the like.
  • Examples thereof include alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as tromethamole, and the blending amount thereof is preferably 0 to 20% by weight based on the total amount of the composition.
  • preservatives include paraoxybenzoic acid esters such as sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride, and benzethonium chloride.
  • examples thereof include quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylenebiguanide, chlorhexidine and the like, and the blending amount thereof is 0 to 0.2% by weight based on the total amount of the composition. Is preferable.
  • antioxidant examples include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like, and the blending amount thereof is preferably 0 to 0.4% by weight based on the total amount of the composition.
  • solubilizing agent examples include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc., and the blending amount thereof is based on the total amount of the composition. 0 to 3% by weight is preferable.
  • thickening agent examples include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like. It is preferably 0 to 70% by weight based on the total amount of the composition.
  • the desired components are mixed with an aqueous solvent such as sterile purified water, physiological saline, a buffer solution (for example, boric acid buffer solution, phosphate buffer solution, etc.), or cotton seed oil, soybean oil, etc. It can be carried out by dissolving or suspending in a non-aqueous solvent such as vegetable oil such as sesame oil and peanut oil, adjusting to a predetermined osmotic pressure, and performing sterilization treatment such as filtration sterilization.
  • aqueous solvent such as sterile purified water, physiological saline, a buffer solution (for example, boric acid buffer solution, phosphate buffer solution, etc.), or cotton seed oil, soybean oil, etc. It can be carried out by dissolving or suspending in a non-aqueous solvent such as vegetable oil such as sesame oil and peanut oil, adjusting to a predetermined osmotic pressure, and performing sterilization treatment such as filtration sterilization.
  • an ointment base can be included in addition to the above-mentioned various components.
  • the ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, polyethylene; an emulsion base obtained by emulsifying an oil phase and an aqueous phase with a surfactant or the like; hydroxypropylmethylcellulose, carboxymethylcellulose. , A water-soluble base made of polyethylene glycol or the like.
  • compositions or therapeutic or prophylactic agents of the present disclosure can be provided as kits.
  • the present disclosure provides drug packs or kits comprising one or more containers filled with one or more components of the compositions or pharmaceuticals of the present disclosure.
  • kits are a unit that is usually divided into two or more compartments and is provided with parts to be provided (for example, therapeutic agents, prophylactic agents, their respective components, instructions, etc.).
  • the form of this kit is preferred when the purpose is to provide a composition that should not be mixed and provided for stability and the like, but is preferably mixed and used immediately before use.
  • kits preferably include instructions or instructions describing how to use the provided parts (eg, therapeutic, prophylactic) or how to treat the reagents. It is advantageous to have.
  • the kit When the kit is used as a reagent kit in the present specification, the kit usually includes instructions and the like describing how to use therapeutic agents, preventive agents, and the like.
  • the "instruction” describes the method of using this disclosure to a doctor or another user.
  • This instruction sheet contains words instructing the detection method of the present disclosure, how to use a diagnostic agent, or administration of a medicine or the like.
  • the instruction sheet may include words instructing the administration to the eye (for example, by eye drops, eye ointment, injection, etc.) as the administration site.
  • This instruction is prepared and approved by the regulatory agency of the country in which this disclosure is implemented (eg, Ministry of Health, Labor and Welfare in Japan, Food and Drug Administration (FDA) in the United States, etc.). It is clearly stated that it has been received.
  • the instruction sheet is a so-called package insert, which is usually provided in a paper medium, but is not limited thereto, and is in a form such as an electronic medium (for example, a homepage provided on the Internet, an e-mail). But can be provided.
  • an eye drop containing nicotine amide mononucleotide containing nicotine amide mononucleotide (NMN), wherein nicotine amide mononucleotide (NMN) is 0.001 ⁇ g / ml or more, 0.01 ⁇ g / ml or more, 0.1 ⁇ g / ml or more.
  • an eye ointment containing nicotine amide mononucleotide containing nicotine amide mononucleotide (NMN), wherein nicotine amide mononucleotide (NMN) is 0.001 ⁇ g / ml or more, 0.01 ⁇ g / ml or more, 0.1 ⁇ g / ml or more.
  • NR nicotine amide riboside
  • a preparation having a concentration equal to or higher than a predetermined amount depending on the dosage form may be advantageous for delivery to the meibomian glands existing on the back of the eyelid rather than on the eyeball.
  • the uses of the present disclosure include, but are not limited to, eye drops, intrathecal injection, sustained release agent impregnation, subconjunctival injection, systemic.
  • Dosage forms administration method and dosage form
  • administration oral administration, intravenous injection
  • the concentration of NMN or NR used in the present disclosure is usually about 0.001 to 1000 ⁇ M ( ⁇ mol / l), preferably about 0.01 to 300 ⁇ M, more preferably about 0.03 to 100 ⁇ M, even more preferably about 0. It is from 1 to about 30 ⁇ M, and other concentration ranges are usually, for example, usually 0.01 nM to 100 ⁇ M, about 0.1 nM to 100 ⁇ M, about 0.001 to 100 ⁇ M, about 0.01 to 75 ⁇ M, about 0.05.
  • ⁇ 50 ⁇ M about 1-10 ⁇ M, about 0.01-10 ⁇ M, about 0.05-10 ⁇ M, about 0.075-10 ⁇ M, about 0.1-10 ⁇ M, about 0.5-10 ⁇ M, about 0.75-10 ⁇ M, About 1.0 to 10 ⁇ M, about 1.25 to 10 ⁇ M, about 1.5 to 10 ⁇ M, about 1.75 to 10 ⁇ M, about 2.0 to 10 ⁇ M, about 2.5 to 10 ⁇ M, about 3.0 to 10 ⁇ M, about 4.0 to 10 ⁇ M, about 5.0 to 10 ⁇ M, about 6.0 to 10 ⁇ M, about 7.0 to 10 ⁇ M, about 8.0 to 10 ⁇ M, about 9.0 to 10 ⁇ M, about 0.01 to 50 ⁇ M, about 0 .05 to 5.0 ⁇ M, about 0.075 to 5.0 ⁇ M, about 0.1 to 5.0 ⁇ M, about 0.5 to 5.0 ⁇ M, about 0.75 to 5.0 ⁇ M, about 1.0 to 5.
  • 0 ⁇ M about 1.25 to 5.0 ⁇ M, about 1.5 to 5.0 ⁇ M, about 1.75 to 5.0 ⁇ M, about 2.0 to 5.0 ⁇ M, about 2.5 to 5.0 ⁇ M, about 3. 0-5.0 ⁇ M, about 4.0-5.0 ⁇ M, about 0.01-3.0 ⁇ M, about 0.05-3.0 ⁇ M, about 0.075-3.0 ⁇ M, about 0.1-3.0 ⁇ M , About 0.5 to 3.0 ⁇ M, about 0.75 to 3.0 ⁇ M, about 1.0 to 3.0 ⁇ M, about 1.25 to 3.0 ⁇ M, about 1.5 to 3.0 ⁇ M, about 1.75 ⁇ 3.0 ⁇ M, about 2.0 to 3.0 ⁇ M, about 0.01 to 1.0 ⁇ M, about 0.05 to 1.0 ⁇ M, about 0.075 to 1.0 ⁇ M, about 0.1 to 1.0 ⁇ M, It is about 0.5 to 1.0 ⁇ M, about 0.75 to 1.0 ⁇ M, about 0.09 to 35 ⁇ M, or about
  • the concentration of the preparation can be determined as a reference, and it is also possible to set a concentration higher than these. For example, about 0.01 ⁇ M ( ⁇ mol / l) to 1000 mM (mmol / l), 0.03 ⁇ M to 1000 mM, about 0.1 ⁇ M to 300 mM, about 0.3 ⁇ M to 300 mM, about 1 ⁇ M to 100 mM, about 3 ⁇ M to 100 mM, about.
  • Effective amounts of the agents of the present disclosure effective in treating a particular disease, disorder or condition may vary depending on the nature of the disorder or condition, but one of ordinary skill in the art can determine by standard clinical techniques as described herein. is there.
  • in vitro assays can be used, if desired, to assist in identifying optimal dosage ranges.
  • the exact dose to be used in the formulation may also vary depending on the route of administration and the severity of the disease or disorder and should be determined according to the discretion of the attending physician and the circumstances of each patient. However, the dose is not particularly limited, and may be, for example, 0.001, 1, 5, 10, 15, 100, or 1000 mg / kg body weight per dose, within the range of any two of these values. There may be.
  • the dosing interval is not particularly limited, but may be administered 1, 2 or 4 times per 1, 7, 14, 21, or 28 days, and 1, 2 or 4 per range of any two values. It may be administered in multiple doses.
  • the dose, number of administrations, administration interval, administration period, and administration method may be appropriately selected depending on the age and weight of the patient, symptoms, administration form, target organ, and the like.
  • the compositions of the present disclosure can be used as eye drops.
  • the therapeutic agent preferably contains a therapeutically effective amount or an effective amount of an active ingredient that exerts a desired action.
  • the effective dose can be estimated from the dose-response curve obtained from in vitro or animal model test systems.
  • Administering more than a predetermined amount of the active ingredient can be advantageous for delivery to the meibomian glands located on the back of the eyelid rather than on the eyeball.
  • the present disclosure may provide methods of improving the activity of Hsd3b6 or its homologs or treating or preventing a disease, disorder or condition associated with the activity of Hsd3b6 or its homologs.
  • the method may include administering to the subject nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR).
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • the method may optionally include measuring the activity of Hsd3b6 or its homologue of the subject.
  • a method may be provided in which the activity of Hsd3b6 or a homolog thereof of a subject is measured and NMN and / or NR is administered if the activity is reduced.
  • the present disclosure may provide methods for improving the function of the meibomian glands or for treating or preventing disease disorders or symptoms associated with meibomian gland dysfunction.
  • the method may include administering to the subject nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR).
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • the present disclosure may provide a method of enhancing testosterone production in the meibomian glands.
  • the method may include administering to the subject nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR).
  • NNN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • the method may include confirming the subject's meibomian gland function, if necessary.
  • a method may be provided that confirms a subject's meibomian gland function and administers NMN and / or NR if that function is impaired.
  • the meibomian gland function can be confirmed by, for example, slit lamp examination, Meibography, Confocal microscopy, DR-1, myboline, meibomian gland, Lipid chemistry, evaporation amount, BUT, subjective symptom questionnaire, and the like.
  • Short Protocols in Molecular Biology A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, FM (1995). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Innis, MA et al. (1995). PCR Strategies, Academic Press; Ausubel, FM (1999). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, JJ et al. (1999). PCR Applications: Protocols for Functional Genomics, Academic Press, Gait, MJ (1985). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Gait, MJ (1990) ).
  • Example 1 Atrophy of meibomian gland tissue with aging, meibomian gland tissue in Hsd3b6 KO
  • Example 2 Atrophy of meibomian gland tissue with aging, meibomian gland tissue in Hsd3b6 KO
  • mice were dislocated from the cervical spine and the skin of the head including the meibomian glands was sampled. It was soaked in 4% paraformaldehyde flat with a pushpin and fixed at 4 ° C for 24 hours using a rotator. Trim the circumference of the meibomian glands, soak them in 50% ethanol at room temperature for 10 minutes, then soak them in 70% ethanol for 20 minutes, and soak them in the stain solution in a falcon tube for 24 hours at room temperature using a rotor. It was. After that, it was soaked in 70% ethanol for 10 minutes, and the washing operation was repeated several times, and it was confirmed that the meibomian glands were dyed cleanly.
  • Glycerin jelly was prepared by first mixing gelatin and ultrapure water with 10 g of gelatin, 60 ml of ultrapure water, and 70 ml of ultrapure water, swelling the gelatin, and adding glycerin while heating after about 1 hour.
  • the test was conducted after breeding 2-month-old mice for 10 days under normal conditions (normal humidity conditions) of free feeding and water intake environment with humidity of 40 to 60%, room temperature of 25 ° C, and dark cycle of 12 hours and 12 hours. ..
  • the 24-month-old mouse is a C57BL / 6J mouse 78-week-old (18-month-old) male mouse purchased from Oriental Bio Service Co., Ltd. and bred under Normal conditions for 6 months.
  • the 6-month-old C57BL / 6J mice were purchased from 6-week-old mice and bred under normal conditions up to 6 months of age.
  • mice The size of meibomian gland tissue and the number of secretory ducts of 2-month-old Hsd3b6 KO mice and wild-type mice are shown in FIG. Similar to the aged mice, Hsd3b6 KO mice were found to show meibomian gland atrophy. Since the number of secretory ducts did not differ by genotype, it was confirmed that meibomian gland atrophy was not an abnormality in the developmental process of the ducts.
  • HBSS Hanks Balanced Salt Solution
  • Substrate preparation After cooling 3 H-DHEA to dryness with nitrogen to room temperature, add 1 ⁇ L / 4,000 cpm (25 ⁇ L measured with a liquid scintillation counter) of propylene glycol, and vortex for 5 minutes to 3 H-. DHEA was melted.
  • HBSS warmed to 37 ° C. 200 ⁇ L of HBSS warmed to 37 ° C. was added to the 2 mL tube in which the meibomian glands remained, the substrate solution was lightly vortexed, and then 24 ⁇ L was added to the HBSS for pipetting.
  • 2 ⁇ L of 100 mM NAD + in D-PBS was added, and the mixture was incubated for 30 minutes while shaking with a micro tube mixer placed in an incubator at 37 ° C.
  • the meibomian gland tissue was precipitated by centrifugation at 700 g at room temperature for 1 minute, and the entire amount of HBSS was taken and transferred to a test tube in which 2 mL of ethyl acetate had been dispensed. Vortexed for 10 seconds and immediately moved to ice as soon as the reaction stopped.
  • the immune response was visualized by (DAB).
  • DAB The immune response was visualized by (DAB).
  • BrdU-positive cells in the basal cell layer of the meibomian glands were counted on digital micrographs taken at 20x magnification.
  • the outer circumference length of the meibomian gland acinus was measured with ImageJ software, and the total number of BrdU-positive cells was normalized by this outer circumference length.
  • the number of BrdU-positive cells was counted using 16 sections per individual.
  • Example 3 A 3-month instillation experiment of NMN or NR into 1.75 year old wild-type mice. [Overview] In this example, the effect of NMN or NR instillation on 1.75 year old wild-type mice for 3 months on meibomian gland tissue volume will be demonstrated.
  • the lipid component in the meibomian glands is normalized as compared with the control Vehicle (phosphate buffered saline) instillation group.
  • Example 5 Quantification of testosterone in meibomian glands
  • the meibomian glands excised from the eyelids were homogenized with methanol / water (75:25, v / v), and then the steroids contained in the homogenate were extracted to dichloromethane using an Isolute SLE + cartridge (Biotage) and evaporated under nitrogen. After that, a residue was obtained.
  • mice lacking Hsd3b6 had a 50% reduction in testosterone locally contained in the meibomian glands. Furthermore, in Hsd3b6 knockout mice from which the gonads (testes) were removed, the amount of testosterone detected locally in the meibomian glands was reduced to 10% or less. From this, it can be seen that in the meibomian gland tissue, not only the circulating testosterone supplied from the testis but also the meibomian gland local testosterone production contributes to the same extent.
  • Hsd3b6 enzyme activity is increased, which promotes testosterone production, which is known to promote lipid production in meibomian glands, and normalizes the lipid component composition in meibomian gland tissue. It is considered to be.

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ES20832373T ES2989969T3 (es) 2019-06-25 2020-06-24 Uso novedoso de mononucleótido de nicotinamida (NMN) y ribósido de nicotinamida (NR)
US17/621,114 US20220370484A1 (en) 2019-06-25 2020-06-24 Novel use of nicotinamide mononucleotide (nmn) and nicotinamide riboside (nr)
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