Agent for improving the deepening of the upper eyelid groove

Abstract

Provided is a novel ameliorating agent for deepening of the upper eyelid sulcus.　The present invention relates to an ameliorating agent for deepening of the upper eyelid sulcus, said ameliorating agent containing an Rho kinase inhibitor.

Description

[Technical Field]

[0001] The present invention relates to an agent for improving deepening of the upper eyelid groove. [Background technology]

[0002] Prostaglandin analogs (PGs), which are widely used in the drug treatment of glaucoma, are known to cause deepening of the upper eyelid sulcus (DUES) as a local ocular side effect (Non-Patent Document 1), which poses a problem that can lead to reduced adherence. The atrophy of adipose tissue caused by PGs themselves is thought to be largely responsible for the occurrence of DUES, and although recovery may occur by discontinuing PGs, no drug-related improvement of DUES is known.

[0003] Rho-associated, coiled-coil-containing protein kinase (ROCK) is a serine-threonine phosphorylating enzyme with a molecular weight of approximately 160 kDa, and its gene is widely conserved from lower animals such as nematodes and fruit flies to humans. Rho-kinase is involved in physiological functions such as smooth muscle cell contraction, cell morphology, migration, and gene expression regulation, and Rho-kinase inhibitors are being developed as therapeutic agents for cardiovascular diseases.

[0004] In recent years, it has also been developed as a topical drug for the treatment of eye diseases such as glaucoma, and "Glanatec (registered trademark) eye drops 0.4%," which contains ripasudil hydrochloride hydrate (4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline monohydrochloride dihydrate) as an active ingredient, is commercially available as a treatment for glaucoma and ocular hypertension.

[0005] Ripasudil is known to be effective in treating glaucoma and ocular hypertension, as well as being useful in treating ocular fundus diseases (Patent Document 1), regulating corneal thickness (Patent Document 2), preventing and treating complications after cataract surgery (Patent Document 3), and suppressing rejection after corneal transplantation (Patent Document 4). However, nothing is known about the effect of Rho kinase inhibitors, including ripasudil, on deepening of the upper eyelid sulcus. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 5557408 [Patent Document 2] International Publication No. WO2016 / 047647 Pamphlet [Patent Document 3] Japanese Patent Application Laid-Open No. 2017-61440 [Patent Document 4] Japanese Patent Application Publication No. 2018-188410 [Non-patent literature]

[0007] [Non-Patent Document 1] Inoue K, et al., J Glaucoma, 22(8), 626-631(2013) Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a new means for improving the deepening of the upper eyelid sulcus. [Means for solving the problem]

[0009] As a result of extensive research to solve the above-mentioned problems, the inventors of the present invention discovered that a Rho-anchase inhibitor, particularly ripasudil or a salt thereof, or a solvate thereof, improves deepening of the upper eyelid sulcus, and thus completed the present invention.

[0010] That is, the present invention provides the following (1) to (17). (1) An agent for improving deepening of the upper eyelid groove containing a Rho kinase inhibitor. (2) The agent for improving deepening of the upper eyelid groove according to (1) above, wherein the Rho kinase inhibitor is ripasudil, a salt thereof, or a solvate thereof. (3) The agent for improving deepening of the upper eyelid groove according to (2), wherein the ripasudil or a salt thereof or a solvate thereof is ripasudil hydrochloride hydrate. (4) The agent for improving deepening of the upper eyelid groove according to (3), wherein the ripasudil hydrochloride hydrate is ripasudil monohydrochloride dihydrate. (5) The upper eyelid groove deepening and improving agent according to any one of (1) to (4), which is a liquid formulation. (6) The agent for improving deepening of the upper eyelid groove according to any one of (1) to (5), which is an eye drop. (7) A method for producing a formulation of an upper eyelid groove deepening and improving agent described in any of (1) to (6), comprising a step of mixing ripasudil or a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier. (8) A method for improving deepening of the upper eyelid sulcus, comprising administering an effective amount of a Rho kinase inhibitor to a patient in need thereof. (9) The method according to (8) above, wherein the Rho kinase inhibitor is ripasudil, a salt thereof, or a solvate thereof. (10) The method according to (9) above, wherein Ripasudil or a salt thereof or a solvate thereof is Ripasudil hydrochloride hydrate. (11) The method according to (10) above, wherein the ripasudil hydrochloride hydrate is ripasudil monohydrochloride dihydrate. (12) The method according to any one of (8) to (11) above, wherein the method is carried out by administering a liquid formulation. (13) The method according to any one of (8) to (12) above, wherein the method is carried out by administering eye drops. (14) Rho kinase inhibitors to improve upper eyelid sulcus deepening. (15) The Rho kinase inhibitor according to (14), which is ripasudil, a salt thereof, or a solvate thereof. (16) Use of a Rho kinase inhibitor for the manufacture of an agent for improving deepening of the upper eyelid sulcus. (17) The use according to (16) above, wherein the Rho kinase inhibitor is ripasudil, a salt thereof, or a solvate thereof. [Effects of the Invention]

[0011] According to the present invention, an agent for improving deepening of the upper eyelid groove can be provided. Furthermore, the agent for improving deepening of the upper eyelid sulcus of the present invention can be provided as an eye drop that places less strain on patients. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the effect of a Rho kinase inhibitor on the DUES model (Experiment 1). [Figure 2] FIG. 2 shows the effect of a Rho kinase inhibitor on the DUES model (Experiment 2). DETAILED DESCRIPTION OF THE INVENTION

[0013] The Rho kinase inhibitor used in the agent for improving deepening of the upper eyelid sulcus of the present invention includes substances having inhibitory activity against Rho kinase. Examples of such Rho kinase inhibitors include compounds with the following generic names and code numbers: ripasudil, netarsudil (AR-13324 (chemical name: 4-[(2S)-3-amino-1-(6-isoquinolinylamino)-1-oxo-2-propanyl]benzyl 2,4-dimethylbenzoate), Verosudil (AR-12286 (chemical name: (2RS)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide)), AS1892802 (chemical name: N-[(1S)-2-hydroxy-1-phenylethyl]-N'-[4-(4-pyridinyl)phenyl]urea), DL0805 (chemical name: 5-nitro-1(2)H-indazole-3-carbonitrile), DW1865 (chemical name: 2-(1H-indazol-5-yl)amino-4-methoxy-6-piperazino triazine), Fasudil (chemical name: 1-(5-isoquinolinesulfonyl)homopiperazine), GSK-269962A (chemical name: [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]oxy}benzamide]), GSK-429286A (chemical name: N-(6-fluoro-1H-indazol-5-yl)-2-methyl-6-oxo-4-[4-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydro-3-pyridinecarboxamide), H-1152 (chemical name: 5- [[(2S)-Hexahydro-2-methyl-1H-1,4-diazepin-1-yl]sulfonyl]-4-methyl-isoquinoline), KD025 (SLx-2119) (chemical name: 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide), PT-262 (chemical name: 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione), RKI-1447 (chemical name: 1-[(3-hydroxyphenyl)methyl]-3-(4-pyridin-4-yl-1,3-thiazol-2-yl)urea), SAR407899 (chemical name: 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one), SB-772077B (chemical name: (3S)-1-[[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]carbonyl]-3-pyrrolidinamine dihydrochloride), SNJ-1656 (Y-39983) (chemical name: (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide), Wf-536 (chemical name: (+)-(R)-4-(1-aminoethyl)-N-(4-pyridyl)benzamide), Y-26732 (Y27632) (chemical name: (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide), AMA0076, AMA0428 (3-[2-(aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl]benzoate), BA-1049, BF -66851, BF-66852, BF-66853, KI-23095, AR-13503, AR-13534, INS-117548, LX7101, (1-benzylpyrrolidin-3-yl)-(1H-indazol-5-yl)amine, (1-benzylpiperidin-4-yl)-(1H-indazol-5-yl)amine, N-[2-(4-fluorophenyl)-6,7-dimethoxy-4-quinazolinyl]-N-(1H-indazol-5-yl)amine, N-4-(1H-indazol-5-yl)-6,7-dimethoxy-N-2-pyridin-4-yl-quinazoline-2,4-diamine, 4-methyl-5-(2-methyl-[1,4]diazepane-1-sulfonyl)isoquinoline, or optical isomers thereof, salts thereof, and solvates thereof. Further, the following patent documents are also available: U.S. Patent No. 4,678,783, Japanese Patent No. 3,421,217, International Publication Nos. 95 / 28387, 97 / 23222, 98 / 06433, 99 / 20620, 99 / 61403, 00 / 09162, 01 / 56988, 02 / 076976, 02 / 076977, 02 / 083175, 02 / 100833, 03 / 059913, 03 / 062225, 03 / 062227, 2004 / 009555, 2004 / 022541, and 20 Examples of such compounds include those disclosed in Patent Publications Nos. 04 / 039796, 2004 / 108724, 2005 / 003101, 2005 / 034866, 2005 / 037197, 2005 / 037198, 2005 / 035501, 2005 / 035503, 2005 / 035506, 2005 / 039564, 2005 / 080394, 2005 / 103050, 2006 / 057270, and 2007 / 026664, or optical isomers thereof, salts thereof, and solvates thereof. Also included are antisense nucleic acids, RNA interference-inducing nucleic acids (e.g., siRNAs), dominant-negative mutants, and expression vectors thereof against ROCK.

[0014] Among these Rho kinase inhibitors, preferred examples of the Rho kinase inhibitor include ripasudil, fasudil, netasudil, velosudil, Y-39983, and Y-26732, and a more preferred example of the Rho kinase inhibitor is ripasudil. Hereinafter, Ripasudil, one of the representative compounds of Rho kinase inhibitors, will be used as an example for explanation.

[0015] Ripasudil is a compound that has substance P antagonistic activity, leukotriene D4 antagonistic activity, and Rho kinase inhibitory activity, and drugs containing ripasudil as an active ingredient are manufactured and sold as therapeutic drugs for glaucoma and ocular hypertension. Ripasudil can be manufactured by known methods, for example, the method described in WO 99 / 20620.

[0016] Examples of salts of Ripasudil include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, and hydrobromic acid, and salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid, with the hydrochloride salt being particularly preferred.

[0017] Ripasudil or a salt thereof can exist not only as a non-solvate but also as a solvate such as a hydrate. Although a hydrate is preferred, the present invention includes all crystalline forms and their hydrates or solvates. A particularly preferred salt of Ripasudil is Ripasudil monohydrochloride, and more preferably Ripasudil monohydrochloride dihydrate.

[0018] In the present invention, the "agent for improving upper eyelid sulcus deepening" refers to a drug that improves upper eyelid sulcus deepening (DUES), which occurs as a side effect in patients receiving PGs for the treatment of glaucoma. Specifically, the agent can restore the adipose tissue of the upper eyelid lost by the administration of PGs, or can suppress the loss of adipose tissue of the upper eyelid caused by the administration of PGs.

[0019] In the present invention, "deepening of the upper eyelid sulcus" is a condition that occurs as a side effect mainly due to the administration of PGs, as described above, and is characterized by a loss of upper eyelid firmness, such as a hollow in the upper eyelid or double eyelids.

[0020] In the present invention, "improving the deepening of the upper eyelid sulcus" means returning the deepened upper eyelid sulcus to a normal state or bringing it closer to a normal state. Furthermore, it also includes suppressing the occurrence of DUES by using it in combination with PGs. The mechanism of action includes, but is not necessarily limited to, the recovery of lost adipose tissue or the suppression of adipose tissue loss.

[0021] The "agent for improving upper eyelid sulcus deepening" of the present invention is formulated into a dosage form suitable for topical administration to the eye by a conventional formulation technique commonly used in the art. Examples of dosage forms include, but are not limited to, eye drops or eye ointments. Preferred formulations include eye drops because of ease of administration. The eye drops of the present invention contain the active ingredient of the present invention, Ripasudil or a salt thereof, or a solvate thereof, and a carrier acceptable for eye drops, and the commercially available product "Glanatec Eye Drops 0.4%" can also be used as is.

[0022] When preparing eye drops, for example, the desired components described above can be dissolved or suspended in an aqueous solvent such as sterilized purified water or physiological saline, or in a non-aqueous solvent such as a vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, and the like, and the resulting solution is adjusted to a predetermined osmotic pressure and subjected to a sterilization treatment such as filtration sterilization. When preparing an eye ointment, in addition to the various ingredients described above, an ointment base may be contained. The ointment base is not particularly limited, but preferred examples include oily bases such as petrolatum, liquid paraffin, and polyethylene; emulsion bases in which an oil phase and an aqueous phase are emulsified with a surfactant or the like; and water-soluble bases such as hydroxypropylmethylcellulose, carboxymethylcellulose, and polyethylene glycol.

[0023] When Ripasudil, a salt thereof, or a solvate thereof is used in the "agent for improving upper eyelid sulcus deepening" of the present invention, the dosage will vary depending on the patient's weight, age, sex, symptoms, dosage form, and number of doses, but typically, for an adult, the daily dosage of Ripasudil is in the range of 0.025 to 10,000 μg, preferably 0.025 to 2,000 μg, more preferably 0.1 to 2,000 μg, even more preferably 0.025 to 200 μg, or even 0.025 to 100 μg.

[0024] When used as eye drops, the active ingredient can be used at a concentration of about 0.0001 to 5 w / v %, preferably about 0.01 to 4 w / v %.

[0025] The number of administrations is not particularly limited, but is preferably once a day or divided into several times a day, and in the case of a liquid eye drop, one to several drops may be administered at a time. The same applies to a combination drug with PGs.

[0026] As used herein, PGs refer to the active ingredients themselves of prostaglandin-related drugs used primarily for the treatment of glaucoma or ocular hypertension, or preparations containing such active ingredients, and specific examples include latanoprost, travoprost, bimatoprost, tafluprost, isopropyl unoprostone, etc., or preparations thereof. In addition, combinations of PGs with active ingredients of other glaucoma treatment drugs, such as β-blockers, are also encompassed by the PGs defined herein.

[0027] One embodiment of the present invention includes a combination with PGs. The combination may involve administering a PG preparation and the agent for improving upper eyelid sulcus deepening of the present invention separately according to their respective formulations, or administering them as a combined preparation of both. Although combination is usually understood to mean administration at the same time, the agent for improving upper eyelid sulcus deepening of the present invention may be administered prior to PGs, or may be administered after a certain period of time has passed since administration of PGs, for example, in addition to PGs to enhance the intraocular pressure-reducing effect. [Example]

[0028] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0029] Example 1 Effect of Rho kinase inhibitors on the induction of adipogenesis in fibroblasts (3D culture) The assay was performed according to a previously published method (Endocrinology 160:20-35, 2019). Fibroblasts were isolated from human orbital adipose tissue and seeded in 150 mm dishes with culture medium (DMEM containing 10% FBS and other ingredients). They were then subcultured 3–6 times at 37°C and 5% CO2 for the experiments. 90% confluent cells were washed with HBSS, detached with 0.25% Tripsin / EDTA, and resuspended in culture medium. After centrifugation, the pellet was resuspended in culture medium containing 0.25% w / v Methocel A4M at approximately 20,000 cells / 25 μL, and 25 μL was added dropwise to each well of a drop culture plate (day 0 of organoid culture). After 24 hours (day 1 of culture), organoids were cultured according to the following group settings. The corresponding medium in each well was replaced with 14 μL of medium once a day.

[0030] Group composition: Experiment 1 (n=10) NT: Control group DIF: Adipogenic differentiation group (250nM dexamethasone, 10nM T3(triiodothyronine) and 10μM troglitazone) RIPA:DIF + Ripasudil 10μM Y27632:DIF+Y27632 10μM LAT:DIF+Latanoprost 100nM LAT + RIPA: DIF + latanoprost 100 nM + ripasudil 10 μM BIM:DIF+bimatoprost 100nM BIM + RIPA: DIF + bimatoprost 100nM + ripasudil 10μM

[0031] Experiment 2 (n=8) NT: Control group DIF: Adipogenic differentiation group (250nM dexamethasone, 10nM T3(triiodothyronine) and 10μM troglitazone) LAT:DIF+Latanoprost 100nM LAT + Y27632: DIF + latanoprost 100nM + Y27632 10μM BIM:DIF+bimatoprost 100nM BIM+Y27632:DIF+bimatoprost 100nM+Y27632 10μM

[0032] On day 10 of culture, organoids were stained with 500-fold diluted boron-dipyrromethene (BODIPY) for 1 hour to evaluate lipid droplets.

[0033] The results are shown in Figures 1 and 2. Figures 1 (Experiment 1) and 2 (Experiment 2) show the fat mass (mean ± SD) for each group. Compared to the control group (NT), fat mass was significantly increased in the adipogenic differentiation-induced (DIF) group. Furthermore, the addition of Rho kinase inhibitors (RIPA, Y27632) also had a significant additive effect. The adipogenic effect was significantly attenuated by the addition of PGs (LAT, BIM), establishing the DUES pathological model. The attenuation of adipocyte size by PGs was rescued by the addition of Rho kinase inhibitors (LAT+RIPA, BIM+RIPA, LAT+Y27632, BIM+Y27632), and all of these effects were significant.

[0034] Therefore, it was suggested that Rho kinase inhibitors may improve DUES.

Claims

1. An agent for improving deepening of the upper eyelid groove, containing ripasudil or its salt or a solvate thereof.

2. An agent for improving deepening of the upper eyelid groove as described in claim 1, wherein ripasudil or its salt or a solvate thereof is ripasudil hydrochloride hydrate.

3. An agent for improving deepening of the upper eyelid groove as described in claim 1 or 2, wherein ripasudil or its salt or a solvate thereof is ripasudil monohydrochloride dihydrate.

4. The agent for improving deepening of the upper eyelid groove according to any one of claims 1 to 3, which is a liquid agent.

5. The agent for improving deepening of the upper eyelid groove according to any one of claims 1 to 4, which is an eye drop.

6. A method for producing a formulation of the agent for improving upper eyelid groove deepening according to any one of claims 1 to 5, comprising a step of mixing ripasudil or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

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