WO2021145356A1 - Drug composition for treating nearsightedness, preventing nearsightedness, and/or minimizing progression of nearsightedness - Google Patents
Drug composition for treating nearsightedness, preventing nearsightedness, and/or minimizing progression of nearsightedness Download PDFInfo
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- WO2021145356A1 WO2021145356A1 PCT/JP2021/000953 JP2021000953W WO2021145356A1 WO 2021145356 A1 WO2021145356 A1 WO 2021145356A1 JP 2021000953 W JP2021000953 W JP 2021000953W WO 2021145356 A1 WO2021145356 A1 WO 2021145356A1
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- Prior art keywords
- myopia
- pharmaceutical composition
- administration
- ester
- salt
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- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
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- 239000004310 lactic acid Substances 0.000 description 1
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
Definitions
- the present invention is a pharmaceutical composition for treating myopia, preventing myopia and / or suppressing the progression of myopia, more specifically 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid or an ester thereof Or related to a pharmaceutical composition comprising salts thereof for the treatment of myopia, prevention of myopia and / or suppression of progression of myopia.
- Myopia is a type of refractive error, in which light entering the eye from a distance forms an image in front of the retina, making objects appear blurry.
- myopia when the refractive force of the cornea or crystalline lens is too strong, it is out of focus on the retina when looking at a distance and is in focus in front of the retina (refractive myopia), or axial length. If (the length from the retina to the retina) is elongated and is too long than normal, even if the crystalline lens is thin enough when looking at a distance, it will not be in focus on the retina and will be in focus in front of the retina. It is said that it develops due to the fact that it ends up (axial myopia). Also, the onset of myopia and the rapid progression of myopia at a young age can lead to severe myopia as an adult with visually impaired pathological myopia lesions.
- Patent Document 1 discloses that atropine (muscarinic receptor antagonist) is useful for the treatment of myopia
- Patent Document 2 describes tiotropium used for the treatment of chronic obstructive pulmonary disease (COPD). It has been disclosed to be effective in preventing myopia, treating myopia and / or suppressing the progression of myopia.
- COPD chronic obstructive pulmonary disease
- Patent Document 3 discloses a huge number of compounds having a strong and continuous effect of lowering intraocular pressure, and one of the compounds is 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-.
- oxepin-3-yl ⁇ butane The acid is disclosed.
- An object of the present invention is to find a novel compound useful for treating myopia, preventing myopia and / or suppressing the progression of myopia.
- the present inventors have a 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(3S, 5aR, 6R, 7R, 8aS) -6-[(3S, 5aR, 6R, 7R, 8aS) -6-[ 1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid or
- the present invention has been completed by finding that the ester or a salt thereof suppresses axial length elongation and refractive error.
- the present invention provides: (1) As an active ingredient, 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl ⁇ butanoic acid or its esters or salts thereof, for the treatment of myopia, prevention of myopia and / or inhibition of myopia progression Pharmaceutical composition.
- Myopia includes axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, strongest myopia, strong myopia, moderate myopia, weak myopia, and glaucoma (especially juvenile myopia).
- the pharmaceutical composition according to (1) above which is myopia that has developed, myopia that is at risk of developing glaucoma, or myopia with high ocular pressure.
- the pharmaceutical composition according to (1) or (2) above which is used for topical ocular administration.
- composition according to (3) above wherein the topical ocular administration is eye drop administration, ophthalmic ointment administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subtenon administration, intraconjunctival insertion or eyelid application. .. (5) The pharmaceutical composition according to any one of (1) to (4) above, which is an eye drop, an eye gel, an eye ointment, or an injection.
- 4-as an active ingredient which has the effects of treating myopia, preventing myopia and / or suppressing the progression of myopia, while suppressing the side effects (mydriasis, etc.) observed with muscarinic receptor antagonists such as atropine.
- muscarinic receptor antagonists such as atropine.
- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyocta
- a pharmaceutical composition comprising hydro-2H-cyclopenta [b] oxepine-3-yl ⁇ butanoic acid or an ester thereof or a salt thereof can be obtained.
- the ester of the present compound is formed by dehydration condensation of the carboxyl group of the present compound with a monohydric alcohol having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms).
- the ester to be used is mentioned.
- examples of such esters are methyl ester, ethyl ester, n-propyl ester, 2-propanol ester (isopropyl ester), n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester.
- n-hexyl ester can be mentioned.
- preferred esters include methyl esters, ethyl esters, n-propyl esters, 2-propanol esters, and most preferably 2-propanol esters.
- the 2-propanol ester of this compound has the chemical name 2-propanol 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy)-.
- 3-Hydroxy-1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl ⁇ is a compound represented by butanoate, and the following formula: It is a compound represented by, and is also called Sepetaprost (CAS Registry Number: 1262873-06-2).
- 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid or its esters are not only 100% pure, but also their isomers, such as geometric isomers, optical isomers, It may contain tautomers (keto, enol) and the like, and may contain less than 50%, for example.
- the present compound or an ester thereof may be in the form of a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
- the salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, and malic acid.
- Citric acid tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, horseuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid , Pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfate, methyl sulfate, naphthalenesulfonic acid, salts with organic acids such as sulfosalicylic acid; sodium , Salts with metals such as potassium, calcium, magnesium; salts with inorganic compounds such as ammonia; and salts with organic amines such as triethylamine, gu
- the compound or an ester thereof or a salt thereof may take the form of a hydrate or a solvate.
- the compound or an ester thereof or a salt thereof can be produced by a known method, for example, the methods described in International Publication No. 2011/013651 and International Publication No. 2018/003945.
- the content of the present compound or an ester thereof or a salt thereof is not particularly limited, but in the case of an eye drop, it is, for example, 0.000001 to 5% (w / v), 0.00001 to 0.05. % (W / v) is more preferable, 0.0001 to 0.01% (w / v) is further preferable, 0.0003 to 0.003% (w / v) is particularly preferable, and 0.001 to 0. 003% (w / v) is most preferable.
- One aspect of the content of the compound or an ester thereof or a salt thereof in the present invention is 0.002% (w / v).
- % (w / v) means the mass (g) of the target component contained in 100 mL of the pharmaceutical composition of the present invention
- % (w / w) is the present invention. It means the mass (g) of the target component contained in 100 g of the pharmaceutical composition of.
- the value when a salt of the present compound or an ester thereof is contained, the value may be the content of the salt of the present compound or the ester thereof or the content of the compound or the ester thereof.
- the value thereof is the hydrate of the compound or the ester thereof or a salt thereof or It may be the content of the hydrate, the content of the compound or an ester thereof or a salt thereof, or the content of the compound or an ester thereof.
- the same shall apply unless otherwise specified.
- myopia is defined as a refracted state of the eye in which parallel rays entering the eye in an unaccommodated state are imaged in front of the retina.
- Myopia in the present invention includes all known classifications and definitions of myopia, such as axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, strongest myopia, strong myopia.
- Moderate myopia, weak myopia, myopia with glaucoma (especially juvenile glaucoma), myopia at risk of developing glaucoma, myopia with high eye pressure, etc. preferably axial myopia
- Examples include extreme myopia, strongest myopia, severe myopia, and myopia developing glaucoma (particularly juvenile glaucoma), more preferably axial myopia.
- treatment means healing or ameliorating any treatment of myopia or its associated symptoms, such as myopia, particularly refractive myopia and / or axial myopia, and alleviating or suppressing the symptoms associated with myopia. Means. It also includes prevention of recurrence of myopia.
- prevention means preventing the onset of myopia, delaying the onset of myopia, and reducing the risk of developing myopia.
- pressing the progression of myopia means delaying the progression of myopia and reducing the progression of myopia.
- treatment of myopia, prevention of myopia and / or suppression of progression of myopia also includes suppression of axial length extension and / or suppression of refractive error.
- compositions of the present invention can be widely used regardless of the age of the patient, prevent myopia in children or teenagers with advanced myopia and adults, and / or in teenagers and adults with advanced pediatrics or myopia. It can be used to suppress the progression of myopia.
- the "patient” means humans and animals such as dogs, cats, horses and the like. Among them, human is preferable.
- the "therapeutically effective amount” means an amount that brings about a therapeutic effect on myopia and its associated symptoms, or an amount that causes a delay in the progression of myopia, as compared with an untreated subject.
- the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable active ingredient other than the compound or an ester thereof or a salt thereof.
- the pharmaceutical composition of the present invention can be orally or parenterally administered.
- the routes of administration include oral administration, intravenous administration, transdermal administration, topical ocular administration (eg, ophthalmic administration, ointment administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subconjunctival administration, intraconjunctival insertion, etc. Eyelid application) and the like.
- the pharmaceutical composition of the present invention is prepared by mixing the compound or an ester thereof or a salt thereof with one or more pharmaceutically acceptable additives, for example, tablets, capsules, granules, powders, troches, syrups.
- pharmaceutically acceptable additives for example, tablets, capsules, granules, powders, troches, syrups.
- Conventional methods in the art for the desired form of oral preparations such as agents, emulsions, suspensions, or parenteral preparations such as eye drops, eye gels, eye ointments, injections, suppositories, nasal preparations.
- Preferred dosage forms of the pharmaceutical composition of the present invention include eye drops, eye gels, eye ointments and injections.
- a desired eye drop When using an eye drop, a desired eye drop can be prepared by adding the compound or an ester thereof or a salt thereof to purified water, a buffer solution, etc., stirring the mixture, and then adjusting the pH with a pH adjuster.
- additives commonly used in eye drops can be used as needed, and the additives include tonicity agents, buffering agents, surfactants, stabilizers, preservatives, solubilizers, and the like. Can be mentioned.
- the pH of the eye drops may be within the range allowed for the ophthalmic preparation, preferably in the range of pH 4 to 8, and more preferably in the range of pH 5 to 7.
- the base When used as an eye ointment, it can be prepared using a general-purpose base, and examples of the base include white petrolatum and liquid paraffin.
- a bulking agent such as lactose, crystalline cellulose, starch, vegetable oil and the like
- examples of the lubricant include magnesium stearate and talc
- examples of the binder include hydroxypropyl cellulose and polyvinylpyrrolidone.
- examples of the disintegrant include carboxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose and the like
- examples of the coating agent include hydroxypropyl methyl cellulose, macrogol, silicon resin and the like
- examples of the film agent include gelatin film and the like.
- the dosage of the pharmaceutical composition of the present invention can be appropriately changed according to the dosage form, the patient's symptoms, age, weight, the age at which myopia develops, the judgment of a doctor, and the like.
- the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but one to several drops per dose is taken from 1 to 1 to 1 day. It can be instilled several times (for example, 1 to 8 times). It can also be used when wearing contact lenses.
- Example 1 Myopia progression (axial length extension and refractive error) suppression test using a guinea pig myopia model (1) The effect of sepetaprost on myopia progression (axial length extension and refractive error) was evaluated according to the following method. (Sample preparation) After dissolving Sepetaprost in purified water containing a solubilizer, a 0.002% Sepetaprost solution was prepared as a sample using a general-purpose method. As a control, saline was used.
- a lens (goggles) was prepared by cutting the tip of the bottom portion of a test tube having a diameter of 18 mm by 10 mm and adhering it to one side of a magic tape (about 20 mm square) having a hole having an appropriate diameter in the center with an adhesive.
- a control group 10 per group.
- 10 ⁇ L of 0.002% sepetaprost solution was applied to the right eye of each guinea pig every day for 14 days until the 13th day. It was administered by eye drops 6 times a day.
- 10 ⁇ L of physiological saline was instilled into the right eye of each guinea pig.
- the left eye of all guinea pigs was instilled with 10 ⁇ L of physiological saline 6 times a day for 14 days from the 0th day to the 13th day. Guinea pigs were bred under normal breeding conditions.
- Difference in refraction (D) right refraction (D) -left refraction (D)
- Refractive error suppression rate (%) (difference in refraction in the 1-0.002% sepetaprost solution administration group / difference in refraction in the control group) ⁇ 100
- Table 2 shows the average values of the difference in axial length and the difference in refraction between the control group and the 0.002% sepetaprost solution administration group.
- Table 3 shows the axial length elongation inhibition rate and the refractive error inhibition rate in the 0.002% sepetaprost solution administration group.
- the axial length elongation inhibition rate was 79% and the refractive error inhibition rate was 91% in the 0.002% sepetaprost solution administration group.
- Example 2 Myopia progression (axial length extension and refractive error) suppression test using a guinea pig myopia model (2) According to the following method, the effects of sepetaprost and timolol maleic acid on myopia progression (axial length extension and refractive error) were evaluated and the effects of lowering intraocular pressure were evaluated.
- Sample preparation After dissolving Sepetaprost in purified water containing a solubilizer, a 0.002% Sepetaprost solution was prepared as a sample using a general-purpose method.
- timoptol (registered trademark) ophthalmic solution which is a 0.5% timolol maleic acid solution, was used as a sample.
- saline was used as a control.
- 10 ⁇ L of 0.002% sepetaprost solution was applied to the right eye of each guinea pig every day for 16 days until the 15th day. It was administered by eye drops 6 times a day.
- Difference in axial length and axial length elongation suppression rate from before the start of instillation administration, difference in refractive error and refractive error suppression rate from before the start of instillation administration, and difference in intraocular pressure from before the start of instillation administration on the 15th day Calculated by the following formula. The calculation was performed in Microsoft Excel based on the measured values.
- Axial length elongation inhibition rate (%) (difference in axial length between 1-0.002% sepetaprost solution administration group (or difference in axial length between 0.5% timolol maleic acid solution administration group) / control group (Difference in axial length) x 100
- Difference in refraction (D) Right refraction on day 14-Right refraction (D) before the start of instillation
- Refractive error suppression rate (%) (difference in refraction of 1-0.002% sepetaprost solution administration group (or difference in refraction of 0.5% timolol maleic acid solution administration group) / difference in refraction of control group Difference) x 100
- Table 5 shows the average values of the difference in axial length, the difference in refraction, and the difference in intraocular pressure between the control group, the 0.002% sepetaprost solution-administered group, and the 0.5% timolol maleic acid solution-administered group.
- Table 6 shows the axial length elongation inhibition rate and the refractive error inhibition rate of the 0.002% sepetaprost solution administration group and the 0.5% timolol maleic acid solution administration group.
- the intraocular pressure lowering effect was observed in the 0.002% sepetaprost solution administration group and the 0.5% timolol maleic acid solution administration group.
- the axial length elongation inhibition rate was 53% and the refractive error inhibition rate was 51% in the 0.002% sepetaprost solution administration group, but in the 0.5% timolol maleic acid solution administration group. No effect of suppressing axial length extension and refractive error was observed.
- sepetaprost was shown to strongly suppress axial length extension and refractive error. Therefore, sepetaprost is useful in the treatment of myopia, prevention of myopia and / or suppression of progression of myopia.
- the pharmaceutical composition of the present invention is 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene.
- -1-yl] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanoic acid or an ester thereof or a salt thereof suppresses axial length elongation and refractive error to treat myopia. It is useful for preventing myopia and / or suppressing the progression of myopia.
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a drug composition for treating nearsightedness, preventing nearsightedness, and/or minimizing progression of nearsightedness, including, as an active ingredient, 4-{(3S, 5ar, 6R, 7R, 8aS)-6-[(1E, 3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-butene-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic acid, an ester thereof or a salt thereof.
Description
本発明は、近視の治療、近視の予防および／または近視の進行抑制のための医薬組成物、より詳しくは、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、近視の治療、近視の予防および／または近視の進行抑制のための医薬組成物に関する。
The present invention is a pharmaceutical composition for treating myopia, preventing myopia and / or suppressing the progression of myopia, more specifically 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof Or related to a pharmaceutical composition comprising salts thereof for the treatment of myopia, prevention of myopia and / or suppression of progression of myopia.
近視は屈折異常の一種で、遠方から目に入ってきた光が網膜より手前で像を結び、物がぼやけて見える状態をいう。近視は、角膜または水晶体の屈折力が強すぎる場合に、遠くを見たときに網膜上でピントが合わず、網膜の手前でピントが合ってしまうこと（屈折性近視）、あるいは、眼軸長（角膜から網膜までの長さ）が伸長し、正常より長すぎる場合に、遠くを見たときに水晶体を十分薄くしても、網膜上でピントが合わず、網膜の手前でピントが合ってしまうこと（軸性近視）が原因で発症するとされている。また、若年齢での近視の発症や近視の急速な進行は、視覚的に障害を与える病的な近視病変を伴う成人としての強度近視になり得る。
Myopia is a type of refractive error, in which light entering the eye from a distance forms an image in front of the retina, making objects appear blurry. In myopia, when the refractive force of the cornea or crystalline lens is too strong, it is out of focus on the retina when looking at a distance and is in focus in front of the retina (refractive myopia), or axial length. If (the length from the retina to the retina) is elongated and is too long than normal, even if the crystalline lens is thin enough when looking at a distance, it will not be in focus on the retina and will be in focus in front of the retina. It is said that it develops due to the fact that it ends up (axial myopia). Also, the onset of myopia and the rapid progression of myopia at a young age can lead to severe myopia as an adult with visually impaired pathological myopia lesions.
近視の治療には、手術、メガネもしくはコンタクトレンズによる矯正または薬物療法が用いられている。近年、近視の治療の一つである薬物療法の研究が盛んに行われており、近視の治療剤として有用であり得る薬物が報告されている。例えば、特許文献１には、アトロピン（ムスカリン受容体アンタゴニスト）が近視の治療に有用であることが開示され、特許文献２には、慢性閉塞性肺疾患（ＣＯＰＤ）の治療に使用されるチオトロピウムが近視予防、近視治療および／または近視進行抑制に有効であることが開示されている。
一方、近視患者の状態は多様であり、それに応じて治療剤を適宜選択できるように新たな近視治療剤の開発が強く望まれている。 Surgery, spectacle or contact lens correction or medication is used to treat myopia. In recent years, research on drug therapy, which is one of the treatments for myopia, has been actively conducted, and drugs that may be useful as therapeutic agents for myopia have been reported. For example, Patent Document 1 discloses that atropine (muscarinic receptor antagonist) is useful for the treatment of myopia, and Patent Document 2 describes tiotropium used for the treatment of chronic obstructive pulmonary disease (COPD). It has been disclosed to be effective in preventing myopia, treating myopia and / or suppressing the progression of myopia.
On the other hand, the conditions of myopia patients are diverse, and the development of new therapeutic agents for myopia is strongly desired so that therapeutic agents can be appropriately selected accordingly.
一方、近視患者の状態は多様であり、それに応じて治療剤を適宜選択できるように新たな近視治療剤の開発が強く望まれている。 Surgery, spectacle or contact lens correction or medication is used to treat myopia. In recent years, research on drug therapy, which is one of the treatments for myopia, has been actively conducted, and drugs that may be useful as therapeutic agents for myopia have been reported. For example, Patent Document 1 discloses that atropine (muscarinic receptor antagonist) is useful for the treatment of myopia, and Patent Document 2 describes tiotropium used for the treatment of chronic obstructive pulmonary disease (COPD). It has been disclosed to be effective in preventing myopia, treating myopia and / or suppressing the progression of myopia.
On the other hand, the conditions of myopia patients are diverse, and the development of new therapeutic agents for myopia is strongly desired so that therapeutic agents can be appropriately selected accordingly.
特許文献３は、強力かつ持続的な眼圧下降作用を有する膨大な数の化合物を開示しており、その化合物の一つとして４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸を開示している。
Patent Document 3 discloses a huge number of compounds having a strong and continuous effect of lowering intraocular pressure, and one of the compounds is 4-{(3S, 5aR, 6R, 7R, 8aS) -6-. [(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butane The acid is disclosed.
本発明は、近視の治療、近視の予防および／または近視の進行抑制に有用な新たな化合物を見出すことを目的とする。
An object of the present invention is to find a novel compound useful for treating myopia, preventing myopia and / or suppressing the progression of myopia.
本発明者らは、上記課題を解決すべく鋭意検討した結果、眼圧下降作用を有し、緑内障の治療に有用な４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩が眼軸長伸長および屈折異常を抑制することを見出し、本発明を完成させた。
As a result of diligent studies to solve the above problems, the present inventors have a 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(3S, 5aR, 6R, 7R, 8aS) -6-[(3S, 5aR, 6R, 7R, 8aS) -6-[ 1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or The present invention has been completed by finding that the ester or a salt thereof suppresses axial length elongation and refractive error.
具体的に、本発明は以下を提供する。
（１）有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、近視の治療、近視の予防および／または近視の進行抑制のための医薬組成物。
（２）近視が、軸性近視、屈折性近視、仮性近視、病的近視、単純近視、極度近視、最強度近視、強度近視、中等度近視、弱度近視、緑内障（特に若年性緑内障）を発症している近視、緑内障を発症するリスクのある近視または高眼圧を伴う近視である、上記（１）に記載の医薬組成物。
（３）眼局所投与に用いられる、上記（１）または（２）に記載の医薬組成物。
（４）眼局所投与が点眼投与、眼軟膏投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与、結膜嚢内挿入または眼瞼塗布である、上記（３）に記載の医薬組成物。
（５）点眼剤、眼ゲル剤、眼軟膏剤または注射剤である、上記（１）～（４）のいずれかに記載の医薬組成物。
（６）４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の含有量が、０．０００００１～５％（ｗ／ｖ）である、上記（１）～（５）のいずれかに記載の医薬組成物。
（７）４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩が、セペタプロストである、上記（１）～（６）のいずれかに記載の医薬組成物。
（８）有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、眼軸長伸長を抑制するための医薬組成物。
（９）有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、屈折異常を抑制するための医薬組成物。
（１０）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、近視の治療および／または予防方法。
（１１）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、近視の進行を抑制する方法。
（１２）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、眼軸長伸長を抑制する方法。
（１３）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、屈折異常を抑制する方法。
（１４）近視および／または予防を治療するための医薬の製造における、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の使用。
（１５）近視の進行を抑制するための医薬の製造における、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の使用。
（１６）近視の治療および／または予防に使用する、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩。
（１７）近視の進行抑制に使用する、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩。 Specifically, the present invention provides:
(1) As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or its esters or salts thereof, for the treatment of myopia, prevention of myopia and / or inhibition of myopia progression Pharmaceutical composition.
(2) Myopia includes axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, strongest myopia, strong myopia, moderate myopia, weak myopia, and glaucoma (especially juvenile myopia). The pharmaceutical composition according to (1) above, which is myopia that has developed, myopia that is at risk of developing glaucoma, or myopia with high ocular pressure.
(3) The pharmaceutical composition according to (1) or (2) above, which is used for topical ocular administration.
(4) The pharmaceutical composition according to (3) above, wherein the topical ocular administration is eye drop administration, ophthalmic ointment administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subtenon administration, intraconjunctival insertion or eyelid application. ..
(5) The pharmaceutical composition according to any one of (1) to (4) above, which is an eye drop, an eye gel, an eye ointment, or an injection.
(6) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] The content of -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is 0.000001 to 5% (w / v), as described above (1). )-(5).
(7) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] The pharmaceutical composition according to any one of (1) to (6) above, wherein -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is sepetaprost. thing.
(8) As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} A pharmaceutical composition comprising butanoic acid or an ester thereof or a salt thereof for suppressing axial length elongation.
(9) As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} A pharmaceutical composition for suppressing refractive error, which comprises butanoic acid or an ester thereof or a salt thereof.
(10) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy Treatment of myopia and administration of -1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof. / Or preventive measures.
(11) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy The progression of myopia, characterized by administration of -1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof. How to suppress.
(12) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy Axial length extension characterized by administration of -1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof. How to suppress.
(13) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy -1-Buten-1-yl] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is administered to suppress refractive error. how to.
(14) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluoro) in the manufacture of drugs for treating myopia and / or prevention. Phenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or its esters or salts thereof.
(15) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy)) in the manufacture of a drug for suppressing the progression of myopia. Use of -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
(16) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3, used for the treatment and / or prevention of myopia -Hydroxy-1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
(17) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-, which is used to suppress the progression of myopia. 1-Buten-1-yl] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
（１）有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、近視の治療、近視の予防および／または近視の進行抑制のための医薬組成物。
（２）近視が、軸性近視、屈折性近視、仮性近視、病的近視、単純近視、極度近視、最強度近視、強度近視、中等度近視、弱度近視、緑内障（特に若年性緑内障）を発症している近視、緑内障を発症するリスクのある近視または高眼圧を伴う近視である、上記（１）に記載の医薬組成物。
（３）眼局所投与に用いられる、上記（１）または（２）に記載の医薬組成物。
（４）眼局所投与が点眼投与、眼軟膏投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与、結膜嚢内挿入または眼瞼塗布である、上記（３）に記載の医薬組成物。
（５）点眼剤、眼ゲル剤、眼軟膏剤または注射剤である、上記（１）～（４）のいずれかに記載の医薬組成物。
（６）４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の含有量が、０．０００００１～５％（ｗ／ｖ）である、上記（１）～（５）のいずれかに記載の医薬組成物。
（７）４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩が、セペタプロストである、上記（１）～（６）のいずれかに記載の医薬組成物。
（８）有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、眼軸長伸長を抑制するための医薬組成物。
（９）有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、屈折異常を抑制するための医薬組成物。
（１０）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、近視の治療および／または予防方法。
（１１）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、近視の進行を抑制する方法。
（１２）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、眼軸長伸長を抑制する方法。
（１３）患者に、治療上の有効量の４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を投与することを特徴とする、屈折異常を抑制する方法。
（１４）近視および／または予防を治療するための医薬の製造における、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の使用。
（１５）近視の進行を抑制するための医薬の製造における、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の使用。
（１６）近視の治療および／または予防に使用する、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩。
（１７）近視の進行抑制に使用する、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩。 Specifically, the present invention provides:
(1) As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or its esters or salts thereof, for the treatment of myopia, prevention of myopia and / or inhibition of myopia progression Pharmaceutical composition.
(2) Myopia includes axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, strongest myopia, strong myopia, moderate myopia, weak myopia, and glaucoma (especially juvenile myopia). The pharmaceutical composition according to (1) above, which is myopia that has developed, myopia that is at risk of developing glaucoma, or myopia with high ocular pressure.
(3) The pharmaceutical composition according to (1) or (2) above, which is used for topical ocular administration.
(4) The pharmaceutical composition according to (3) above, wherein the topical ocular administration is eye drop administration, ophthalmic ointment administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subtenon administration, intraconjunctival insertion or eyelid application. ..
(5) The pharmaceutical composition according to any one of (1) to (4) above, which is an eye drop, an eye gel, an eye ointment, or an injection.
(6) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] The content of -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is 0.000001 to 5% (w / v), as described above (1). )-(5).
(7) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] The pharmaceutical composition according to any one of (1) to (6) above, wherein -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is sepetaprost. thing.
(8) As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} A pharmaceutical composition comprising butanoic acid or an ester thereof or a salt thereof for suppressing axial length elongation.
(9) As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene-1 -Il] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} A pharmaceutical composition for suppressing refractive error, which comprises butanoic acid or an ester thereof or a salt thereof.
(10) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy Treatment of myopia and administration of -1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof. / Or preventive measures.
(11) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy The progression of myopia, characterized by administration of -1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof. How to suppress.
(12) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy Axial length extension characterized by administration of -1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof. How to suppress.
(13) For patients, therapeutically effective amounts of 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy -1-Buten-1-yl] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is administered to suppress refractive error. how to.
(14) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluoro) in the manufacture of drugs for treating myopia and / or prevention. Phenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or its esters or salts thereof.
(15) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy)) in the manufacture of a drug for suppressing the progression of myopia. Use of -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
(16) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3, used for the treatment and / or prevention of myopia -Hydroxy-1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
(17) 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-, which is used to suppress the progression of myopia. 1-Buten-1-yl] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
上記（１）から（１７）の各構成は、任意に２以上を選択して組み合わせることができる。
Each configuration of (1) to (17) above can be arbitrarily selected and combined with two or more.
本発明によれば、アトロピンなどのムスカリン受容体アンタゴニストで見られる副作用（散瞳など）を抑えつつ、近視の治療、近視の予防および／または近視の進行抑制の効果をもたらす、有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む医薬組成物を得ることができる。
According to the present invention, 4-as an active ingredient, which has the effects of treating myopia, preventing myopia and / or suppressing the progression of myopia, while suppressing the side effects (mydriasis, etc.) observed with muscarinic receptor antagonists such as atropine. {(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyocta A pharmaceutical composition comprising hydro-2H-cyclopenta [b] oxepine-3-yl} butanoic acid or an ester thereof or a salt thereof can be obtained.
以下に、本発明について詳細に説明する。
The present invention will be described in detail below.
本発明において、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸（以下、本化合物ともいう）は、下式：
で表される化合物である（ＣＡＳ登録番号：１２６２８７３－４８－２）。
In the present invention, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-Hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid (hereinafter, also referred to as this compound) is expressed by the following formula:
It is a compound represented by (CAS Registry Number: 1262873-48-2).
本発明において、本化合物のエステルは、本化合物のカルボキシル基が炭素数１～６（好ましくは炭素数１～４、より好ましくは炭素数１～３）の１価アルコールと脱水縮合することで形成されるエステルが挙げられる。そのエステルの例としては、メチルエステル、エチルエステル、ｎ－プロピルエステル、２－プロパニルエステル（イソプロピルエステル）、ｎ－ブチルエステル、イソブチルエステル、ｓｅｃ－ブチルエステル、ｔｅｒｔ－ブチルエステル、ｎ－ペンチルエステルまたはｎ－ヘキシルエステルが挙げられる。好ましいエステルの例として、メチルエステル、エチルエステル、ｎ－プロピルエステル、２－プロパニルエステルが挙げられ、最も好ましくは２－プロパニルエステルが挙げられる。
In the present invention, the ester of the present compound is formed by dehydration condensation of the carboxyl group of the present compound with a monohydric alcohol having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms). The ester to be used is mentioned. Examples of such esters are methyl ester, ethyl ester, n-propyl ester, 2-propanol ester (isopropyl ester), n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester. Alternatively, n-hexyl ester can be mentioned. Examples of preferred esters include methyl esters, ethyl esters, n-propyl esters, 2-propanol esters, and most preferably 2-propanol esters.
本化合物の２－プロパニルエステルは、化学名２－プロパニル ４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタノアートで表される化合物であり、また下式：
で表される化合物であり、セペタプロストとも称される（ＣＡＳ登録番号：１２６２８７３－０６－２）。
The 2-propanol ester of this compound has the chemical name 2-propanol 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy)-. 3-Hydroxy-1-butene-1-yl] -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} is a compound represented by butanoate, and the following formula:
It is a compound represented by, and is also called Sepetaprost (CAS Registry Number: 1262873-06-2).
本発明において、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸またはそのエステルは、１００％純粋なものだけでなく、その異性体、例えば、幾何異性体、光学異性体、互変異性体（ケト体、エノール体）などを含んでもよく、例えば、５０％未満含んでもよい。
In the present invention, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl ] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or its esters are not only 100% pure, but also their isomers, such as geometric isomers, optical isomers, It may contain tautomers (keto, enol) and the like, and may contain less than 50%, for example.
本発明において、本化合物またはそのエステルは、塩形態であってもよく、医薬として許容される塩であれば特に制限されない。その塩としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸などの無機酸との塩；酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、ラウリル硫酸、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸などの有機酸との塩；ナトリウム、カリウム、カルシウム、マグネシウムなどの金属との塩；アンモニアなどの無機化合物との塩；および、トリエチルアミン、グアニジンなどの有機アミンとの塩が挙げられる。
In the present invention, the present compound or an ester thereof may be in the form of a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, and malic acid. Citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, horseuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid , Pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfate, methyl sulfate, naphthalenesulfonic acid, salts with organic acids such as sulfosalicylic acid; sodium , Salts with metals such as potassium, calcium, magnesium; salts with inorganic compounds such as ammonia; and salts with organic amines such as triethylamine, guanidine.
本発明において、本化合物もしくはそのエステルまたはそれらの塩は、水和物または溶媒和物の形態をとってもよい。
In the present invention, the compound or an ester thereof or a salt thereof may take the form of a hydrate or a solvate.
本発明において、本化合物もしくはそのエステルまたはそれらの塩は、公知の方法、例えば、国際公開第２０１１／０１３６５１号および国際公開第２０１８／００３９４５号に記載の方法により製造することができる。
In the present invention, the compound or an ester thereof or a salt thereof can be produced by a known method, for example, the methods described in International Publication No. 2011/013651 and International Publication No. 2018/003945.
本発明において、本化合物もしくはそのエステルまたはそれらの塩の含有量は、特に制限されないが、点眼剤の場合、例えば０．０００００１～５％（ｗ／ｖ）であり、０．００００１～０．０５％（ｗ／ｖ）がより好ましく、０．０００１～０．０１％（ｗ／ｖ）がさらに好ましく、０．０００３～０．００３％（ｗ／ｖ）がことさら好ましく、０．００１～０．００３％（ｗ／ｖ）が最も好ましい。本発明における本化合物もしくはそのエステルまたはそれらの塩の含有量の一態様は、０．００２％（ｗ／ｖ）である。眼軟膏剤の場合、それらの含有量は、例えば０．０００００１～５％（ｗ／ｗ）であり、０．００００１～０．０５％（ｗ／ｗ）がより好ましい。
なお、本発明において、「％（ｗ／ｖ）」は、本発明の医薬組成物１００ｍＬ中に含まれる対象成分の質量（ｇ）を意味し、「％（ｗ／ｗ）」は、本発明の医薬組成物１００ｇ中に含まれる対象成分の質量（ｇ）を意味する。本発明において、本化合物またはそのエステルの塩が含有される場合、その値は本化合物またはそのエステルの塩の含有量であっても、本化合物またはそのエステルの含有量であってもよい。また、本発明において本化合物もしくはそのエステルまたはそれらの塩が、水和物または溶媒和物の形態をとって配合される場合、その値は本化合物もしくはそのエステルまたはそれらの塩の水和物または溶媒和物の含有量であっても、本化合物もしくはそのエステルまたはそれらの塩の含有量であっても、本化合物またはそのエステルの含有量であってもよい。以下、特に断りがない限り同様とする。 In the present invention, the content of the present compound or an ester thereof or a salt thereof is not particularly limited, but in the case of an eye drop, it is, for example, 0.000001 to 5% (w / v), 0.00001 to 0.05. % (W / v) is more preferable, 0.0001 to 0.01% (w / v) is further preferable, 0.0003 to 0.003% (w / v) is particularly preferable, and 0.001 to 0. 003% (w / v) is most preferable. One aspect of the content of the compound or an ester thereof or a salt thereof in the present invention is 0.002% (w / v). In the case of eye ointments, their content is, for example, 0.000001 to 5% (w / w), more preferably 0.00001 to 0.05% (w / w).
In the present invention, "% (w / v)" means the mass (g) of the target component contained in 100 mL of the pharmaceutical composition of the present invention, and "% (w / w)" is the present invention. It means the mass (g) of the target component contained in 100 g of the pharmaceutical composition of. In the present invention, when a salt of the present compound or an ester thereof is contained, the value may be the content of the salt of the present compound or the ester thereof or the content of the compound or the ester thereof. In addition, when the present compound or an ester thereof or a salt thereof is blended in the form of a hydrate or a solvent in the present invention, the value thereof is the hydrate of the compound or the ester thereof or a salt thereof or It may be the content of the hydrate, the content of the compound or an ester thereof or a salt thereof, or the content of the compound or an ester thereof. Hereinafter, the same shall apply unless otherwise specified.
なお、本発明において、「％（ｗ／ｖ）」は、本発明の医薬組成物１００ｍＬ中に含まれる対象成分の質量（ｇ）を意味し、「％（ｗ／ｗ）」は、本発明の医薬組成物１００ｇ中に含まれる対象成分の質量（ｇ）を意味する。本発明において、本化合物またはそのエステルの塩が含有される場合、その値は本化合物またはそのエステルの塩の含有量であっても、本化合物またはそのエステルの含有量であってもよい。また、本発明において本化合物もしくはそのエステルまたはそれらの塩が、水和物または溶媒和物の形態をとって配合される場合、その値は本化合物もしくはそのエステルまたはそれらの塩の水和物または溶媒和物の含有量であっても、本化合物もしくはそのエステルまたはそれらの塩の含有量であっても、本化合物またはそのエステルの含有量であってもよい。以下、特に断りがない限り同様とする。 In the present invention, the content of the present compound or an ester thereof or a salt thereof is not particularly limited, but in the case of an eye drop, it is, for example, 0.000001 to 5% (w / v), 0.00001 to 0.05. % (W / v) is more preferable, 0.0001 to 0.01% (w / v) is further preferable, 0.0003 to 0.003% (w / v) is particularly preferable, and 0.001 to 0. 003% (w / v) is most preferable. One aspect of the content of the compound or an ester thereof or a salt thereof in the present invention is 0.002% (w / v). In the case of eye ointments, their content is, for example, 0.000001 to 5% (w / w), more preferably 0.00001 to 0.05% (w / w).
In the present invention, "% (w / v)" means the mass (g) of the target component contained in 100 mL of the pharmaceutical composition of the present invention, and "% (w / w)" is the present invention. It means the mass (g) of the target component contained in 100 g of the pharmaceutical composition of. In the present invention, when a salt of the present compound or an ester thereof is contained, the value may be the content of the salt of the present compound or the ester thereof or the content of the compound or the ester thereof. In addition, when the present compound or an ester thereof or a salt thereof is blended in the form of a hydrate or a solvent in the present invention, the value thereof is the hydrate of the compound or the ester thereof or a salt thereof or It may be the content of the hydrate, the content of the compound or an ester thereof or a salt thereof, or the content of the compound or an ester thereof. Hereinafter, the same shall apply unless otherwise specified.
本発明において、「近視」とは、無調節の状態で眼に入る平行光線が網膜の前方で結像する眼の屈折状態と定義づけられる。本発明における「近視」には、あらゆる公知の近視の分類および定義が含まれ、例えば、軸性近視、屈折性近視、仮性近視、病的近視、単純近視、極度近視、最強度近視、強度近視、中等度近視、弱度近視、緑内障（特に若年性緑内障）を発症している近視、緑内障を発症するリスクのある近視、高眼圧を伴う近視などが挙げられ、好ましくは、軸性近視、極度近視、最強度近視、強度近視、緑内障（特に若年性緑内障）を発症している近視が挙げられ、より好ましくは、軸性近視が挙げられる。
In the present invention, "myopia" is defined as a refracted state of the eye in which parallel rays entering the eye in an unaccommodated state are imaged in front of the retina. "Myopia" in the present invention includes all known classifications and definitions of myopia, such as axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, strongest myopia, strong myopia. , Moderate myopia, weak myopia, myopia with glaucoma (especially juvenile glaucoma), myopia at risk of developing glaucoma, myopia with high eye pressure, etc., preferably axial myopia, Examples include extreme myopia, strongest myopia, severe myopia, and myopia developing glaucoma (particularly juvenile glaucoma), more preferably axial myopia.
本発明において、「治療」とは、近視またはそれに伴う症状のあらゆる治療、例えば、近視、特に屈折性近視および／または軸性近視を治癒または改善すること、近視に伴う症状を緩和または抑制することを意味する。また、近視の再発の防止も含まれる。
本発明において、「予防」とは、近視の発症を阻止すること、近視の発症を遅らせること、近視の発症の危険性を低下させることを意味する。
本発明において、「近視の進行抑制」とは、近視の進行を遅らせること、近視の進行を減退させることを意味する。
また、本発明において、「近視の治療、近視の予防および／または近視の進行抑制」とは、眼軸長伸長を抑制することおよび／または屈折異常を抑制することも含む。 In the present invention, "treatment" means healing or ameliorating any treatment of myopia or its associated symptoms, such as myopia, particularly refractive myopia and / or axial myopia, and alleviating or suppressing the symptoms associated with myopia. Means. It also includes prevention of recurrence of myopia.
In the present invention, "prevention" means preventing the onset of myopia, delaying the onset of myopia, and reducing the risk of developing myopia.
In the present invention, "suppressing the progression of myopia" means delaying the progression of myopia and reducing the progression of myopia.
Further, in the present invention, "treatment of myopia, prevention of myopia and / or suppression of progression of myopia" also includes suppression of axial length extension and / or suppression of refractive error.
本発明において、「予防」とは、近視の発症を阻止すること、近視の発症を遅らせること、近視の発症の危険性を低下させることを意味する。
本発明において、「近視の進行抑制」とは、近視の進行を遅らせること、近視の進行を減退させることを意味する。
また、本発明において、「近視の治療、近視の予防および／または近視の進行抑制」とは、眼軸長伸長を抑制することおよび／または屈折異常を抑制することも含む。 In the present invention, "treatment" means healing or ameliorating any treatment of myopia or its associated symptoms, such as myopia, particularly refractive myopia and / or axial myopia, and alleviating or suppressing the symptoms associated with myopia. Means. It also includes prevention of recurrence of myopia.
In the present invention, "prevention" means preventing the onset of myopia, delaying the onset of myopia, and reducing the risk of developing myopia.
In the present invention, "suppressing the progression of myopia" means delaying the progression of myopia and reducing the progression of myopia.
Further, in the present invention, "treatment of myopia, prevention of myopia and / or suppression of progression of myopia" also includes suppression of axial length extension and / or suppression of refractive error.
本発明の医薬組成物は、患者の年齢に関係なく広く使用することができ、小児もしくは近視が進行したティーンエイジャーや成人における近視の予防、および／または小児もしくは近視が進行したティーンエイジャーや成人における近視の進行抑制のために使用することができる。
The pharmaceutical compositions of the present invention can be widely used regardless of the age of the patient, prevent myopia in children or teenagers with advanced myopia and adults, and / or in teenagers and adults with advanced pediatrics or myopia. It can be used to suppress the progression of myopia.
本発明において、「患者」とは、ヒトおよび動物、例えば、イヌ、ネコ、ウマなどを意味する。その中でも、ヒトが好ましい。
In the present invention, the "patient" means humans and animals such as dogs, cats, horses and the like. Among them, human is preferable.
本発明において、「治療上の有効量」とは、未治療対象と比べて、近視およびそれに伴う症状の治療効果をもたらす量、または近視の進行の遅延をもたらす量を意味する。
In the present invention, the "therapeutically effective amount" means an amount that brings about a therapeutic effect on myopia and its associated symptoms, or an amount that causes a delay in the progression of myopia, as compared with an untreated subject.
本発明の医薬組成物は、特に断りのない限り、本化合物もしくはそのエステルまたはそれらの塩以外の医薬的に許容される活性成分を含んでいてもよい。
Unless otherwise specified, the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable active ingredient other than the compound or an ester thereof or a salt thereof.
本発明の医薬組成物は、経口または非経口投与することができる。投与経路としては、経口投与、静脈内投与、経皮投与、眼局所投与（例えば、点眼投与、眼軟膏投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与、結膜嚢内挿入、眼瞼塗布）などが挙げられる。
The pharmaceutical composition of the present invention can be orally or parenterally administered. The routes of administration include oral administration, intravenous administration, transdermal administration, topical ocular administration (eg, ophthalmic administration, ointment administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subconjunctival administration, intraconjunctival insertion, etc. Eyelid application) and the like.
本発明の医薬組成物は、本化合物もしくはそのエステルまたはそれらの塩を１以上の医薬的に許容される添加剤と混合して、例えば、錠剤、カプセル剤、顆粒剤、散剤、トローチ剤、シロップ剤、乳剤、懸濁剤などの経口剤、または点眼剤、眼ゲル剤、眼軟膏剤、注射剤、坐剤、経鼻剤などの非経口剤の所望の形態に該技術分野における通常の方法で調製することができる。本発明の医薬組成物の好ましい剤型として点眼剤、眼ゲル剤、眼軟膏剤および注射剤が挙げられる。
The pharmaceutical composition of the present invention is prepared by mixing the compound or an ester thereof or a salt thereof with one or more pharmaceutically acceptable additives, for example, tablets, capsules, granules, powders, troches, syrups. Conventional methods in the art for the desired form of oral preparations such as agents, emulsions, suspensions, or parenteral preparations such as eye drops, eye gels, eye ointments, injections, suppositories, nasal preparations. Can be prepared with. Preferred dosage forms of the pharmaceutical composition of the present invention include eye drops, eye gels, eye ointments and injections.
点眼剤とする場合は、精製水、緩衝液などに本化合物もしくはそのエステルまたはそれらの塩を添加、撹拌した後、ｐＨ調整剤によりｐＨを調整することで所望の点眼剤を調製できる。また、必要に応じて点眼剤に汎用されている添加剤を用いることができ、添加剤としては、等張化剤、緩衝化剤、界面活性剤、安定化剤、防腐剤、可溶化剤などが挙げられる。
When using an eye drop, a desired eye drop can be prepared by adding the compound or an ester thereof or a salt thereof to purified water, a buffer solution, etc., stirring the mixture, and then adjusting the pH with a pH adjuster. In addition, additives commonly used in eye drops can be used as needed, and the additives include tonicity agents, buffering agents, surfactants, stabilizers, preservatives, solubilizers, and the like. Can be mentioned.
点眼剤のｐＨは眼科製剤に許容される範囲内にあればよく、ｐＨ４～８の範囲が好ましく、ｐＨ５～７の範囲がより好ましい。
The pH of the eye drops may be within the range allowed for the ophthalmic preparation, preferably in the range of pH 4 to 8, and more preferably in the range of pH 5 to 7.
眼軟膏剤とする場合は、汎用される基剤を用いて調製することができ、基剤としては、白色ワセリン、流動パラフィンなどが挙げられる。
When used as an eye ointment, it can be prepared using a general-purpose base, and examples of the base include white petrolatum and liquid paraffin.
錠剤、カプセル剤、顆粒剤、散剤などの経口剤とする場合は、増量剤、滑沢剤、結合剤、崩壊剤、コーティング剤、皮膜剤などを必要に応じて加え調製することができる。増量剤としては、乳糖、結晶セルロース、デンプン、植物油などが挙げられ、滑沢剤としては、ステアリン酸マグネシウム、タルクなどが挙げられ、結合剤としては、ヒドロキシプロピルセルロース、ポリビニルピロリドンなどが挙げられ、崩壊剤としては、カルボキシメチルセルロースカルシウム、低置換ヒドロキシプロピルメチルセルロースなどが挙げられ、コーティング剤としては、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂などが挙げられ、皮膜剤としては、ゼラチン皮膜などが挙げられる。
When used as an oral preparation such as tablets, capsules, granules, and powders, it can be prepared by adding a bulking agent, a lubricant, a binder, a disintegrant, a coating agent, a film agent, etc. as necessary. Examples of the bulking agent include lactose, crystalline cellulose, starch, vegetable oil and the like, examples of the lubricant include magnesium stearate and talc, and examples of the binder include hydroxypropyl cellulose and polyvinylpyrrolidone. Examples of the disintegrant include carboxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose and the like, examples of the coating agent include hydroxypropyl methyl cellulose, macrogol, silicon resin and the like, and examples of the film agent include gelatin film and the like.
本発明の医薬組成物の用法用量は、剤形、患者の症状、年齢、体重、近視を発症した年齢、医師の判断などに応じて適宜変えることができる。例えば、本発明の医薬組成物を点眼剤として眼局所投与する場合、所望の薬効を奏するのに十分であれば用法用量に特に制限はないが、１回量１～数滴を１日１～数回（例えば、１～８回）点眼することができる。また、コンタクトレンズ装用時においても使用することができる。
The dosage of the pharmaceutical composition of the present invention can be appropriately changed according to the dosage form, the patient's symptoms, age, weight, the age at which myopia develops, the judgment of a doctor, and the like. For example, when the pharmaceutical composition of the present invention is locally administered to the eye as an eye drop, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but one to several drops per dose is taken from 1 to 1 to 1 day. It can be instilled several times (for example, 1 to 8 times). It can also be used when wearing contact lenses.
以下に実施例を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。
Examples are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.
実施例１：モルモット近視モデルを用いた近視進行(眼軸長伸長および屈折異常)抑制試験（１）
以下の方法にしたがって、セペタプロストの近視進行（眼軸長伸長および屈折異常）抑制効果を評価した。
（試料の調製）
セペタプロストを可溶化剤を含む精製水に溶解した後、汎用される方法を用いて、試料として０．００２％セペタプロスト溶液を調製した。対照として、生理食塩液を使用した。 Example 1: Myopia progression (axial length extension and refractive error) suppression test using a guinea pig myopia model (1)
The effect of sepetaprost on myopia progression (axial length extension and refractive error) was evaluated according to the following method.
(Sample preparation)
After dissolving Sepetaprost in purified water containing a solubilizer, a 0.002% Sepetaprost solution was prepared as a sample using a general-purpose method. As a control, saline was used.
以下の方法にしたがって、セペタプロストの近視進行（眼軸長伸長および屈折異常）抑制効果を評価した。
（試料の調製）
セペタプロストを可溶化剤を含む精製水に溶解した後、汎用される方法を用いて、試料として０．００２％セペタプロスト溶液を調製した。対照として、生理食塩液を使用した。 Example 1: Myopia progression (axial length extension and refractive error) suppression test using a guinea pig myopia model (1)
The effect of sepetaprost on myopia progression (axial length extension and refractive error) was evaluated according to the following method.
(Sample preparation)
After dissolving Sepetaprost in purified water containing a solubilizer, a 0.002% Sepetaprost solution was prepared as a sample using a general-purpose method. As a control, saline was used.
（モルモット近視モデルの作製）
直径１８ｍｍの試験管の底部分先端を１０ｍｍ切断し、中心に適当な直径の穴を開けたマジックテープ（約２０ｍｍ四方）の片面と接着剤にて接着させ、レンズ（ゴーグル）を作製した。入手した生後３週齢のモルモット（Ｓｌｃ：Ｈａｒｔｌｅｙ）（ｎ＝１２）の右眼に作製したゴーグルを接着剤にて装着させて近視を誘導して、モルモット近視モデルを作製した。なお、ゴーグルを装着していない左眼は対照とした。 (Creation of guinea pig myopia model)
A lens (goggles) was prepared by cutting the tip of the bottom portion of a test tube having a diameter of 18 mm by 10 mm and adhering it to one side of a magic tape (about 20 mm square) having a hole having an appropriate diameter in the center with an adhesive. A guinea pig myopia model was prepared by attaching the prepared goggles to the right eye of the obtained 3-week-old guinea pig (Slc: Hartley) (n = 12) with an adhesive to induce myopia. The left eye without goggles was used as a control.
直径１８ｍｍの試験管の底部分先端を１０ｍｍ切断し、中心に適当な直径の穴を開けたマジックテープ（約２０ｍｍ四方）の片面と接着剤にて接着させ、レンズ（ゴーグル）を作製した。入手した生後３週齢のモルモット（Ｓｌｃ：Ｈａｒｔｌｅｙ）（ｎ＝１２）の右眼に作製したゴーグルを接着剤にて装着させて近視を誘導して、モルモット近視モデルを作製した。なお、ゴーグルを装着していない左眼は対照とした。 (Creation of guinea pig myopia model)
A lens (goggles) was prepared by cutting the tip of the bottom portion of a test tube having a diameter of 18 mm by 10 mm and adhering it to one side of a magic tape (about 20 mm square) having a hole having an appropriate diameter in the center with an adhesive. A guinea pig myopia model was prepared by attaching the prepared goggles to the right eye of the obtained 3-week-old guinea pig (Slc: Hartley) (n = 12) with an adhesive to induce myopia. The left eye without goggles was used as a control.
（試料の投与）
作製されたモルモット近視モデルを０．００２％セペタプロスト溶液投与群と対照群に無作為に分類した（１群あたりｎ＝６）。０．００２％セペタプロスト溶液投与群では、右眼をゴーグルで遮蔽した日（０日目とする）から、各モルモットの右眼に０．００２％セペタプロスト溶液１０μＬを１３日目まで１４日間毎日、１日６回点眼投与した。０．００２％セペタプロスト溶液投与群と同様に、対照群では、各モルモットの右眼に生理食塩液１０μＬを点眼投与した。なお、すべてのモルモットの左眼には、生理食塩液１０μＬを０日目から１３日目まで１４日間毎日、１日６回点眼投与した。モルモットは通常の飼育条件で飼育した。
(Sample administration)
The guinea pig myopia model prepared was randomly classified into a 0.002% sepetaprost solution-administered group and a control group (n = 6 per group). In the 0.002% sepetaprost solution administration group, from the day when the right eye was shielded with goggles (referred to as day 0), 10 μL of 0.002% sepetaprost solution was applied to the right eye of each guinea pig every day for 14 days until the 13th day. It was administered by eye drops 6 times a day. Similar to the 0.002% sepetaprost solution administration group, in the control group, 10 μL of physiological saline was instilled into the right eye of each guinea pig. The left eye of all guinea pigs was instilled with 10 μL of physiological saline 6 times a day for 14 days from the 0th day to the 13th day. Guinea pigs were bred under normal breeding conditions.
作製されたモルモット近視モデルを０．００２％セペタプロスト溶液投与群と対照群に無作為に分類した（１群あたりｎ＝６）。０．００２％セペタプロスト溶液投与群では、右眼をゴーグルで遮蔽した日（０日目とする）から、各モルモットの右眼に０．００２％セペタプロスト溶液１０μＬを１３日目まで１４日間毎日、１日６回点眼投与した。０．００２％セペタプロスト溶液投与群と同様に、対照群では、各モルモットの右眼に生理食塩液１０μＬを点眼投与した。なお、すべてのモルモットの左眼には、生理食塩液１０μＬを０日目から１３日目まで１４日間毎日、１日６回点眼投与した。モルモットは通常の飼育条件で飼育した。
(Sample administration)
The guinea pig myopia model prepared was randomly classified into a 0.002% sepetaprost solution-administered group and a control group (n = 6 per group). In the 0.002% sepetaprost solution administration group, from the day when the right eye was shielded with goggles (referred to as day 0), 10 μL of 0.002% sepetaprost solution was applied to the right eye of each guinea pig every day for 14 days until the 13th day. It was administered by eye drops 6 times a day. Similar to the 0.002% sepetaprost solution administration group, in the control group, 10 μL of physiological saline was instilled into the right eye of each guinea pig. The left eye of all guinea pigs was instilled with 10 μL of physiological saline 6 times a day for 14 days from the 0th day to the 13th day. Guinea pigs were bred under normal breeding conditions.
（評価方法）
近視を誘導して１４日目にモルモット左右眼球の眼軸長を超音波眼軸長測定装置ＥＣＨＯＳＣＡＮ ＵＳ－５００(ニデック社)によるＡ－ｓｃａｎにて測定し、屈折度をオートレフラクトメーターＡＲ－１ａ(ニデック社)により測定した。眼軸長の差および眼軸長伸長抑制率ならびに屈折度の差および屈折異常抑制率を、以下の式にて算出した。計算は、実測値を基にMicrosoft Excelにおいて実施した。 (Evaluation method)
On the 14th day after inducing myopia, the axial lengths of the left and right eyeballs of the guinea pig were measured with A-scan using an ultrasonic axial length measuring device ECHOSCAN US-500 (Nidek), and the refractive index was measured with the autorefractometer AR-1a. Measured by (Nidek). The difference in axial length, the rate of inhibition of axial length elongation, the difference in refractive error, and the rate of refractive error suppression were calculated by the following formulas. The calculation was performed in Microsoft Excel based on the measured values.
近視を誘導して１４日目にモルモット左右眼球の眼軸長を超音波眼軸長測定装置ＥＣＨＯＳＣＡＮ ＵＳ－５００(ニデック社)によるＡ－ｓｃａｎにて測定し、屈折度をオートレフラクトメーターＡＲ－１ａ(ニデック社)により測定した。眼軸長の差および眼軸長伸長抑制率ならびに屈折度の差および屈折異常抑制率を、以下の式にて算出した。計算は、実測値を基にMicrosoft Excelにおいて実施した。 (Evaluation method)
On the 14th day after inducing myopia, the axial lengths of the left and right eyeballs of the guinea pig were measured with A-scan using an ultrasonic axial length measuring device ECHOSCAN US-500 (Nidek), and the refractive index was measured with the autorefractometer AR-1a. Measured by (Nidek). The difference in axial length, the rate of inhibition of axial length elongation, the difference in refractive error, and the rate of refractive error suppression were calculated by the following formulas. The calculation was performed in Microsoft Excel based on the measured values.
眼軸長の差（ｍｍ）＝右眼軸長（ｍｍ）－左眼軸長（ｍｍ）
眼軸長伸長抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の眼軸長の差／対照群の眼軸長の差）×１００ Difference in axial length (mm) = right axial length (mm) -left axial length (mm)
Axial length elongation inhibition rate (%) = (difference in axial length of 1-0.002% sepetaprost solution administration group / difference in axial length of control group) × 100
眼軸長伸長抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の眼軸長の差／対照群の眼軸長の差）×１００ Difference in axial length (mm) = right axial length (mm) -left axial length (mm)
Axial length elongation inhibition rate (%) = (difference in axial length of 1-0.002% sepetaprost solution administration group / difference in axial length of control group) × 100
屈折度の差（Ｄ）＝右屈折度（Ｄ）－左屈折度（Ｄ）
屈折異常抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の屈折度の差／対照群の屈折度の差）×１００ Difference in refraction (D) = right refraction (D) -left refraction (D)
Refractive error suppression rate (%) = (difference in refraction in the 1-0.002% sepetaprost solution administration group / difference in refraction in the control group) × 100
屈折異常抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の屈折度の差／対照群の屈折度の差）×１００ Difference in refraction (D) = right refraction (D) -left refraction (D)
Refractive error suppression rate (%) = (difference in refraction in the 1-0.002% sepetaprost solution administration group / difference in refraction in the control group) × 100
（試験結果）
対照群および０．００２％セペタプロスト溶液投与群の眼軸長の差および屈折度の差の平均値を表２に示す。
(Test results)
Table 2 shows the average values of the difference in axial length and the difference in refraction between the control group and the 0.002% sepetaprost solution administration group.
対照群および０．００２％セペタプロスト溶液投与群の眼軸長の差および屈折度の差の平均値を表２に示す。
(Test results)
Table 2 shows the average values of the difference in axial length and the difference in refraction between the control group and the 0.002% sepetaprost solution administration group.
０．００２％セペタプロスト溶液投与群の眼軸長伸長抑制率および屈折異常抑制率を表３に示す。
Table 3 shows the axial length elongation inhibition rate and the refractive error inhibition rate in the 0.002% sepetaprost solution administration group.
Table 3 shows the axial length elongation inhibition rate and the refractive error inhibition rate in the 0.002% sepetaprost solution administration group.
表３に示されるように、０．００２％セペタプロスト溶液投与群の眼軸長伸長抑制率は７９％、屈折異常抑制率は９１％であった。
As shown in Table 3, the axial length elongation inhibition rate was 79% and the refractive error inhibition rate was 91% in the 0.002% sepetaprost solution administration group.
実施例２：モルモット近視モデルを用いた近視進行(眼軸長伸長および屈折異常)抑制試験（２）
以下の方法にしたがって、セペタプロストおよびチモロールマレイン酸の近視進行（眼軸長伸長および屈折異常）抑制効果および眼圧下降作用を評価した。
（試料の調製）
セペタプロストを可溶化剤を含む精製水に溶解した後、汎用される方法を用いて、試料として０．００２％セペタプロスト溶液を調製した。また、０．５％チモロールマレイン酸溶液である市販のチモプトール（登録商標）点眼液を試料として使用した。対照として、生理食塩液を使用した。 Example 2: Myopia progression (axial length extension and refractive error) suppression test using a guinea pig myopia model (2)
According to the following method, the effects of sepetaprost and timolol maleic acid on myopia progression (axial length extension and refractive error) were evaluated and the effects of lowering intraocular pressure were evaluated.
(Sample preparation)
After dissolving Sepetaprost in purified water containing a solubilizer, a 0.002% Sepetaprost solution was prepared as a sample using a general-purpose method. In addition, a commercially available timoptol (registered trademark) ophthalmic solution, which is a 0.5% timolol maleic acid solution, was used as a sample. As a control, saline was used.
以下の方法にしたがって、セペタプロストおよびチモロールマレイン酸の近視進行（眼軸長伸長および屈折異常）抑制効果および眼圧下降作用を評価した。
（試料の調製）
セペタプロストを可溶化剤を含む精製水に溶解した後、汎用される方法を用いて、試料として０．００２％セペタプロスト溶液を調製した。また、０．５％チモロールマレイン酸溶液である市販のチモプトール（登録商標）点眼液を試料として使用した。対照として、生理食塩液を使用した。 Example 2: Myopia progression (axial length extension and refractive error) suppression test using a guinea pig myopia model (2)
According to the following method, the effects of sepetaprost and timolol maleic acid on myopia progression (axial length extension and refractive error) were evaluated and the effects of lowering intraocular pressure were evaluated.
(Sample preparation)
After dissolving Sepetaprost in purified water containing a solubilizer, a 0.002% Sepetaprost solution was prepared as a sample using a general-purpose method. In addition, a commercially available timoptol (registered trademark) ophthalmic solution, which is a 0.5% timolol maleic acid solution, was used as a sample. As a control, saline was used.
（モルモット近視モデルの作製）
実施例１の（モルモット近視モデルの作製）と同様の方法にしたがって、モルモット近視モデルを作製した（ｎ＝１８）。 (Creation of guinea pig myopia model)
A guinea pig myopia model was prepared according to the same method as in Example 1 (Preparation of a guinea pig myopia model) (n = 18).
実施例１の（モルモット近視モデルの作製）と同様の方法にしたがって、モルモット近視モデルを作製した（ｎ＝１８）。 (Creation of guinea pig myopia model)
A guinea pig myopia model was prepared according to the same method as in Example 1 (Preparation of a guinea pig myopia model) (n = 18).
（試料の投与）
作製されたモルモット近視モデルを０．００２％セペタプロスト溶液投与群、０．５％チモロールマレイン酸溶液投与群および対照群に無作為に分類した（１群あたりｎ＝６）。０．００２％セペタプロスト溶液投与群では、右眼をゴーグルで遮蔽した日（０日目とする）から、各モルモットの右眼に０．００２％セペタプロスト溶液１０μＬを１５日目まで１６日間毎日、１日６回点眼投与した。０．００２％セペタプロスト溶液投与群と同様に、０．５％チモロールマレイン酸溶液投与群および対照群では、各モルモットの右眼に０．５％チモロールマレイン酸溶液および生理食塩液１０μＬをそれぞれ、点眼投与した。モルモットは通常の飼育条件で飼育した。
(Sample administration)
The guinea pig myopia model prepared was randomly classified into a 0.002% sepetaprost solution-administered group, a 0.5% timolol maleic acid solution-administered group, and a control group (n = 6 per group). In the 0.002% sepetaprost solution administration group, from the day when the right eye was shielded with goggles (referred to as day 0), 10 μL of 0.002% sepetaprost solution was applied to the right eye of each guinea pig every day for 16 days until the 15th day. It was administered by eye drops 6 times a day. Similar to the 0.002% sepetaprost solution administration group, in the 0.5% timolol maleic acid solution administration group and the control group, 0.5% timolol maleic acid solution and 10 μL of physiological saline were instilled in the right eye of each guinea pig. It was administered. Guinea pigs were bred under normal breeding conditions.
作製されたモルモット近視モデルを０．００２％セペタプロスト溶液投与群、０．５％チモロールマレイン酸溶液投与群および対照群に無作為に分類した（１群あたりｎ＝６）。０．００２％セペタプロスト溶液投与群では、右眼をゴーグルで遮蔽した日（０日目とする）から、各モルモットの右眼に０．００２％セペタプロスト溶液１０μＬを１５日目まで１６日間毎日、１日６回点眼投与した。０．００２％セペタプロスト溶液投与群と同様に、０．５％チモロールマレイン酸溶液投与群および対照群では、各モルモットの右眼に０．５％チモロールマレイン酸溶液および生理食塩液１０μＬをそれぞれ、点眼投与した。モルモットは通常の飼育条件で飼育した。
(Sample administration)
The guinea pig myopia model prepared was randomly classified into a 0.002% sepetaprost solution-administered group, a 0.5% timolol maleic acid solution-administered group, and a control group (n = 6 per group). In the 0.002% sepetaprost solution administration group, from the day when the right eye was shielded with goggles (referred to as day 0), 10 μL of 0.002% sepetaprost solution was applied to the right eye of each guinea pig every day for 16 days until the 15th day. It was administered by eye drops 6 times a day. Similar to the 0.002% sepetaprost solution administration group, in the 0.5% timolol maleic acid solution administration group and the control group, 0.5% timolol maleic acid solution and 10 μL of physiological saline were instilled in the right eye of each guinea pig. It was administered. Guinea pigs were bred under normal breeding conditions.
（評価方法）
近視を誘導する前日（点眼投与開始前）および近視を誘導して１４日目の１回目の点眼投与後にモルモット右眼球の眼軸長を超音波眼軸長測定装置ＥＣＨＯＳＣＡＮ ＵＳ－５００(ニデック社)によるＡ－ｓｃａｎにて測定し、屈折度をオートレフラクトメーターＡＲ－１ａ(ニデック社)により測定した。点眼投与開始前および１５日目の１回目の点眼投与１時間後にモルモット右眼球の眼圧をＴｏｎｏｌａｂ Ｔｏｎｏｍｅｔｅｒ(ｉＣａｒｅ Ｆｉｎｌａｎｄ社)により測定した。点眼投与開始前との眼軸長の差および眼軸長伸長抑制率、点眼投与開始前との屈折度の差および屈折異常抑制率ならびに１５日目の点眼投与開始前との眼圧の差を、以下の式にて算出した。計算は、実測値を基にMicrosoft Excelにおいて実施した。 (Evaluation method)
The day before inducing myopia (before the start of instillation) and after the first instillation on the 14th day after inducing myopia, the axial length of the right eyeball of the guinea pig was measured by the ultrasonic axial length measuring device ECHOSCAN US-500 (Nidek). The refractive index was measured with an autorefractometer AR-1a (Nidek Co., Ltd.). The intraocular pressure of the right eyeball of the guinea pig was measured by Tonolab Tonometer (ICare Findand) before the start of instillation and 1 hour after the first instillation on the 15th day. Difference in axial length and axial length elongation suppression rate from before the start of instillation administration, difference in refractive error and refractive error suppression rate from before the start of instillation administration, and difference in intraocular pressure from before the start of instillation administration on the 15th day , Calculated by the following formula. The calculation was performed in Microsoft Excel based on the measured values.
近視を誘導する前日（点眼投与開始前）および近視を誘導して１４日目の１回目の点眼投与後にモルモット右眼球の眼軸長を超音波眼軸長測定装置ＥＣＨＯＳＣＡＮ ＵＳ－５００(ニデック社)によるＡ－ｓｃａｎにて測定し、屈折度をオートレフラクトメーターＡＲ－１ａ(ニデック社)により測定した。点眼投与開始前および１５日目の１回目の点眼投与１時間後にモルモット右眼球の眼圧をＴｏｎｏｌａｂ Ｔｏｎｏｍｅｔｅｒ(ｉＣａｒｅ Ｆｉｎｌａｎｄ社)により測定した。点眼投与開始前との眼軸長の差および眼軸長伸長抑制率、点眼投与開始前との屈折度の差および屈折異常抑制率ならびに１５日目の点眼投与開始前との眼圧の差を、以下の式にて算出した。計算は、実測値を基にMicrosoft Excelにおいて実施した。 (Evaluation method)
The day before inducing myopia (before the start of instillation) and after the first instillation on the 14th day after inducing myopia, the axial length of the right eyeball of the guinea pig was measured by the ultrasonic axial length measuring device ECHOSCAN US-500 (Nidek). The refractive index was measured with an autorefractometer AR-1a (Nidek Co., Ltd.). The intraocular pressure of the right eyeball of the guinea pig was measured by Tonolab Tonometer (ICare Findand) before the start of instillation and 1 hour after the first instillation on the 15th day. Difference in axial length and axial length elongation suppression rate from before the start of instillation administration, difference in refractive error and refractive error suppression rate from before the start of instillation administration, and difference in intraocular pressure from before the start of instillation administration on the 15th day , Calculated by the following formula. The calculation was performed in Microsoft Excel based on the measured values.
眼軸長の差（ｍｍ）＝１４日目の右眼軸長（ｍｍ）－点眼投与開始前の右眼軸長（ｍｍ）
眼軸長伸長抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の眼軸長の差（あるいは、０．５％チモロールマレイン酸溶液投与群の眼軸長の差）／対照群の眼軸長の差）×１００ Difference in axial length (mm) = right axial length (mm) on day 14-right axial length (mm) before the start of instillation
Axial length elongation inhibition rate (%) = (difference in axial length between 1-0.002% sepetaprost solution administration group (or difference in axial length between 0.5% timolol maleic acid solution administration group) / control group (Difference in axial length) x 100
眼軸長伸長抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の眼軸長の差（あるいは、０．５％チモロールマレイン酸溶液投与群の眼軸長の差）／対照群の眼軸長の差）×１００ Difference in axial length (mm) = right axial length (mm) on day 14-right axial length (mm) before the start of instillation
Axial length elongation inhibition rate (%) = (difference in axial length between 1-0.002% sepetaprost solution administration group (or difference in axial length between 0.5% timolol maleic acid solution administration group) / control group (Difference in axial length) x 100
屈折度の差（Ｄ）＝１４日目の右屈折度（Ｄ）－点眼投与開始前の右屈折度（Ｄ）
屈折異常抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の屈折度の差（あるいは、０．５％チモロールマレイン酸溶液投与群の屈折度の差）／対照群の屈折度の差）×１００ Difference in refraction (D) = Right refraction on day 14-Right refraction (D) before the start of instillation
Refractive error suppression rate (%) = (difference in refraction of 1-0.002% sepetaprost solution administration group (or difference in refraction of 0.5% timolol maleic acid solution administration group) / difference in refraction of control group Difference) x 100
屈折異常抑制率（％）＝（１－０．００２％セペタプロスト溶液投与群の屈折度の差（あるいは、０．５％チモロールマレイン酸溶液投与群の屈折度の差）／対照群の屈折度の差）×１００ Difference in refraction (D) = Right refraction on day 14-Right refraction (D) before the start of instillation
Refractive error suppression rate (%) = (difference in refraction of 1-0.002% sepetaprost solution administration group (or difference in refraction of 0.5% timolol maleic acid solution administration group) / difference in refraction of control group Difference) x 100
眼圧の差（ｍｍＨｇ）＝１５日目の右眼圧（ｍｍＨｇ）－点眼投与開始前の右眼圧（ｍｍＨｇ）
Difference in intraocular pressure (mmHg) = right intraocular pressure on day 15 (mmHg) -right intraocular pressure (mmHg) before the start of instillation
（試験結果）
対照群、０．００２％セペタプロスト溶液投与群および０．５％チモロールマレイン酸溶液投与群の眼軸長の差、屈折度の差および眼圧の差の平均値を表５に示す。
(Test results)
Table 5 shows the average values of the difference in axial length, the difference in refraction, and the difference in intraocular pressure between the control group, the 0.002% sepetaprost solution-administered group, and the 0.5% timolol maleic acid solution-administered group.
対照群、０．００２％セペタプロスト溶液投与群および０．５％チモロールマレイン酸溶液投与群の眼軸長の差、屈折度の差および眼圧の差の平均値を表５に示す。
(Test results)
Table 5 shows the average values of the difference in axial length, the difference in refraction, and the difference in intraocular pressure between the control group, the 0.002% sepetaprost solution-administered group, and the 0.5% timolol maleic acid solution-administered group.
０．００２％セペタプロスト溶液投与群および０．５％チモロールマレイン酸溶液投与群の眼軸長伸長抑制率および屈折異常抑制率を表６に示す。
Table 6 shows the axial length elongation inhibition rate and the refractive error inhibition rate of the 0.002% sepetaprost solution administration group and the 0.5% timolol maleic acid solution administration group.
Table 6 shows the axial length elongation inhibition rate and the refractive error inhibition rate of the 0.002% sepetaprost solution administration group and the 0.5% timolol maleic acid solution administration group.
表５に示されるように、０．００２％セペタプロスト溶液投与群および０．５％チモロールマレイン酸溶液投与群では、眼圧下降作用が認められた。表６に示されるように、０．００２％セペタプロスト溶液投与群では眼軸長伸長抑制率は５３％、屈折異常抑制率は５１％であったものの、０．５％チモロールマレイン酸溶液投与群では眼軸長伸長および屈折異常を抑制する効果が認められなかった。
As shown in Table 5, the intraocular pressure lowering effect was observed in the 0.002% sepetaprost solution administration group and the 0.5% timolol maleic acid solution administration group. As shown in Table 6, the axial length elongation inhibition rate was 53% and the refractive error inhibition rate was 51% in the 0.002% sepetaprost solution administration group, but in the 0.5% timolol maleic acid solution administration group. No effect of suppressing axial length extension and refractive error was observed.
上記実施例の結果から明らかなように、セペタプロストは、強力に眼軸長伸長および屈折異常を抑制することが示された。よって、セペタプロストは、近視の治療、近視の予防および／または近視の進行抑制に有用である。
As is clear from the results of the above examples, sepetaprost was shown to strongly suppress axial length extension and refractive error. Therefore, sepetaprost is useful in the treatment of myopia, prevention of myopia and / or suppression of progression of myopia.
本発明の医薬組成物は、４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩が眼軸長伸長および屈折異常を抑制することにより、近視の治療、近視の予防および／または近視の進行抑制に有用である。
The pharmaceutical composition of the present invention is 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-butene. -1-yl] -7-Hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof suppresses axial length elongation and refractive error to treat myopia. It is useful for preventing myopia and / or suppressing the progression of myopia.
Claims (9)
- 有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、近視の治療、近視の予防および／または近視の進行抑制のための医薬組成物。 As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] A pharmaceutical composition comprising -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof for the treatment of myopia, prevention of myopia and / or suppression of progression of myopia. thing.
- 近視が、軸性近視、屈折性近視、仮性近視、病的近視、単純近視、極度近視、最強度近視、強度近視、中等度近視、弱度近視、緑内障を発症している近視、緑内障を発症するリスクのある近視または高眼圧を伴う近視である、請求項１に記載の医薬組成物。 Myopia develops axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, strongest myopia, strong myopia, moderate myopia, weak myopia, glaucoma, and glaucoma. The pharmaceutical composition according to claim 1, which is myopia with a risk of myopia or myopia with high ocular pressure.
- 眼局所投与に用いられる、請求項１また２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, which is used for topical ocular administration.
- 眼局所投与が点眼投与、眼軟膏投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与、結膜嚢内挿入または眼瞼塗布である、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the local ocular administration is eye drop administration, ophthalmic ointment administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subtenon administration, intraconjunctival insertion or eyelid application.
- 点眼剤、眼ゲル剤、眼軟膏剤または注射剤である、請求項１～４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, which is an eye drop, an eye gel, an eye ointment, or an injection.
- ４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩の含有量が、０．０００００１～５％（ｗ／ｖ）である、請求項１～５のいずれか一項に記載の医薬組成物。 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7- The content of hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is 0.000001 to 5% (w / v), according to claims 1 to 5. The pharmaceutical composition according to any one of the above.
- ４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩が、セペタプロストである、請求項１～６のいずれか一項に記載の医薬組成物。 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7- The pharmaceutical composition according to any one of claims 1 to 6, wherein the hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof is sepetaprost.
- 有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、眼軸長伸長を抑制するための医薬組成物。 As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] A pharmaceutical composition for suppressing axial length elongation, which comprises -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
- 有効成分として４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタン酸もしくはそのエステルまたはそれらの塩を含む、屈折異常を抑制するための医薬組成物。 As an active ingredient, 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2,5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] A pharmaceutical composition for suppressing refractive error, which comprises -7-hydroxyoctahydro-2H-cyclopentane [b] oxepin-3-yl} butanoic acid or an ester thereof or a salt thereof.
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| WO2023204297A1 (en) | 2022-04-22 | 2023-10-26 | 参天製薬株式会社 | Composition for ophthalmic use containing sepetaprost |
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