WO2022123836A1 - 小児の近視進行抑制用点眼剤及び小児の近視進行抑制剤のスクリーニング方法 - Google Patents

小児の近視進行抑制用点眼剤及び小児の近視進行抑制剤のスクリーニング方法 Download PDF

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Publication number
WO2022123836A1
WO2022123836A1 PCT/JP2021/032067 JP2021032067W WO2022123836A1 WO 2022123836 A1 WO2022123836 A1 WO 2022123836A1 JP 2021032067 W JP2021032067 W JP 2021032067W WO 2022123836 A1 WO2022123836 A1 WO 2022123836A1
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Prior art keywords
myopia
pathway
atf6
eye
perk
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PCT/JP2021/032067
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English (en)
French (fr)
Japanese (ja)
Inventor
一男 坪田
俊英 栗原
真一 池田
紀和子 森
效炎 姜
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Rohto Pharmaceutical Co Ltd
Tsubota Laboratory Inc
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Rohto Pharmaceutical Co Ltd
Tsubota Laboratory Inc
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Application filed by Rohto Pharmaceutical Co Ltd, Tsubota Laboratory Inc filed Critical Rohto Pharmaceutical Co Ltd
Priority to KR1020237022414A priority Critical patent/KR20230135054A/ko
Priority to CA3204753A priority patent/CA3204753A1/en
Priority to MA61683A priority patent/MA61683A1/fr
Priority to CN202180082953.5A priority patent/CN116761595A/zh
Priority to TNP/2023/000138A priority patent/TN2023000138A1/en
Priority to JP2022568049A priority patent/JPWO2022123836A1/ja
Priority to EP21902941.0A priority patent/EP4257147A4/en
Priority to AU2021396680A priority patent/AU2021396680A1/en
Priority to PE2023001843A priority patent/PE20240227A1/es
Priority to MX2023006723A priority patent/MX2023006723A/es
Priority to US18/266,102 priority patent/US20240041806A1/en
Priority to IL303499A priority patent/IL303499A/en
Publication of WO2022123836A1 publication Critical patent/WO2022123836A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5041—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects involving analysis of members of signalling pathways
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells

Definitions

  • the present invention relates to an eye drop used for suppressing the progression of myopia in children and a screening method for an agent for suppressing the progression of myopia in children. More specifically, the present invention "normalizes" the normal eye growth of a child ("normal eye growth of a child” by suppressing ATF6 and / or PERK, which are the causative genes of the progression of myopia in a child.
  • Non-Patent Document 1 The latest research on myopia and severe myopia predicts a significant increase in the world's myopia population, with about 5 billion myopia and about 1 billion severe myopia in 2050. (See Non-Patent Document 1).
  • the human eye has hyperopia immediately after birth, and the degree of hyperopia decreases due to the extension of the optical axis due to the extension of the optical axis in the anterior-posterior direction during the growth period (up to 8 years old). By becoming, it becomes hypermetropic. This is called “physiological axis extension", and if this physiological axis extension is impaired for some reason, hyperopia remains due to insufficient eye axis extension, and the QOL (Quality of Life) of children is significantly deteriorated. ..
  • the present inventors have involved the degree of involvement of the signal transduction system (pathway) of endoplasmic reticulum stress response genes (PERK, ATF6, IRE1) in pathological axial elongation, and the contribution rate to the suppression of axial elongation by suppressing each pathway. , Or a synergistic effect when suppressed in combination was examined. As a result, it was found that the effect of suppressing pathological axial elongation is enhanced by suppressing the PERK pathway and / or the ATF6 pathway.
  • PERK endoplasmic reticulum stress response genes
  • An object of the present invention is to provide a screening method for searching for a component that suppresses the PERK pathway and / or the ATF6 pathway. Another object of the present invention is to obtain an active ingredient that suppresses the progression of myopia without inhibiting the normal growth (emmetropia) of a child's eyeball by the screening method, and to provide an eye drop containing the active ingredient.
  • various components considered to be effective for myopia are the components safe for children with pathological axial elongation and physiological axial elongation at the same time, that is, for hyperopia due to insufficient elongation or myopia due to excessive elongation? It is to provide a way to verify that it does not happen.
  • the present invention [1] An eye drop for suppressing the progression of myopia in children, which comprises an inhibitor of the PERK (PKR-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient.
  • PERK PSR-like endoplasmic reticulum kinase
  • ATF6 Activating transcription factor 6
  • a method for screening a pediatric myopia progression inhibitor including.
  • the present invention it is possible to provide a screening method for searching for a component that suppresses the signal transduction system of PERK and / or ATF6.
  • a screening method for searching for a component that suppresses the signal transduction system of PERK and / or ATF6.
  • FIG. 1 It is explanatory drawing of the myopia induction in a young mouse.
  • A is a schematic structural diagram of myopia induction
  • (b) is a photograph of a myopia-induced juvenile mouse. It is a graph which shows that myopia induction induces axial elongation and endoplasmic reticulum stress in the sclera.
  • FIG. 3 is a graph showing changes in axial elongation and refraction (myopia) due to instillation of various inhibitors of the PERK pathway, ATF6 pathway, and IRE1 pathway to mice.
  • STF STF080310
  • GSK GSK2656157
  • NFV Nerphinavir
  • Is. It is a graph which shows the change (myopia) of the axial extension and refraction by instillation of various inhibitors of the PERK pathway, the ATF6 pathway, and the IRE1 pathway to a mouse in the inhibitor different from FIG.
  • 3 is a graph evaluating the involvement of the ATF6 pathway in suppressing the progression of myopia in children in Test Example 4. It is a graph which showed the influence by the difference of the administration form on the lens thickening by myopia induction in Test Example 5.
  • the eye drop for suppressing the progression of myopia in children contains an inhibitor of the PERK (PKR-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient.
  • PERK PSR-like endoplasmic reticulum kinase
  • ATF6 Activating transcription factor 6
  • the inhibitor of the PERK pathway and / or the ATF6 pathway is a substance having an inhibitory effect on the signal transduction system of PERK (PERK pathway) and / or the signal transduction system of ATF6 (ATF6 pathway).
  • PERK pathway signal transduction system of PERK
  • ATF6 pathway signal transduction system of ATF6
  • the inhibitory effect on these signal transduction systems can be evaluated by a known method using changes in genes and / or proteins involved in these signal transduction systems as an index, as in the examples described later.
  • a substance having an inhibitory effect on both the PERK pathway and the ATF6 pathway can be an active ingredient for suppressing the progression of myopia in children.
  • a compound that targets and reduces genes and proteins involved in PERK and / or ATF6 signal transduction and nucleic acids such as antisense oligonucleotides and siRNA that reduce protein expression in the PERK pathway and / or ATF6 pathway. It can be added to eye drops as an effective ingredient for suppressing the progression of myopia in children.
  • the inhibitor of the PERK pathway or the ATF6 pathway means a substance having an inhibitory effect on the signal transduction system of PERK or the signal transduction system of ATF6 in the endoplasmic reticulum.
  • the inhibitory effect on these signal transduction systems should be evaluated by the method described in the experimental examples described later or by a known method, using changes in genes and / or proteins involved in these signal transduction systems as indicators. Can be done.
  • the evaluation is made by changing the expression of the factor by at least 1% depending on the candidate substance as compared with the control in which the candidate substance is not added. It is possible.
  • the expression of the factor fluctuates by at least 1% depending on the candidate substance as compared with the control in which the candidate substance is not added. It is possible to evaluate.
  • PERK is an endoplasmic reticulum transmembrane kinase, and as factors involved in its signal transduction, for example, eIF2 ⁇ (eucaryotic initiation factor 2 ⁇ ), ATF4 (Activating protein factor 4), CHOP (C / EBPhomo) Growth arrest DNA and damage protein 34) and the like can be mentioned.
  • eIF2 ⁇ eucaryotic initiation factor 2 ⁇
  • ATF4 Activating protein factor 4
  • CHOP C / EBPhomo Growth arrest DNA and damage protein 34
  • ATF6 is a membrane-bound transcription factor belonging to the CREB / ATF family, and examples of factors involved in its signal transduction include BiP (Binding immunoglobulin protein, also referred to as “GRP78”) and Txndc12 (thioredoxin dominant proteining). 12, (also referred to as "ERp18"), S1P (site-1 protease), S2P (site-2 protease) and the like.
  • the present invention is not limited to these, and at least a component specified as a component that suppresses the ATF6 pathway and a component newly specified as a component that suppresses the PERK pathway and the ATF6 pathway can also be used.
  • the inhibitor of the ATF6 pathway is not limited, but sodium phenylbutyrate is preferable from the viewpoint of solubility in eye drops.
  • sodium phenylbutyrate is preferable because it can inhibit the PERK pathway in addition to the ATF6 pathway.
  • Inhibitors of the PERK pathway and / or the ATF6 pathway may be synthesized and used by a known method, or commercially available products may be obtained and used.
  • the "pharmaceutically acceptable salt” is not particularly limited, and specific examples thereof include organic acid salts, inorganic acid salts, organic bases, and inorganic bases.
  • organic acid salt include monocarboxylates such as acetate, trifluoroacetate, butyrate, palmitate and stearate; fumarate, maleate, succinate, malonate and the like.
  • Examples of the inorganic acid salt include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate.
  • Examples of the salt with an organic base include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picolin and ethylenediamine.
  • Examples of the salt with an inorganic base include ammonium salts; alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, and various salts such as salts with metals such as aluminum. These salts may be used alone or in any combination of two or more.
  • the "pharmaceutically acceptable salt” may include a solvate or hydrate of the salt.
  • the content of the inhibitor of the PERK pathway and / or the ATF6 pathway can be appropriately changed depending on the usage, dosage, type of additive and the like. For example, 0.01% by mass or more is preferable, 0.05% by mass or more is more preferable, and 0.1% by mass or more is further preferable with respect to the total amount of eye drops (total mass; the same applies in the present specification). , 0.2% by mass or more is particularly preferable.
  • the content of the inhibitor of the PERK pathway and / or the ATF6 pathway is, for example, preferably 5% by mass or less, more preferably 4% by mass or less, still more preferably 3% by mass or less, based on the total amount of the eye drops. Mass% or less is particularly preferable.
  • the content of the inhibitor of the PERK pathway and / or the ATF6 pathway is, for example, preferably 0.01 to 5% by mass, more preferably 0.05 to 4% by mass, and 0.1 to 0.1% by mass, based on the total amount of eye drops. It is more preferably to 3% by mass, and particularly preferably 0.2 to 2% by mass.
  • the content thereof is, for example, relative to the total amount of eye drops. Therefore, 0.01 to 5% by mass is preferable, 0.05 to 4% by mass is more preferable, 0.1 to 3% by mass is further preferable, and 0.2 to 2% by mass is particularly preferable.
  • the eye drops according to the present invention are used for suppressing the progression of myopia in children.
  • a child is a child between the ages of 7 and 15 years.
  • the degree of refraction of the eye is mild hyperopia after birth, and the axis of the eye extends until it becomes almost emmetropic by school age.
  • Axial length grows rapidly from birth to about 2 years old, and then gradually grows.
  • the extension of the eye axis to the emmetropia accompanying such growth is called “physiological extension of the eye axis” and is an indispensable phenomenon for the normal growth of the eye.
  • physiological extension of the eye axis is an indispensable phenomenon for the normal growth of the eye.
  • continued elongation of the axial length even after school age is considered to be “pathological axial elongation” because it leads to the progression of myopia.
  • pathological axial extension an extension of 1 mm axial length in an adult eye leads to an increase in myopia of about 3.0D, and the axial extension is irreversible.
  • the composition according to the present invention is used as an eye drop.
  • the dosage form of the eye drop for suppressing the progression of myopia in children is not limited, and examples thereof include an aqueous eye drop, a time-dissolving eye drop, a suspension eye drop, an oil-based eye drop, and an eye ointment. Be done. Among these, an aqueous eye drop is preferable from the viewpoint of remarkably exerting the effect of the present invention.
  • active ingredients can be added to the eye drops.
  • active ingredients are not particularly limited, and are, for example, decongestion components, eye muscle regulator components, anti-inflammatory drug components, astringent drug components, antihistamine drug components, antiallergic drug components, vitamins, amino acids, and antibacterial components.
  • examples thereof include drug components, sugars, polymer compounds or derivatives thereof, cellulose or derivatives thereof, local anesthetic components and the like.
  • various ingredients and additives are appropriately selected according to a conventional method according to the use and form thereof, as long as the effects of the present invention are not impaired, and one or two or more of them are contained in combination.
  • those components or additives for example, carriers, fragrances or refreshing agents, preservatives, bactericides or antibacterial agents, pH regulators, chelating agents, stabilizers, etc., which are generally used for preparing liquids and the like, etc.
  • examples thereof include various additives such as a tensioning agent, a buffering agent, and a thickening agent.
  • the following are examples of typical ingredients used in eye drops, but are not limited thereto.
  • the carrier examples include an aqueous solvent such as water and hydrous ethanol.
  • a solubilizer may be used.
  • the solubilizer include polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, povidone, polysorbate 80 and the like.
  • fragrance or refreshing agent examples include terpenes (specifically, anethole, eugenol, camphor, geraniol, cineole, borneol, menthol, limonene, ryuno, etc., which may be d-form, l-form or dl-form. Good), essential oils (eucalyptol oil, cool mint oil, kehi oil, spear mint oil, sardine water, sardine oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.) and the like.
  • terpenes specifically, anethole, eugenol, camphor, geraniol, cineole, borneol, menthol, limonene, ryuno, etc.
  • essential oils eucalyptol oil, cool mint oil, kehi oil, spear mint oil, sardine water, sardine oil, peppermint oil, berga
  • preservatives, bactericides or antibacterial agents examples include polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, etc.
  • pH adjusting agent examples include hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid and the like.
  • chelating agent examples include ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.
  • the stabilizer examples include sodium edetate hydrate, povidone, polysorbate 80, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium pyrosulfate, monoethanolamine, aluminum monostearate, and the like. Examples thereof include glycerin monostearate.
  • tonicity agent examples include potassium chloride, sodium chloride, concentrated glycerin, glucose, D-mannitol and the like.
  • buffering agent examples include sodium citrate hydrate, sodium acetate hydrate, sodium hydrogen carbonate, trometamol, boric acid, borosand, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate and the like.
  • thickening agent examples include carboxyvinyl polymer, povidone, polyvinyl alcohol (partially saponified product), hydroxyethyl cellulose, hypromellose, methyl cellulose, glycerin and the like.
  • the additive can be blended in the range where the effect of the present invention is expected or the effect of the present invention is not impaired.
  • the content thereof is not particularly limited, but is preferably about 0.001 to 1% by mass with respect to the total amount of eye drops.
  • the pH of the eye drops may be 3 to 10, preferably 4 to 9 from the viewpoint of usability, and more preferably 5 to 8.5 from the viewpoint of usability.
  • a known eye drop container can be used without limitation.
  • the eye drop container a container having a shape that allows the eye drop to be dropped onto the eye, for example, a shape having a nozzle and a container mouth at the tip of the nozzle can be used.
  • the instillation container has a structure in which a nozzle separately molded is attached to the container, and a container in which the nozzle portion (liquid pouring portion) and the container body are integrally molded (for example,). It may be any of the single-use type instillation containers, etc.).
  • the eye drop container may usually be a plastic container.
  • the constituent materials of the plastic container are not particularly limited, but for example, one of polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, and polyimide, copolymers thereof, or two or more thereof. Can be mentioned.
  • polyethylene terephthalate, polyarylate, polyethylene naphthalate, a copolymer thereof, or a mixture of two or more thereof is preferable from the viewpoint that the effect of the present invention can be easily exerted by adjusting the extrusion or the like.
  • the eye drops may be filled in a transparent container (a container having transparency enough to observe foreign substances) containing such a material as a main material, or may be filled in a light-shielded container. good.
  • the light shielding may be performed, for example, by adding a colorant to the transparent container material, or by covering the container with a shrink film, an outer box, or the like.
  • the capacity of the container is preferably about 0.5 to 50 mL, more preferably about 3 to 20 mL, in order to further facilitate the effect of the present invention by adjusting the extrusion or the like.
  • the structure and constituent materials of the nozzle provided in the eye drop container are not particularly limited.
  • the structure of the nozzle may be any structure generally adopted as the nozzle of the eye drop container.
  • the constituent material of the nozzle for example, the same material as the constituent material of the plastic container is exemplified. From the viewpoint of further improving the drainage of the eye drops and suppressing the variation in the dropping amount, a nozzle containing polyethylene or polypropylene as a constituent material is suitable.
  • Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene, and among them, a nozzle containing low-density polyethylene as a constituent material is preferable.
  • the eye drops according to the present invention can be prepared by a method commonly used or known to those skilled in the art. For example, after each component is dispersed on a carrier such as water, a solubilizer is added if necessary, heated as necessary, homogenized, dissolved or emulsified using a homomixer or the like to adjust the pH. It may be prepared by adjusting the pH with an agent. Further, as a method for sterilizing the preparation, a method such as electron beam sterilization, autoclave sterilization, or filtration sterilization can be selected.
  • the usage and dosage of the eye drops according to the present invention vary depending on the patient's symptoms and the like, but usually, about 1 to 6 times a day, about 1 to 2 drops may be instilled.
  • the eye drops according to the present invention can be applied to children.
  • an eye drop containing at least one selected from the group consisting of phenylbutyric acid and a pharmaceutically acceptable salt thereof, for example, as an inhibitor of the PERK pathway and / or the ATF6 pathway without limitation. It is possible to instill the eye drops once or twice a day with one or two drops at a time, and it is preferable to instill one drop once a day.
  • the eye drops according to the present invention can be used for children, for example, before taking a nap, before going to bed, or other times when the activity is not active.
  • the method for screening a pediatric myopia progression inhibitor is a step of contacting a candidate substance with cells derived from the eye, and a protein and / or gene of the signal transduction system of PERK and / or ATF6 in the cells. It includes a step of selecting a candidate substance using a change as an index.
  • cells are contacted in the presence or absence of a candidate substance, and changes in PERK and / or ATF6 signaling system proteins and / or genes due to the candidate substance are measured and compared. This can lead to screening of candidate substances.
  • the cells derived from the eye are not limited, but are preferably cells in the sclera, and more preferably scleral fibroblasts, from the viewpoint of remarkably exerting the effect of the present invention.
  • the cells derived from the eye are preferably cells derived from the animal model that induced myopia.
  • a myopia induction model a known animal model can be used.
  • examples of the myopia-inducing model include an animal model in which a minus lens is worn to induce myopia, and an animal model in which a myopia-inducing agent is administered to induce myopia.
  • a negative lens As such a negative lens, a -20 to -40 diopter (D) can be used, and a -25 to -35 diopter (D) is preferable.
  • a method of wearing the minus lens a known method can be used, and the method of wearing the minus lens is not limited, and examples thereof include fixing the minus lens in front of the eyes of an animal using a fixative.
  • the wearing period of the minus lens can be, for example, at least one week, preferably two weeks or more, and more preferably three weeks or more.
  • the myopia inducer a known substance can be used, but for example, as the myopia inducer, tunicamycin, thapsigargin and the like can be used as evaluated in the experimental examples described later. be.
  • an activator of the PERK pathway and an activator of the ATF6 pathway can be used in combination.
  • Examples of the PERK pathway activator include CCT020312 and the like, and examples of the ATF6 pathway activator include AA147 and the like, which can be administered alone or in combination, and these can be administered in combination. It is preferable to do so.
  • Such myopia inducers are not limited, but can be administered as, for example, an injection or an eye drop from the viewpoint of acting on cells of the eye such as the sclera, and should be administered as an eye drop. Is preferable.
  • tunicamycin When used as an eye drop, it can be, for example, 10 to 100 ⁇ g / mL, preferably 20 to 80 ⁇ g / mL, and more preferably 40 to 60 ⁇ g / mL.
  • Thapsigargin When Thapsigargin is used as an eye drop, it can be, for example, 1 to 100 ⁇ M, preferably 2 to 60 ⁇ M, and more preferably 5 to 30 ⁇ M.
  • mice it is preferable to use young-aged animals from the viewpoint of using an animal model assuming application to children.
  • the mice it is preferable to start wearing a minus lens at the time of weaning, and it is more preferable that the mice are 3 weeks old.
  • physiological axial elongation occurs from 3 to 6 weeks of age. Therefore, by inducing myopia from the age of 3 weeks, it is possible to promote excessive axial elongation in addition to physiological axial elongation, and thus it is possible to cause pathological axial elongation.
  • the candidate substance it is preferable to apply the candidate substance to 3-week-old mice before and after myopia induction, or during the period during which myopia induction is performed. According to this method, it is possible to evaluate the effect of the candidate substance on physiological axial elongation and pathological axial elongation.
  • white Leghorn it is preferable to use, for example, 5-day-old white Leghorn chicks from the viewpoint of making an animal model assuming application to children.
  • the step of bringing the candidate substance into contact with cells derived from the eye is preferably administered by oral, intraperitoneal injection or eye drops, and more preferably by eye drops.
  • the candidate substance can be contained in eye drops and administered.
  • a known evaluation method can be used in the step of measuring the protein of the signal transduction system of PERK and / or ATF6 by the candidate substance and / or the gene change.
  • gene expression and protein expression or secretion can be measured by known methods such as microarray, real-time PCR method, PCR method, Western blotting method, ELISA method, and immune tissue staining.
  • RNA extraction method when measuring changes in genes in the signal transduction system of PERK or ATF6, it is possible to extract RNA from cultured cells using a known RNA extraction method and use it as a step for quantitative analysis of mRNA expression.
  • the step of quantitatively analyzing the expression of mRNA is not limited, but it is preferable to use the real-time PCR method.
  • the factor involved in signal transduction described above in the item inhibitor of PERK pathway and ATF6 pathway
  • Examples of factors involved in the PERK pathway include CHOP, ATF4, GADD34 and the like.
  • factors involved in the ATF6 pathway include GRP78, GRP94, PDI, Cnex, HYOU, ERdj3 and the like.
  • the candidate substance is selected as an inhibitor of the PERK pathway and / or the ATF6 pathway, and myopia in children. It can be used as a progress inhibitor.
  • the present invention may also have the following aspects.
  • An eye drop for suppressing the progression of myopia in children which contains an inhibitor of the PERK (PKRK-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient; Eye drops containing an inhibitor of the PERK (PKRK-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient for use in suppressing the progression of myopia in children; Use of PERK (PKRK-like endoplasmic reticulum kinase) and / or ATF6 (Activating transcription factor 6) pathway inhibitors for the manufacture of eye drops for the inhibition of myopia progression in children; A method for suppressing the progression of myopia in children, which comprises ingesting an inhibitor of the PERK (PKRK-like endoplasmic reticulum kinase) pathway and / or the ATF6
  • the screening method according to the above, wherein the cells derived from the eye are cells derived from an animal model that induced myopia;
  • the screening method according to the above, wherein the negative lens is a -20 to -40 diopter (D) lens;
  • the screening method according to the above, wherein the wearing period of the minus lens is at least one week;
  • the screening method according to the above, wherein the myopia inducer comprises tunicamycin and / or thapsigargin;
  • the screening method according to the above, wherein the concentration of the tunicamycin in the case of eye drop administration is 10 to 100 ⁇ g / mL;
  • the screening method according to the above, wherein the concentration of Thapsigargin in the case of eye drop administration is 1 to 100 ⁇ M;
  • Non-Patent Document 3 the human eye has hyperopia immediately after birth, and then the axis of the eye extends (that is, myopia) and becomes emmetropic in school age (around 8 years old). Further, as described in Non-Patent Document 6, the eye axis is elongated with the growth of the mouse (C57BL6) during the period of 3 to 6 weeks of age. Therefore, this myopia-induced juvenile mouse corresponds to about 8 years of age in humans in terms of the dynamics of myopia progression, which corresponds to a real infant / child (school age). By using this animal model, it is possible to elucidate the mechanism of myopia progression in human children and to screen for therapeutic agents for myopia progression in children.
  • Fig. 1 (a) schematically shows the mechanism by which axial myopia is induced by wearing a minus lens.
  • Emmetropia is a state in which the image is clearly visible because the parallel rays that enter the eye form an image on the retina.
  • axial myopia is a state in which parallel rays entering the eye form an image in front of the retina due to the long axial length of the eye, and therefore cannot be clearly seen.
  • the axis of the eye extends to the position where the image is formed when the minus lens is worn, that is, the state where the image is clearly visible when the minus lens is worn.
  • the axis of the eye is elongated, and it is possible to create an eye condition similar to that of axial myopia.
  • a myopia-induced juvenile mouse is prepared as follows.
  • myopia guidance, axial length and refraction were measured by the same method as in Non-Patent Documents 4 and 5.
  • male C57BL6J mice were housed in standard clear cages in a temperature controlled clean room under a 12 hour light-dark cycle. Animals were allowed free intake of standard feed and high pressure steam sterilized tap water.
  • mice Immediately after weaning, 3-week-old mice are anesthetized with a three-kind mixed anesthesia of Domitor (Nippon Zenyaku Kogyo Co., Ltd.), Betorfar (Meiji Seika Pharma Co., Ltd.), and Midazolam (Sand Co., Ltd.), and the skull is exposed with scissors.
  • a support is erected on the skull and fixed with dental cement (Super-Bond, Sun Medical Co., Ltd.).
  • the stanchion is provided with a thread so that the adjustment device described later can be fixed with a nut.
  • a -30 diopter (D) minus lens (Rainbow Contact, Rainbow Optical Laboratory Co., Ltd.) as the right eye (myopia-guided eye), and use a 0D lens as a control, or only the frame as the left eye. Attach it to (control eye).
  • D diopter
  • a protector having a shape protruding laterally is adhered to the frame portion at the bottom of the lens so that the mouse is not damaged by the front legs or the like.
  • the protector prevents the mouse from touching the lens and does not scratch the lens.
  • the protector used here is one that is glued to the frame and integrated, but it is not necessary that the protector is integrated with the lens as long as the action of the mouse does not damage the lens. For example, it may be shaped like an Elizabethan collar worn by a traumatized animal.
  • An adjustment device for adjusting the width and angle of the attached lens is adhered to the frame above the lens as the mouse grows.
  • the adjuster is bent into a dogleg shape, one with a lens glued on it and the other with a slotted hole for attachment to a strut erected on the head.
  • the mouse By passing a long hole through a support and screwing it with a nut, the mouse can be firmly attached to the skin and fixed without pressing the periphery of both eyes.
  • a three-point adjustment mechanism consisting of a support, a nut, and an adjustment device, the width and angle can be adjusted according to the growth of the mouse, and the lens can be adjusted so that it is at the position of the mouse's eyes. Further, since the lens can be removed, it is possible to measure changes in the axial length and the refraction value with time.
  • Quantitative real-time PCR was performed on PowerUp SYBR Green Master Mix (Applied Biosystems, CA, USA) using the StepOnePlus real-time PCR system. Expression levels were standardized by ⁇ -actin.
  • FIG. 2 shows the axial elongation (a) and the refractive change (b) after myopia induction for 3 weeks
  • FIG. 3 shows the gene expression change in the sclera at that time.
  • the pathway of the endoplasmic reticulum stress response gene is shown in FIG.
  • FIG. 4 shows the expression of genes downstream of PERK, ATF6, and IRE1, which are the major genes for endoplasmic reticulum stress response
  • FIGS. 6-a and 6-b show axial extension (a) and inflection (b) after instillation of 60 ⁇ M STF, 100 ⁇ M GSK, and 100 ⁇ M NFV once daily for 10 days during the period of myopia induction in mice. ..
  • FIGS. 6-c and d show axial elongation (c) and inflection change (d) after similarly instilling a combination of these inhibitors (STF + GSK: S + G, GSK + NFV: G + N, NFV + STF: N + S, STF + GSK + NTF: S + G + N).
  • FIG. 7 shows the axial extension (a) and the refractive change (b) after similarly instilling 100 ⁇ M GSK2606414, Ceapin-A7, and 4 ⁇ 8C, respectively.
  • the axial length is significantly suppressed only when at least two types of PERK inhibitor and ATF6 inhibitor are present (G + N, S + G + N), myopia of refraction is suppressed, and single instillation is performed. No axial extension of the control eye was observed (Fig. 6-c, d). Furthermore, the changes in axial length and refraction due to single instillation of the inhibitors GSK2606414, Ceapin-A7, 4 ⁇ 8C, which are different from those in FIG. 6, are exactly the same as the results in FIG. 6, and neither axial elongation nor refraction myopia is suppressed. With single instillation other than 4 ⁇ 8C, it extended to the axis of the control eye (Fig. 7).
  • Test Example 3 4-Inhibition of endoplasmic reticulum stress pathway by PBA and TUDCA> In Test Example 2, it was considered effective to search for a component that suppresses both the PERK pathway and the ATF6 pathway in order to search for an agent for suppressing the progression of myopia in children.
  • the inhibition profile of the endoplasmic reticulum stress pathway was evaluated for components known to inhibit elongation (sodium phenylbutyrate ⁇ 4-PBA ⁇ , tauroursodeoxycholic acid ⁇ TUDCA ⁇ ).
  • FIG. 8 shows changes in gene expression after daily intraperitoneal injection of 4-PBA throughout the period of myopia induction in mice.
  • FIG. 9 shows the axial extension (a) and the refractive change (b) at the first week and the third week of myopia induction by 4-PBA administration.
  • FIG. 10 shows axial extension (a) and refractive change (b) after instillation of 0.2% and 2% 4-PBA into mice undergoing myopia induction.
  • FIG. 11 shows axial extension (b) and inflection (a) after daily intraperitoneal injection of TUDCA throughout the myopia induction period.
  • 4-PBA and TUDCA suppress the PERK pathway and ATF6 pathway, which are the mechanisms of suppression of myopia progression in children, in the endoplasmic reticulum stress pathway (Fig. 12), and are physiologically associated with normal eye growth. It was confirmed that the axial elongation was not suppressed, but only the pathological axial elongation was suppressed. That is, components that suppress both PERK and ATF6, such as 4-PBA, TUDCA, and combinations of PERK and ATF6 inhibitors, do not inhibit or exceed the normal inflection of children from hyperopia to emmetropia. It was confirmed that only the progression of myopia was suppressed.
  • the method of instilling a single inhibitor of each of PERK, ATF6, and IRE1 in the sclera of a myopia-induced juvenile mouse, or the method of instilling an instillation using a combination of inhibitors, and the like are based on the description of Test Example 2.
  • ATF6-N The value obtained by dividing the amount of ATF6 activation form (ATF6-N) by the amount of ATF6 precosor form (ATF6-P) is shown in FIG. 13 as an index of activation.
  • the value obtained by dividing the amount of ATF6-N of ATF6 by the amount of ATF6-P of ATF6 showed significantly higher values in some groups.
  • the group in which the active ATF6 value was high was consistent with the group in which the pathological axial elongation and the decrease in the refractive value shown in FIGS. 6c and 6d were observed, respectively.
  • STF indicates an IRE1 inhibitor
  • G indicates a PERK inhibitor
  • NFV or "N” indicates an ATF6 inhibitor. It is the same as the previous test examples.
  • the results summarized in Table 1 show that in the sclera of the myopic eye, activation of the ATF6 pathway triggers a decrease in the refractive index associated with axial elongation, and conversely, inactivation of the ATF6 pathway causes the axial axis. It is shown that the decrease in the refraction value due to the elongation is suppressed.
  • a drug (4-PBA) having this medicinal effect and pharmacology is effective for the treatment / prevention of myopia progression in children.
  • FIG. 14 (B) when 4-PBA was administered by eye drops, no thickening of the crystalline lens was observed in the -30D lens wearing group. That is, it was shown that eye drops are suitable as a method for administering 4-PBA in terms of reachability to the target tissue.

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PCT/JP2021/032067 2020-12-11 2021-09-01 小児の近視進行抑制用点眼剤及び小児の近視進行抑制剤のスクリーニング方法 Ceased WO2022123836A1 (ja)

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CA3204753A CA3204753A1 (en) 2020-12-11 2021-09-01 Eyedrops for inhibiting myopia progression in children and screening method for inhibitor of myopia progression in children
MA61683A MA61683A1 (fr) 2020-12-11 2021-09-01 Collyre pour inhiber la progression de la myopie chez les enfants et méthode de criblage pour un inhibiteur de la progression de la myopie chez les enfants
CN202180082953.5A CN116761595A (zh) 2020-12-11 2021-09-01 抑制儿童近视进展用滴眼剂及儿童近视进展抑制剂的筛选方法
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EP21902941.0A EP4257147A4 (en) 2020-12-11 2021-09-01 EYE DROPS FOR INHIBITING MYOPIA PROGRESSION IN CHILDREN AND SCREENING METHOD FOR MYOPIA PROGRESSION INHIBITOR IN CHILDREN
AU2021396680A AU2021396680A1 (en) 2020-12-11 2021-09-01 Eyedrops for inhibiting myopia progression in children and screening method for inhibitor of myopia progression in children
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US18/266,102 US20240041806A1 (en) 2020-12-11 2021-09-01 Eyedrops for Inhibiting Myopia Progression in Children and Screening Method for Inhibitor of Myopia Progression in Children
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