Medicine containing heterocyclideneacetamide derivatives

Abstract

The present disclosure provides means for treating dry eye. In the present disclosure, a composition or the use thereof may be provided for treating dry eye, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. In the present disclosure, a composition or the use thereof may be provided for treating dry eye, comprising a Vi / Vc region inhibitor.

Description

Technology Field

[0001] The present disclosure relates to fields such as medicine, healthcare, biology, and biotechnology. The present disclosure relates, in particular, to the application of Vi / Vc region inhibitors and / or the improvement of symptoms of dry eye. Background Technology

[0002] It is estimated that the population of dry eye patients in Japan is at least about 8 million, and if potential patients using commercially available eye drops without visiting a doctor are included, the number reaches about 22 million; it is also reported that there are over 1 billion people worldwide. It is widely known that in modern society, the increased use of televisions, computers, and mobile devices leads to more screen-gazing, which reduces the frequency of blinking. Furthermore, the use of air conditioners dries out the air, consequently accelerating tear evaporation and causing dry eye. Additionally, refractive surgery and the use of contact lenses can result in dry eye. Symptoms associated with dry eye include discomfort, dryness, burning, and irritation of the eye surface. More severe forms of dry eye are caused by the destruction of the lacrimal glands due to autoimmune diseases such as Sjögren's syndrome or diseases such as Stevens-Johnson syndrome (Non-patent Literature 1).

[0003] The therapeutic effect of dry eye is evaluated from both external observation and assessment (objective findings) and the patient's subjective perspective, such as eye discomfort or foreign body sensation (subjective symptoms). Regarding objective findings, tear volume and the observation of areas of damage in the corneal and conjunctival epithelium are evaluated. However, while sodium hyaluronate, dicuafosol sodium, and rebamipide sold in Japan, and cyclosporine sold in the United States, are each approved as prescription eye drops for dry eye, few have been approved to satisfy the improvement of subjective symptoms as a primary evaluation criterion in addition to the improvement of objective findings. Prior art literature

[0004] Pharmacia Vol.50 No.3 2014:201 to 206 The problem to be solved

[0005] The present disclosure relates to a novel dry eye treatment using (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, which is one of the heterocyclideneacetamide derivatives, and a method for the use, treatment, or prevention thereof. The present disclosure also relates to a Vi / Vc region inhibitor using said compound, and a method for the use, treatment, or prevention thereof.

[0006] Another aspect of the present disclosure relates to a composition for preventing and / or treating dry eye using a Vi / Vc region inhibitor, the use thereof, and a method for treating or preventing it.

[0007] Treatment for dry eye may involve the improvement of subjective symptoms of dry eye. Treatment for dry eye may also include the improvement of objective symptoms of dry eye. In the present disclosure, treatment for dry eye may include the improvement of both subjective and objective symptoms of dry eye.

[0008] Examples of embodiments of the present disclosure include the following.

[0009] (Item 1) A composition for treating dry eye, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0010] (Item 2) A composition described in the above item for improving the subjective symptoms of dry eye.

[0011] (Item 2A) The above dry eye is a composition described in the above item that is accompanied by subjective symptoms.

[0012] (Item 3) A composition described in any of the above items for suppressing eye discomfort associated with dryness.

[0013] (Item 3A) The above dry eye is a composition described in any of the above items that is accompanied by eye discomfort associated with dryness.

[0014] (Item 4) A composition described in any of the above items for improving the symptoms of dry eye.

[0015] (Item 4A) The above dry eye is a composition described in any of the above items that is accompanied by a visual symptom.

[0016] (Item 5) A composition described in any of the above items for improving subjective and objective symptoms of dry eye.

[0017] (Item 5A) The above dry eye is a composition described in any of the above items that involves subjective symptoms and objective symptoms.

[0018] (Item 6) A composition described in any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is about 0.1 to about 1.0 w / v%.

[0019] (Item 7) An eye drop, a composition described in any of the above items.

[0020] (Item 8) A composition described in any of the above items, which is a suspension.

[0021] (Item 9) The above dry eye is a tear-reducing dry eye, a composition described in any of the above items.

[0022] (Item 10) A composition described in any of the above items, characterized by administering the above composition to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0023] (Item 11) A composition comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for suppressing eye discomfort associated with dryness.

[0024] (Item 12) A composition comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for improving the subjective symptoms of dry eye.

[0025] (Item 13) A composition comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for improving the symptoms of dry eye.

[0026] (Item 14) A composition for treating corneal epithelial disorders comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0027] (Item 15) A suspension comprising about 0.3 to about 1.0 w / v% of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for suppressing eye discomfort associated with dryness.

[0028] (Item 16) Vi / Vc zone inhibitor comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0029] (Item 17) A composition for treating dry eye comprising a Vi / Vc region inhibitor.

[0030] (Item 18) A composition described in the above item for improving the subjective symptoms of dry eye.

[0031] (Item 19) A composition described in any of the above items for suppressing eye discomfort associated with dryness.

[0032] (Item 20) A composition described in any of the above items for improving the symptoms of dry eye.

[0033] (Item 21) An eye drop, a composition described in any of the above items.

[0034] (Item 22) A composition described in any of the above items, which is a suspension.

[0035] (Item 23) The above dry eye is a tear-reducing dry eye, a composition described in any of the above items.

[0036] (Item 24) A composition described in any of the above items, characterized by administering the above composition to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0037] (Item 25) A composition for suppressing eye discomfort associated with dryness comprising a Vi / Vc region inhibitor.

[0038] (Item 26) A composition for improving subjective symptoms of dry eye comprising a Vi / Vc region inhibitor.

[0039] (Item 27) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is a composition described in any of the above items which is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0040] Examples of other embodiments of the present disclosure include the following.

[0041] (Item A1) A method for treating dry eye in a patient requiring treatment, comprising the process of administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0042] (Item A2) A method described in the above item for improving the subjective symptoms of dry eye.

[0043] (Item A2A) The above dry eye is a method described in the above item that involves subjective symptoms.

[0044] (Item A3) A method described in any of the above items for suppressing eye discomfort associated with dryness.

[0045] (Item A3A) The above dry eye is a method described in any of the above items that involves eye discomfort associated with dryness.

[0046] (Item A4) A method described in any of the above items for improving the symptoms of dry eye.

[0047] (Item A4A) The above dry eye is a method described in any of the above items that involves symptoms of optic retardation.

[0048] (Item A5) A method described in any of the above items for improving subjective and objective symptoms of dry eye.

[0049] (Item A5A) The above dry eye is a method described in any of the above items that involves subjective symptoms and objective symptoms.

[0050] (Item A6) A method described in any of the above items in which the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is administered at a concentration of about 0.1 to about 1.0 w / v%.

[0051] (Item A7) A method described in any of the above items in which the above compound is administered as an eye drop.

[0052] (Item A8) A method described in any of the above items in which the above compound is administered as a suspension.

[0053] (Item A9) The above dry eye is a tear-reducing dry eye, a method described in any of the above items.

[0054] (Item A10) A method described in any of the above items, characterized by administering the above compound to a patient diagnosed with dry eye who has recognized symptoms of eye discomfort.

[0055] (Item A11) A method for suppressing eye discomfort associated with dryness in a patient who requires it, comprising the step of administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0056] (Item A12) A method for improving subjective symptoms of dry eye in a patient who requires it, comprising the process of administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0057] (Item A13) A method for improving the objective symptoms of dry eye in a patient requiring it, comprising the process of administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0058] (Item A14) A method for treating corneal epithelial disorders in patients requiring treatment, comprising the step of administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0059] (Item A15) A method for suppressing eye discomfort associated with dryness in a patient who requires it, comprising the step of administering to the patient a suspension comprising about 0.3 to about 1.0 w / v% of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0060] (Item A16) A method for inhibiting the Vi / Vc region comprising the process of administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0061] (Item A17) A method for treating dry eye in patients requiring it, comprising a process of administering a Vi / Vc region inhibitor.

[0062] (Item A18) A method described in the above item for improving the subjective symptoms of dry eye.

[0063] (Item A19) A method described in any of the above items for suppressing eye discomfort associated with dryness.

[0064] (Item A20) A method described in any of the above items for improving the symptoms of dry eye.

[0065] (Item A21) A method described in any of the above items in which the above-mentioned Vi / Vc region inhibitor is administered as an eye drop.

[0066] (Item A22) A method described in any of the above items, wherein the above-mentioned Vi / Vc region inhibitor is administered as a suspension.

[0067] (Item A23) The above dry eye is a tear-reducing dry eye, a method described in any of the above items.

[0068] (Item A24) A method described in any of the above items, characterized by administering the above-mentioned Vi / Vc region inhibitor to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0069] (Item A25) A method for suppressing eye discomfort associated with dryness in patients requiring it, comprising the process of administering a Vi / Vc region inhibitor to the patient.

[0070] (Item A26) A method for improving subjective symptoms of dry eye in patients requiring it, comprising the process of administering a Vi / Vc region inhibitor to said patient.

[0071] (Item A27) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is a method described in any of the above items which is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0072] Examples of other embodiments of the present disclosure include the following.

[0073] (Item B1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, for use in the treatment of dry eye.

[0074] (Item B2) A compound for use described in the above item to improve the subjective symptoms of dry eye.

[0075] (Item B2A) The above dry eye is a compound for use described in the above item that is accompanied by subjective symptoms.

[0076] (Item B3) A compound for use described in any of the above items for suppressing eye discomfort associated with dryness.

[0077] (Item B3A) The above dry eye is a compound for use described in any of the above items, which is accompanied by eye discomfort associated with dryness.

[0078] (Item B4) A compound for use described in any of the above items for improving the symptoms of dry eye.

[0079] (Item B4A) The above dry eye is a compound for use described in any of the above items, which is accompanied by visceral symptoms.

[0080] (Item B5) A compound for use described in any of the above items for improving subjective and objective symptoms of dry eye.

[0081] (Item B5A) The above dry eye is a compound for use described in any of the above items, which is accompanied by subjective and objective symptoms.

[0082] (Item B6) A compound for use described in any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, is about 0.1 to about 1.0 w / v%.

[0083] (Item B7) A compound for use described in any of the above items, contained in an eye drop.

[0084] (Item B8) A compound for use described in any of the above items, contained in a suspension.

[0085] (Item B9) The above dry eye is a tear-reducing dry eye, a compound for use described in any of the above items.

[0086] (Item B10) A compound for use described in any of the above items, characterized by being administered to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0087] (Item B11) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, for use in suppressing eye discomfort associated with dryness.

[0088] (Item B12) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, for use in improving subjective symptoms of dry eye.

[0089] (Item B13) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, for use in the improvement of objective symptoms of dry eye.

[0090] (Item B14) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, for use in the treatment of corneal epithelial disorders.

[0091] (Item B15) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for suppressing eye discomfort associated with dryness, wherein said compound is contained in a composition that is a suspension at about 0.3 to about 1.0 w / v%.

[0092] (Item B16) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, for use in inhibiting the Vi / Vc region.

[0093] (Item B17) Vi / Vc zone inhibitors for use in the treatment of dry eye.

[0094] (Item B18) Vi / Vc zone inhibitors for use described in the above item for improving subjective symptoms of dry eye.

[0095] (Item B19) A Vi / Vc zone inhibitor for use described in any of the above items, for suppressing eye discomfort associated with dryness.

[0096] (Item B20) A Vi / Vc zone inhibitor for use described in any of the above items for improving the symptoms of dry eye.

[0097] (Item B21) An ophthalmic agent, a Vi / Vc zone inhibitor for use as described in any of the above items.

[0098] (Item B22) A Vi / Vc zone inhibitor for use described in any of the above items, which is a suspension.

[0099] (Item B23) The above dry eye is a tear-reducing dry eye, a Vi / Vc zone inhibitor for use as described in any of the above items.

[0100] (Item B24) A Vi / Vc region inhibitor for use described in any of the above items, characterized by administering the above inhibitor to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0101] (Item B25) Vi / Vc zone inhibitors for use in suppressing eye discomfort associated with dryness.

[0102] (Item B26) Vi / Vc zone inhibitors for use in improving subjective symptoms of dry eye.

[0103] (Item B27) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is a compound or Vi / Vc zone inhibitor for use described in any of the above items, which is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide.

[0104] Examples of other embodiments of the present disclosure include the following.

[0105] (Item C1) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the manufacture of a medicine for treating dry eye.

[0106] (Item C2) Use described in the above item, wherein the above medicine is intended to improve the subjective symptoms of dry eye.

[0107] (Item C2A) The above dry eye is used as described in the above item, which involves subjective symptoms.

[0108] (Item C3) Use described in any of the above items, wherein the above medicine is intended to suppress eye discomfort associated with dryness.

[0109] (Item C3A) The above dry eye is used in any of the above items, which involves eye discomfort associated with dryness.

[0110] (Item C4) Use described in any of the above items, wherein the above medicine is intended to improve the symptoms of dry eye.

[0111] (Item C4A) The above dry eye is used in any of the above items, which is accompanied by symptoms of visceral vision.

[0112] (Item C5) Use described in any of the above items, wherein the above medicine is intended to improve subjective and objective symptoms of dry eye.

[0113] (Item C5A) The above dry eye is used in any of the above items, which is accompanied by subjective and objective symptoms.

[0114] (Item C6) Use described in any of the above items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the above medicine is about 0.1 to about 1.0 w / v%.

[0115] (Item C7) Use described in any of the above items, where the above medicine is an eye drop.

[0116] (Item C8) Use described in any of the above items, where the above medicine is a suspension.

[0117] (Item C9) The above dry eye is a tear-reducing dry eye, used as described in any of the above items.

[0118] (Item C10) Use described in any of the above items, characterized by administering the above medicine to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0119] (Item C11) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the manufacture of a medicine for suppressing eye discomfort associated with dryness.

[0120] (Item C12) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the manufacture of a medicine for improving the subjective symptoms of dry eye.

[0121] (Item C13) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the manufacture of a medicine for improving the objective symptoms of dry eye.

[0122] (Item C14) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the manufacture of medicines for treating corneal epithelial disorders.

[0123] (Item C15) Use of a suspension comprising about 0.3 to about 1.0 w / v% of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicine for suppressing eye discomfort associated with dryness.

[0124] (Item C16) Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate, in the manufacture of a medicine for inhibition of the Vi / Vc region.

[0125] (Item C17) Use of Vi / Vc zone inhibitors in the manufacture of medicines for treating dry eye.

[0126] (Item C18) Use described in the above item, wherein the above medicine is intended to improve the subjective symptoms of dry eye.

[0127] (Item C19) Use described in any of the above items, wherein the above medicine is for suppressing eye discomfort associated with dryness.

[0128] (Item C20) Use of the above medicine for improving the objective symptoms of dry eye as described in any of the above items.

[0129] (Item C21) Use described in any of the above items, where the above medicine is an eye drop.

[0130] (Item C22) Use described in any of the above items, where the above medicine is a suspension.

[0131] (Item C23) The above dry eye is a tear-reducing dry eye, used as described in any of the above items.

[0132] (Item C24) Use described in any of the above items, characterized by administering the above medicine to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort.

[0133] (Item C25) Use of Vi / Vc zone inhibitors in the manufacture of medicines to suppress eye discomfort associated with dryness.

[0134] (Item C26) Use of Vi / Vc zone inhibitors in the manufacture of medicines to improve subjective symptoms of dry eye.

[0135] (Item C27) Use of any of the above items, which is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, preferably (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. Effects of the invention

[0136] By the present disclosure, a novel means for the prevention and / or treatment of dry eye is provided, which preferably enables the improvement of subjective symptoms, and more preferably, the improvement of both subjective and objective symptoms. Furthermore, the composition or method of the present disclosure can provide an immediate treatment for dry eye. Brief explanation of the drawing

[0137] Figure 1 is a diagram illustrating the change in punctate superficial keratosis (SPK) scores in rats after drug administration. The 0.3% w / v compound (1) suspension eye drops significantly reduced the SPK score 7 days after administration (15 days after surgery) compared to the base eye drops, and the effect continued 14 days after administration (22 days after surgery). Additionally, the scopolamine-induced rat dry eye model is described as SCOP, and the model filled with physiological saline instead of scopolamine is described as Saline. FIG. 2 is a diagram showing the number of blinks in 5 minutes after 0.5 hours of administration of a base eye drop or a suspension of compound (1) at 0.1 w / v%, 0.3 w / v%, or 1.0 w / v%. Compound (1) reduced the number of blinks in the range from 0.1 w / v% to 1.0 w / v%, and a significant effect was shown at 0.3 w / v% and 1.0 w / v%. FIG. 3 is a figure showing the number of blinks over 5 minutes after 0.5 hours of single administration of base eye drops or after 0.5, 4, or 8 hours of single administration of a suspension of 1.0 w / v% compound (1). The number of blinks after 0.5, 4, and 8 hours after administration of the suspension of 1.0 w / v% compound (1) can be reduced compared to the number of blinks after 0.5 hours after administration of base eye drops, and in particular, the number of blinks after 0.5 and 4 hours was significantly reduced. FIG. 4 is a diagram showing the change in SPK score in rats after repeated eye drop administration of base eye drops or 1.0 w / v% compound (1) suspension eye drops for 8 days. The 1.0 w / v% compound (1) suspension eye drops reduced the SPK score after 7 days of administration (15 days after surgery) compared to the base eye drops. FIG. 5 is a diagram showing the number of blinks in 5 minutes in rats after repeated eye drops of the base eye solution or a suspension of 1.0 w / v% compound (1) for 8 days. The suspension of 1.0 w / v% compound (1) reduced the number of blinks compared to the base eye solution. Specific details for implementing the invention

[0138] The present disclosure is described below. Throughout this specification, it should be understood that singular expressions include the concept of their plural forms unless specifically stated otherwise. Accordingly, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the concept of their plural forms unless specifically stated otherwise. Furthermore, terms used in this specification should be understood to be used in the sense commonly used in the relevant field unless specifically stated otherwise. Accordingly, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as generally understood by those skilled in the art to which this disclosure pertains. In case of contradiction, this specification (including definitions) shall prevail.

[0139] (definition)

[0140] In this specification, "about" means ±10% of the following values ​​unless specifically stated otherwise.

[0141] In this specification, the term “subject” refers to a subject to administration (transplantation) of a medicine or method for treatment and prevention of the present disclosure. Examples of subjects may include mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs, cattle, horses, sheep, monkeys, etc.), but primates are preferred, and humans are particularly preferred.

[0142] In this specification, “or” is used when “at least one” of the items enumerated in the sentence can be adopted. The same applies to “or” and “or”. In this specification, where “within a range” of “two values” is specified, the range includes the two values ​​themselves.

[0143] In this specification, "treatment" means the healing, improvement, suppression, or alleviation of a disease or symptom. "Treating dry eye" includes treating objective or subjective symptoms.

[0144] In this specification, "prophylaxis" means preventing the onset of a disease or symptom in advance, and this concept includes delaying the onset of a disease or symptom or minimizing the onset of a disease or symptom by treatment before onset.

[0145] In this specification, "pharmaceutically acceptable salt" means a relatively non-toxic acid addition salt of an inorganic or organic compound of the present disclosure. These salts may be prepared by reacting the compound, purified to its free base form, with a suitable organic or inorganic acid separately, or by isolating the salt thus formed.

[0146] In this specification, "solvent" refers to a solvate of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and includes, for example, a solvate with an organic solvent (e.g., an alcohol (ethanol, etc.) solvate), a hydrate, etc. When forming a hydrate, it may be coordinated with any number of water molecules. Examples of hydrates include monohydrates, dihydrates, etc.

[0147] In this specification, "dry eye" refers to a disease diagnosed as "dry eye" according to clinical diagnostic criteria and is defined as "a disease of tears and the surface of the eye caused by various factors, and a multifactorial disease accompanied by eye discomfort, visual dysfunction, instability of the tear film, or disorder of the surface of the eye." The diagnosis of dry eye is typically made by observing that the BUT (Body-to-Use Time) by fluorescein staining is 5 seconds or less, and that there are subjective symptoms (eye discomfort or visual dysfunction).

[0148] In this specification, "subjective symptom" refers to a symptom among the symptoms of a disease that can be perceived by a patient suffering from the disease.

[0149] In this specification, "objective symptom" refers to a symptom of a disease that can be objectively proven by findings (objective findings), such as imaging findings or numerical values ​​of examination results.

[0150] In this specification, "eye discomfort" refers to a symptom where the eyes are unpleasant or constantly bothersome.

[0151] In this specification, "eye discomfort associated with dryness" refers to eye discomfort caused by dryness, such as low humidity, and does not include eye pain.

[0152] In this specification, "tear-reducing dry eye" refers to a dry eye in which the amount of tears is reduced, caused by tissue destruction of the lacrimal gland or impaired tearing from the lacrimal gland to the surface of the eye due to Sjögren's syndrome, the disease, or graft-versus-host disease (GVHD).

[0153] In this specification, "inhibition" of a certain object refers to reducing or eliminating a phenomenon occurring in vivo by the object of inhibition, and "antagonism" refers to a mode in which an inhibitory action is realized by competing with a molecule (ligand, substrate, etc.) that is originally supposed to interact during "inhibition."

[0154] In this specification, "inhibits the Vi / Vc region" refers to reducing or eliminating the transmission of signals regarding neural excitation, i.e., nociceptive reception, in the Vi / Vc region of the medulla oblongata.

[0155] In this specification, "Vi / Vc region inhibitor" refers to a substance for inhibiting the Vi / Vc region. Examples of "Vi / Vc region inhibitors" include any substance, factor, or means that reduces or eliminates neural excitation in the Vi / Vc region compared to the absence of a substance, factor, or means having the said action.

[0156] In this specification, the term “kit” refers to a unit in which parts to be provided (e.g., therapeutic drugs, preventive drugs, their respective components, instructions, etc.) are provided, typically divided into two or more compartments.

[0157] In this specification, "instructions" refers to a description of how to use the present disclosure for a doctor or other user.

[0158] (compound)

[0159] In the present disclosure, compositions comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or pharmaceutically acceptable salts or solvates thereof, or methods of their use may be provided. (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide includes the R-body (CAS. No. 920332-28-1), the S-body (CAS. No. 920332-29-2), or the racemic mixture (CAS. No. 920332-27-0), but more preferably, the R-body ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide (also referred to as compound (1) in the present disclosure)).

[0160] As pharmaceutically acceptable salts of the compounds of the present disclosure, the salts are not particularly limited as long as they are pharmaceutically acceptable, but specifically include inorganic acids such as hydrochloric acid, hydrobromide, hydroiodide, sulfuric acid, nitric acid, and phosphoric acid; aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, and mandelic acid; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid; and aliphatic tricarboxylic acids such as citric acid. Examples include organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, aliphatic sulfonic acids, aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; acid addition salts with acidic amino acids such as aspartic acid and glutamic acid, salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium, salts with organic bases such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, and ornithine, or ammonium salts.

[0161] These salts can be obtained by conventional methods, for example, by mixing an equivalent amount of the group of compounds disclosed herein with a solution containing a desired acid or base, and collecting the desired salt by filtering or by distilling the solvent. Additionally, the compounds of the present disclosure or their salts may form solvates with solvents such as water, ethanol, and glycerol.

[0162] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide has excellent antagonistic activity against Transient Receptor Potential Vanilloid 1 (hereinafter referred to as “TRPV1”. TRPV1 is also called “transient receptor potential vanilloid 1” or “vanilloid receptor 1 (VR1)”).

[0163] For the R-body (compound (1)), S-body, or racemic mixture of ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, refer to Pamphlet No. 2007 / 010383, Japanese Patent No. 4754566, Japanese Patent No. 6230743, and Pamphlet No. 2018 / 221543. The above R-body (compound (1)), S-body, or racemic mixture may be prepared by the manufacturing method described in the said publication. Furthermore, all contents of the said publication are incorporated by reference in this specification.

[0164] TRPV1 is a TRP channel that has been cloned from the dorsal root ganglion (DRG) as a capsaicin-responsive cation channel, is sensitive to heat above 43°C and protons, and is being studied as a major molecule for nociception (Biochemistry Vol. 85, No. 7: 561 to 565). It is known that TRPV1's activity increases during inflammation or tissue damage, causing hyperalgesia. For this reason, TRPV1 is being considered as a candidate drug target for pain treatment.

[0165] TRPV1 antagonists have long been reported to be effective against various pain models, such as inflammatory pain, neuropathic pain, and osteoarthritis (Biochemistry Vol. 85, No. 7: 561 to 565).

[0166] In the embodiments of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is shown to be usable as a Vi / Vc region inhibitor. In the present disclosure, a Vi / Vc region inhibitor comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof may be provided. (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide has inhibitory activity in the Vi / Vc region, so as to be described in detail in other parts of this specification, it can be used to improve subjective symptoms of dry eye, and in particular, it can be expected to be effective for eye discomfort associated with dryness.

[0167] (Dry Eye)

[0168] In the present disclosure, compositions, medicines, methods, etc. for preventing and / or treating dry eye may be provided. In the present disclosure, it is shown that (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide (which may be a pharmaceutically acceptable salt, solvate, etc. thereof) may be used for the treatment of dry eye. In addition, in another embodiment of the present disclosure, it is shown that a Vi / Vc region inhibitor may be used for the treatment of dry eye. The treatment or prevention of dry eye treated by the composition of the present disclosure is not particularly limited, but may include the improvement of subjective symptoms or objective symptoms.

[0169] (Improvement of subjective symptoms)

[0170] In one embodiment, the composition, medicine, or method of the present disclosure may be intended to improve subjective symptoms of dry eye. In another embodiment, the composition, medicine, or method of the present disclosure may be intended to improve dry eye accompanied by subjective symptoms. By improving subjective symptoms, the composition of the present disclosure may improve, but is not particularly limited, eye discomfort, dryness, visual function, eye strain, foreign body sensation, stigmatism, or foggy vision. The composition of the present disclosure preferably improves eye discomfort or dryness, more preferably eye discomfort, in the view that it effectively suppresses milder irritation.

[0171] (Eye discomfort)

[0172] In one embodiment, the composition of the present disclosure can suppress eye discomfort. The eye discomfort suppressed by the composition of the present disclosure is not particularly limited, but is caused by dryness, inflammation, or instability of the tear film. The composition of the present disclosure preferably suppresses eye discomfort associated with dryness, in the view that it has a more therapeutic effect.

[0173] (Improvement of objective symptoms)

[0174] In one embodiment, the composition, medicine, or method of the present disclosure may be intended to improve objective symptoms of dry eye. In another embodiment, the composition, medicine, or method of the present disclosure may be intended to improve dry eye accompanied by objective symptoms. Improvement of objective symptoms of dry eye may include, for example, changes or improvements in values ​​such as the Schirmer test, fluorescein staining test, tear film breakup time (BUT) test, and blink count. By improving objective symptoms, the composition of the present disclosure may improve, but is not particularly limited to, punctate superficial keratosis (SPK), tear film breakup time (BUT), tear secretion, hyperemia, or corneal and conjunctival epithelial disorders. The composition of the present disclosure preferably improves punctate superficial keratosis (SPK) in order to have a more therapeutic effect.

[0175] (Improvement of subjective and objective symptoms)

[0176] In a preferred embodiment, the composition, medicine, or method of the present disclosure may be intended to improve both subjective and objective symptoms of dry eye. In another preferred embodiment, the composition, medicine, or method of the present disclosure may be intended to improve dry eye accompanied by both subjective and objective symptoms. Subjective symptoms and objective symptoms may be any of those described elsewhere in this specification. In a preferred embodiment, the composition of the present disclosure may be advantageous in that it can simultaneously improve, treat, or suppress subjective and objective symptoms, although it is not desired to be bound by theory.

[0177] (Corneal epithelial disorder)

[0178] In another aspect, the composition of the present disclosure can treat corneal epithelial disorders. The corneal epithelial disorders treated by the composition of the present disclosure are diseases involving damage to corneal epithelial cells (i.e., wounds or defects), and are not particularly limited but may include endogenous diseases such as dystonia, Sjögren's syndrome, Stevens-Johnson syndrome, and dry eye syndrome; corneal epithelial disorders caused by exogenous diseases such as post-surgery, pharmaceuticals, trauma, or contact lens use. Additionally, the composition of the present disclosure can promote corneal wound healing.

[0179] (Type of Dry Eye)

[0180] Although several methods of classification have been proposed for dry eye, it is primarily divided into "hypotonic," "hyperevaporative," and "BUT shortening" types. The hypotonic type is dry eye that develops due to tissue destruction of the lacrimal gland or impaired tear evaporation from the gland to the ocular surface caused by Sjögren's syndrome, senile edema, or graft-versus-host disease (GVHD). In severe patients, severe corneal epithelial damage often occurs ("Read and You'll Know! Know and You'll Change! Dry Eye Clinical Practice," Source: Medical Vusa, published October 1, 2017, pp. 46-58; "Ophthalmic Clinical Practice Qualify 19 for Specialists: The Path of a Dry Eye Specialist," Source: Kabushiki Kaisha Nakayama Shoten, published November 5, 2013, pp. 103-106). Meanwhile, the hyperevaporative type is a dry eye that develops when moisture is excessively lost from the exposed eye surface due to factors such as meibomian gland dysfunction, lagophthalmos, reduced blinking caused by VDT (Visual Display Terminal) work, etc., even though tear secretion function is normal. (Frostbite.) In addition, the BUT shortening type is a type of dry eye in which the BUT is short and subjective symptoms of dry eye are present, but tear secretion and corneal and conjunctival epithelium are almost normal (Revision of the Japanese Definition and Diagnostic Criteria for Dry Eye (2016 Edition), New Ophthalmology, Source: Medical Aoi Publishing, March 2017 issue, pp. 309-313). Dry eyes that can be treated or prevented by the composition of the present disclosure are not particularly limited, but include tear-reducing dry eye, hyperevaporative dry eye, or BUT shortening dry eye. From the view that the composition of the present disclosure has a more therapeutic effect, it is preferable to treat tear-reducing dry eye.

[0181] (Inhibition of the Vi / Vc region)

[0182] In normal animals, when the eye area is forcibly dried, the number of positive cells for c-Fos, a neurotransmitter marker, increases in the Vi / Vc region of the medulla oblongata, suggesting that the eye discomfort associated with dryness is caused by nerves passing through the Vi / Vc region (The Journal of Neuroscience, April 28, 2004·24(17): 4224-4232). In addition, in the extraorbital lacrimal gland enucleated rat dry eye model, which is a model of hypotonic dry eye, the number of positive cells for c-Fos increases in the Vi / Vc region of the medulla oblongata (Neuroscience. 2015. 290. 204-213), suggesting that the eye discomfort associated with dryness, which is a subjective symptom of hypotonic dry eye, is caused by nerves passing through the Vi / Vc region.

[0183] The trigeminal nerve spinal nuclei are classified into the hilar nucleus (Vo), intermediate nucleus (Vi), and caudal nucleus (Vc), which relay the transmission of nociceptive or nonciceptive signals, such as pain or touch, from the orofacial region. Stimulation of the cornea is mainly transmitted via the pathways of the Vc / c1 or Vi / Vc regions (J Neurophysiol. 1997 Jan;77(1):43-56.), and the responding region differs depending on the type of stimulus. It is known that the Vc / c1 region responds to nociceptive stimuli, such as heat or capsaicin, so-called strong stimuli (Headache. 2012 February; 52(2): 262-273, “Effect of Estrogen on Nociceptive Stimulation by Capsaicin to Trigeminal Nerve Regions” by Kazuaki Yamagata, Osaka University paper), whereas the Vi / Vc region responds to weak stimuli such as dryness (The Journal of Neuroscience, April 28, 2004·24(17):4224-4232).

[0184] Most current eye drops approved as prescription medications for dry eye primarily improve objective symptoms, and to the applicant's knowledge, there are no readily apparent eye drops that directly treat subjective symptoms in addition to objective symptoms. Therefore, an eye drop for treating dry eye that improves both objective and subjective symptoms is highly desirable.

[0185] The composition of the present disclosure may be characterized by administering said composition to a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort. The composition of the present disclosure may be characterized by administering said composition to a patient diagnosed with dry eye who has recognized objective findings of punctate superficial keratosis (SPK).

[0186] (Vi / Vc region inhibitor)

[0187] In one aspect of the present disclosure, a Vi / Vc region inhibitor may be provided. The Vi / Vc region inhibitor of the present disclosure may alter the transmission of signals for nodular reception in the Vi / Vc region, and, for example, may reduce the number of c-Fos-expressing cells in the Vi / Vc region after nodular reception. When behavioral experiments related to memory or anxiety are performed, an increase in c-Fos expression is observed in neurons that respond to the stimulus, at the mRNA level after about 30 minutes and at the protein level after 1 to 2 hours. c-Fos is used as an indicator of neuronal activity.

[0188] As Vi / Vc region inhibitors, substances that inhibit the excitation of the Vi / Vc region or substances that inhibit the function of the Vi / Vc region may be included, but combinations of multiple substances that achieve inhibition of Vi / Vc region excitation are also included in the Vi / Vc region inhibitor. In the present disclosure, the Vi / Vc region inhibitor may be a Vi / Vc region inhibitor compound. Representative examples of Vi / Vc region inhibitor compounds include, but are not limited to, compounds described in (Vi / Vc region inhibitor compound) provided in the present disclosure (e.g., (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or compound (1) or pharmaceutically acceptable salts, solvates, etc. thereof). Other biomolecules with specified functions, such as antibodies and nucleic acids, may also be used as substances that can be used as Vi / Vc region inhibitors.

[0189] Examples of other Vi / Vc region inhibitors include, for instance, means for performing genetic modification to inhibit the excitation or function of the Vi / Vc region, or cells having activity that inhibits the excitation or function of the Vi / Vc region. The Vi / Vc region inhibitors of the present disclosure may also be effective for diseases or conditions where the regulation of the Vi / Vc region is useful.

[0190] Examples of substances that inhibit the excitation of the Vi / Vc region or inhibit the function of the Vi / Vc region include small molecule compounds, large molecule compounds, nucleic acids, or antibodies that inhibit the excitation of the Vi / Vc region, or small molecule compounds, large molecule compounds, nucleic acids, or antibodies that inhibit the function of the Vi / Vc region.

[0191] (Vi / Vc region inhibitory compound)

[0192] In an embodiment of the present disclosure, a compound that can be used as a Vi / Vc region inhibitor is provided. Compounds that can be used as a Vi / Vc region inhibitor include, for example, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide described herein or compound (1) or pharmaceutically acceptable salts and solvates thereof.

[0193] Pharmaceutically acceptable salts of compounds that can be used as Vi / Vc range inhibitors are not particularly limited as long as they are pharmaceutically acceptable salts, but specifically include inorganic acids such as hydrochloric acid, hydrobromide, hydroiodide, sulfuric acid, nitric acid, and phosphoric acid; aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, and mandelic acid; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid; and aliphatic tricarboxylic acids such as citric acid; Examples include organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, aliphatic sulfonic acids, aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; acid addition salts with acidic amino acids such as aspartic acid and glutamic acid, salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium, salts with organic bases such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, and ornithine, or ammonium salts.

[0194] (Uses of Vi / Vc region inhibitors)

[0195] In one aspect of the present disclosure, a composition, medicine, or method of using the same for preventing or treating dry eye may be provided, comprising a Vi / Vc region inhibitor. A composition, medicine, or method of using the same comprising a Vi / Vc region inhibitor may be intended to improve subjective symptoms of dry eye, for example, to suppress eye discomfort associated with dryness. A composition or method of using the same comprising a Vi / Vc region inhibitor may also be intended to improve dry eye. A composition comprising a Vi / Vc region inhibitor may be an eye drop. A composition comprising a Vi / Vc region inhibitor may be a suspension. As for dry eye, tear-reducing dry eye may be the target of treatment. A composition comprising a Vi / Vc region inhibitor may be characterized by administering said composition to a patient diagnosed with dry eye in whom subjective symptoms of eye discomfort are recognized. In the present disclosure, a composition for suppressing eye discomfort associated with dryness may be provided, comprising a Vi / Vc region inhibitor. In addition, the present disclosure may provide a composition for improving the subjective symptoms of dry eye comprising a Vi / Vc region inhibitor.

[0196] In another aspect, a composition, medicine, or method of using the same may be provided for suppressing or improving eye discomfort associated with dryness, comprising a Vi / Vc region inhibitor. For this use, the patient may not need to be diagnosed with dry eye. In the present disclosure, it has been discovered that eye discomfort can be suppressed or improved by controlling the Vi / Vc region, and thus the use said use is provided.

[0197] Subjective symptoms of dry eye, particularly tear-reducing dry eye (e.g., eye discomfort accompanied by dryness), are thought to be perceived particularly through the Vi / Vc region, and these symptoms can be improved by a Vi / Vc region inhibitor. In addition, the embodiments of this specification indicate that improvement of objective symptoms of dry eye (e.g., SPK (punctate superficial keratosis)) can be provided by a Vi / Vc region inhibitor.

[0198] (Formulation)

[0199] The composition of the present disclosure may be formulated into a suitable formulation. For example, when the composition of the present disclosure is an ophthalmic composition, it may be provided as an eye injection solution, an eye ointment, eye drops, or an eye irrigation solution. The composition may be formulated into any formulation such as an aerosol, liquid, extract, elixir, capsule, granule, pill, ointment, powder, tablet, solution, suspension, or emulsion.

[0200] For example, an ophthalmic composition may be provided in the form of a suspension in which an active ingredient is suspended in an aqueous solvent (e.g., phosphate-buffered physiological saline) or in the form of a liquid formulation in which the active ingredient is dissolved. The composition of the present disclosure may be an eye drop. The composition of the present disclosure may be a suspension.

[0201] The composition of the present disclosure may be administered by any suitable route determined by a person skilled in the art and may be formulated suitable for administration by a route of administration selected from, but not limited to, ocular injection, topical application (including application to the eye), ophthalmic injection, intravenous injection, drip, oral, parenteral, transdermal, etc.

[0202] (Additives and / or excipients)

[0203] The composition may include any pharmaceutically acceptable additives and / or excipients known in the art. Examples of additives include, but are not limited to, stabilizers, pH adjusters, buffers, preservatives, and surfactants.

[0204] Examples of stabilizers include sodium bisulfite, and the content thereof is preferably 0 to about 1 w / v% with respect to the total amount of the composition.

[0205] As pH adjusters, acids such as carbonic acid, acetic acid, and citric acid may be used, and alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, alkali metal acetates such as sodium acetate, and alkali metal citrates such as sodium citrate may be used, and the content thereof may be, for example, 0 to about 20 w / v% with respect to the total amount of the composition.

[0206] Examples of preservatives include parahydroxybenzoic acid esters such as sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate; chlorhexidine gluconate; quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride; alkyl polyaminoethylglycine; chlorobutanol; polyquad; polyhexamethylene biguanide; and chlorhexidine. The content thereof may be appropriately varied depending on the type, but for example, 0 to about 0.2 w / v% may be used with respect to the total amount of the composition.

[0207] Surfactants are not particularly limited, but examples include nonionic surfactants, anionic surfactants, or cationic surfactants. In the view that they are less toxic, nonionic surfactants are preferred.

[0208] As nonionic surfactants, examples include polyoxyethylene (40) monostearate (polyoxylate 40), sorbitan sesquioleate (sorbitan sesquioleate), or polyoxyethylene (20) sorbitan monooleate (polysorbate 80), although not specifically limited.

[0209] Anionic surfactants are not particularly limited, but examples include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, α-olefin sulfonic acid, etc.

[0210] Cationic surfactants are not particularly limited, but examples include benzalkonium chloride, benzethonium chloride, etc.

[0211] The content of the surfactant is not particularly limited, but, for example, is 0 to about 1.0 w / v% with respect to the total amount of the composition.

[0212] When manufacturing eye drops, for example, the desired above-mentioned ingredient may be dissolved or suspended in an aqueous solvent such as sterile purified water, physiological saline solution, or a buffer solution (e.g., phosphate buffer, citric acid buffer, or acetic acid buffer, etc.), or in a non-aqueous solvent such as vegetable oils such as cottonseed oil, soybean oil, sesame oil, or peanut oil, adjusted to a predetermined osmotic pressure, and sterilized by filtration sterilization. When used as a suspension, a surfactant may be included.

[0213] In addition, when manufacturing an eye ointment, an ointment base may be included in addition to the various ingredients mentioned above. The ointment base is not particularly limited, but may include oily bases such as petroleum jelly, liquid paraffin, and polyethylene; water-soluble bases such as emulsifying bases in which an oil phase and a water phase are emulsified by a surfactant, etc.

[0214] The composition of the present disclosure may be provided as a therapeutic or prophylactic agent as a kit. In specific embodiments, the present disclosure provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the composition or medicine of the present disclosure. In some cases, information indicating authorization for manufacture, use, or sale for human administration by a government agency may be attached to such containers in a form prescribed by a government agency regulating the manufacture, use, or sale of the medicine or biological product.

[0215] (Kit)

[0216] In this specification, the term "kit" is used when the purpose is to provide a composition that, for the sake of stability, is not particularly limited but is preferably mixed immediately before use rather than provided in a mixed state. It is advantageous for such a kit to preferably include instructions or a manual describing how to use the provided parts (e.g., therapeutic drugs, preventive drugs) or how to handle reagents. In this specification, when the kit is used as a reagent kit, the kit typically includes instructions, etc., describing the method of use of therapeutic drugs, preventive drugs, etc.

[0217] (directions)

[0218] In this specification, the "instruction sheet" contains, for example, wording instructing the detection method of the present disclosure, the method of using a diagnostic drug, or the administration of a drug, etc., although it is not specifically limited. Additionally, the instruction sheet may contain wording instructing administration to the eye (for example, by eye drops, eye ointment, or injection, etc.) as the site of administration. This instruction sheet is prepared in accordance with the format prescribed by the supervisory authority of the country where the present disclosure is implemented (for example, the Ministry of Health, Labour and Welfare in Japan, the Food and Drug Administration (FDA) in the United States, etc.), and indicates that it has been approved by such supervisory authority. The instruction sheet is a so-called package insert or label, and is usually provided in a paper medium, but is not limited thereto and may also be provided in the form of, for example, an electronic medium (for example, a website provided via the internet, email).

[0219] (Information in the attached document)

[0220] In light of the information on which the clinical trials provided in this disclosure are based, instructions such as accompanying documents (labels in the U.S., etc.) may describe efficacy and effects (which may include characteristics of target patients or target diseases, disorders or symptoms), methods of administration or dosage, and precautions for use.

[0221] (Route of administration)

[0222] In one embodiment, the use of the present disclosure may be, for example, ophthalmic preparations, but is not limited thereto, and may also be forms of administration (methods of administration and formulations) such as eye ointments, injection into the anterior chamber, impregnation into sustained-release formulations, subconjunctival injection, and systemic administration (oral, intravenous injection).

[0223] (volume)

[0224] The concentration of the compound of the present disclosure is not particularly limited, but is typically about 0.1 to about 100,000 μM (μl / l). In the view that it is less toxic and more effective, it is preferably about 0.5 to about 80,000 μM, in the view that it is more significant, it is more preferably about 5 to about 80,000 μM, more preferably about 50 to about 75,000 μM, particularly preferably about 500 to about 70,000 μM, further preferably about 2,000 to about 50,000 μM, and most preferably about 5,000 to about 30,000 μM. Other concentration ranges include, for example, typically about 0.1 to about 1 μM, about 1 to about 10 μM, about 10 to about 100 μM, about 100 to about 1000 μM, about 1000 to about 2000 μM, about 2000 to about 4000 μM, about 4000 to about 7000 μM, about 7000 to about 10000 μM, about 10000 to about 12000 μM, about 12000 to about 15000 μM, about 15000 to about 20000 μM, about 20000 to about 22000 μM, about 22000 to about 25000 μM, about 25000 to about 30000 μM, about 30000 to about Examples include 40,000 μM, about 40,000 to about 50,000 μM, about 50,000 to about 70,000 μM, about 70,000 to about 85,000 μM, or about 85,000 to about 100,000 μM, but are not limited to these. The upper and lower limits thereof may be set by appropriately combining them.

[0225] The concentration of the compound of the present disclosure is not particularly limited, but may be about 0.00001 to about 5.0 w / v%. Preferably, from the view that it is less toxic and more effective, it is about 0.00003 to about 3.0 w / v%; more preferably, from the view that a more significant effect is recognized, it is about 0.0003 to about 3.0 w / v%; even more preferably, about 0.003 to about 2.0 w / v%; particularly preferably, about 0.03 to about 1.5 w / v%; further preferably, about 0.1 to about 1.0 w / v%; and most preferably, about 0.3 to about 1.0 w / v%. The compound of the present disclosure may be effective over a wide range of concentrations. Other examples of concentrations of the compounds of the present disclosure include about 0.00001 to about 0.0001 w / v%, about 0.0001 to about 0.001 w / v%, about 0.001 to about 0.01 w / v%, about 0.01 to about 0.02 w / v%, about 0.02 to about 0.05 w / v%, about 0.05 to about 0.1 w / v%, about 0.1 to about 0.2 w / v%, about 0.2 to about 0.3 w / v%, about 0.3 to about 0.4 w / v%, about 0.4 to about 0.5 w / v%, about 0.5 to about 0.6 w / v%, about 0.6 to about 0.7 w / v%, about 0.7 to about 0.8 w / v%, about Examples include 0.8 to about 0.9 w / v%, about 0.9 to about 1 w / v%, about 1 to about 1.1 w / v%, about 1.1 to about 1.2 w / v%, about 1.2 to about 1.3 w / v%, about 1.3 to about 1.4 w / v%, about 1.4 to about 1.5 w / v%, etc. These upper and lower limits can be set by appropriately combining them.

[0226] The concentration as an eye drop is not particularly limited, but may be about 0.00001 to about 5.0 w / v%. Preferably, from the view that it is less toxic and more effective, it is about 0.00003 to about 3.0 w / v%; more preferably, from the view that a more significant effect is recognized, it is about 0.0003 to about 3.0 w / v%; even more preferably, about 0.003 to about 2.0 w / v%; particularly preferably, about 0.03 to about 1.5 w / v%; further preferably, about 0.1 to about 1.0 w / v%; and most preferably, about 0.3 to about 1.0 w / v%. The compounds of the present disclosure may be effective over a wide range of concentrations. Other examples of concentrations of the compounds of the present disclosure include about 0.00001 to about 0.0001 w / v%, about 0.0001 to about 0.001 w / v%, about 0.001 to about 0.01 w / v%, about 0.01 to about 0.02 w / v%, about 0.02 to about 0.05 w / v%, about 0.05 to about 0.1 w / v%, about 0.1 to about 0.2 w / v%, about 0.2 to about 0.3 w / v%, about 0.3 to about 0.4 w / v%, about 0.4 to about 0.5 w / v%, about 0.5 to about 0.6 w / v%, about 0.6 to about 0.7 w / v%, about 0.7 to about 0.8 w / v%, about Examples include 0.8 to about 0.9 w / v%, about 0.9 to about 1 w / v%, about 1 to about 1.1 w / v%, about 1.1 to about 1.2 w / v%, about 1.2 to about 1.3 w / v%, about 1.3 to about 1.4 w / v%, about 1.4 to about 1.5 w / v%, etc. These upper and lower limits can be set by appropriately combining them.

[0227] The effective dose of the medicine disclosed herein effective for the treatment of a specific disease, disorder, or condition may vary depending on the nature of the disorder or condition, but a person skilled in the art can determine it by standard clinical techniques based on the description in this specification. Additionally, if necessary, it is possible to use an in vitro assay to assist in identifying the optimal dosage range. The exact dose intended for use in the formulation must also be determined according to the judgment of the attending physician and the condition of each patient, as it may also vary depending on the route of administration and the severity of the disease or disorder. However, the dosage is not particularly limited, but may be, for example, 0.001, 1, 5, 10, 15, 100, or 1000 mg / kg body weight per dose, or within the range of any two of these values.

[0228] (Durability)

[0229] The duration of the effect when the composition of the present disclosure is administered is not particularly limited, but is 12 hours. From the perspective of obtaining a more therapeutic effect, it is preferably 8 hours, and more preferably 4 hours.

[0230] (Immediate effect)

[0231] The immediate effect when the composition of the present disclosure is administered is not particularly limited, but the effect is shown in 5 minutes to 2 hours. From the perspective of obtaining a more therapeutic effect, it is preferably 10 minutes to 1 hour, more preferably 20 minutes to 50 minutes, and even more preferably 30 minutes.

[0232] (Administration interval)

[0233] The administration interval is not specifically limited, but can be administered at a general interval, for example, 1 to 6 times per day. Preferably, for better efficacy and to improve patient compliance, it is 2 to 5 times per day, and more preferably 2 to 4 times per day. The dosage, number of administrations, administration interval, duration of administration, and method of administration may be appropriately selected according to the patient's age or weight, symptoms, form of administration, target organ, etc. For example, the composition of the present disclosure may be used as an eye drop. Furthermore, it is preferable that the therapeutic agent contains a therapeutically effective amount or an effective amount of an active ingredient that exerts a desired action. The effective dose can be estimated from a dose-response curve obtained in vitro or from an animal model test system.

[0234] In one embodiment, the present disclosure may include a description of dosage and administration such as, for example, "use in a patient diagnosed with dry eye who has recognized subjective symptoms of eye discomfort," "use in a patient diagnosed with dry eye who has recognized objective findings of punctate superficial keratosis (SPK)," or "use in a patient diagnosed with dry eye who has recognized corneal and conjunctival epithelial disorders."

[0235] (General Technology)

[0236] The molecular biological, biochemical, and microbiological methods used herein are well known and commonly used in the art, such as, for example, Sambrook J. et al. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor and its 3rd Ed. (2001); Ausubel, FM (1987). Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Ausubel, FM (1989). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Innis, MA (1990). PCR Protocols: A Guide to Methods and Applications, Academic Press; Ausubel, FM (1992). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, FM (1995). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Innis, M.A. et al. (1995). PCR Strategies, Academic Press; Ausubel, F. M. (1999).Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, J. J. et al. (1999). PCR Applications: Protocols for Functional Genomics, Academic Press, Gait, MJ (1985). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Gait, M. J. (1990). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein, F. (1991). Oligonucleotides and Analogues: A Practical Approach, IRL Press; Adams, R.L. et al. (1992). The Biochemistry of the Nucleic Acids, Chapman & Hall; Shabarova, Z. et al. (1994). Advanced Organic Chemistry of Nucleic Acids, Weinheim; Blackburn, G.M. et al. (1996). Nucleic Acids in Chemistry and Biology, Oxford University Press; Hermanson, GT (1996). Bioconjugate Techniques, Academic Press, Supplementary Volume Experimental Medicine “Gene Introduction & Expression Analysis Methods” Yodosha, 1997, etc. These are referred to by reference in the relevant parts (may be all) of this specification.

[0237] References cited in this specification, such as scientific literature, patents, and patent applications, are incorporated herein by reference in their entirety to the same extent as they are specifically described.

[0238] The present disclosure has been described above with reference to preferred embodiments for ease of understanding. The present disclosure is described below based on examples, but the description above and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Accordingly, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is limited only by the claims.

[0239] Examples

[0240] Examples of the present disclosure are described below. Where applicable, the handling of biological samples, etc., was carried out in compliance with standards prescribed by the Ministry of Health, Labour and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, etc., and where applicable, in accordance with the Helsinki Declaration or ethical regulations established based on the Declaration.

[0241] (Test Example 1) Effect of 0.3 w / v% compound (1) in a scopolamine-induced rat dry eye model

[0242] (Used animals)

[0243] Male SD rats (weighing 254.6g to 281.5g at the time of arrival) purchased from Nihon Charles River were used. From the time of arrival until the end of the experiment, the animals were housed in a rearing room set to a room temperature of 23℃±3℃, humidity of 55%RH±10%RH, and 12-hour lighting (08:00 on, 20:00 off). The animals were fed solid feed (product name: Labo MR Stock, manufactured by Nihon Nosan Kogyo) by a continuous feeding method, and were allowed to freely consume tap water that had passed through an animal beverage sterilization device via an automatic water dispenser. This experiment was conducted with the approval of the Animal Experiment Ethics Committee based on the Animal Welfare and Management Act (Act No. 105 of October 1, 1973; last amended: Act No. 46 of May 30, 2014, 1914), etc.

[0244] (Test substance)

[0245] Compound (1) was used as the test substance. Compound (1) was suspended in a base shown in Table 1 to a concentration of 0.3 w / v% and used as a suspension eye drop. Additionally, as a control, a base eye drop containing only a base (Table 1) that does not contain compound (1) was used.

[0246]

[0247] (Test Method)

[0248] (Construction of a scopolamine-induced rat dry eye model)

[0249] Scopolamine hydrobromide trihydrate (Tokyo Kasei High School) was dissolved in physiological saline solution (Otsuka Seiyaku Gojo) to a concentration of 208.3 mg / mL (hereinafter referred to as SC solution). The SC solution was filled into an osmotic pump (product name: Alzet (registered trademark) osmotic pump (model: 2ML4), manufactured by DURECT Corporation).

[0250] General anesthesia was administered by shaving the hair between the left and right shoulder blades of the rat (near the implantation site of the osmotic pressure pump) and inhaling isoflurane (trade name: Foren (registered trademark), manufactured by Abbott Japan). After disinfecting the shaved area alternately with 10% isodine solution (trade name: Isodine solution (registered trademark) 10%, manufactured by Mundi Pharma) and 70% ethanol, a sterile drape was placed over the incision site and the skin was incised by conduction. Forceps were inserted into the incision to bluntly dissect the subcutaneous connective tissue, a pocket sized to accommodate the implantation of the osmotic pressure pump was created, and the pump was implanted. The subcutaneous connective tissue was sutured along the width of the incision using absorbable sutures (trade name: Vicryl, thread thickness: J463, manufactured by Johnson & Johnson). Next, the skin was sutured along the width of the incision using a restraining suture (product name: needle-equipped shoulder blade suture, product number: F17-30, manufactured by Natsume Seisakusho). For postoperative pain care, 0.05 mg / kg of buprenorphine hydrochloride injection (product name: Repetan (registered trademark) 0.3 mg injection, manufactured by Otsuka Seisakusho) and 20,000 units / unit of benzylpenicillin potassium (product name: Penicillin G potassium for injection 200,000 units, manufactured by Meiji Seika Pharma) were each administered subcutaneously once to a site spaced apart from the incision.

[0251] (Post-surgery care)

[0252] After implanting the osmotic pressure pump, on the next day and the day after next, 0.05 mg / kg of buprenorphine hydrochloride injection and 20,000 units / individual of benzylpenicillin potassium were each administered subcutaneously once to a site separated from the surgical site.

[0253] (administration)

[0254] For a total of 14 days, from 8 to 21 days after implanting the osmotic pressure pump, base eye drops or a suspension of 0.3 w / v% compound (1) was administered ophthalmologically. Ophthalmic administration was performed four times a day with an interval of at least 2 hours, administering 5 μL to the right eye using a micropipette. Additionally, base eye drops were administered ophthalmologically to the Sham group.

[0255] (Observation of punctate superficial keratosis (SPK))

[0256] Under general anesthesia by inhalation of isoflurane, 5 μL of 0.1% sodium fluorescein solution (hereinafter referred to as FL solution) was administered ophthalmologically to the right eye using a micropipette. After rinsing off the excess FL solution by administering a few drops of physiological saline, the cornea was observed by dividing it into three parts—upper, middle, and lower—using a slit lamp (Topcon), and scored according to Table 2 with 0 to 3 points for each part, for a total maximum of 9 points.

[0257]

[0258] (Preparation of Zamboni fixative)

[0259] NaH2PO4·2H2O (Nakaritetsu Co., Ltd.), Na2HPO4·12H2O (Wako Junyaku High School Co., Ltd.), paraformaldehyde (Wako Junyaku High School Co., Ltd.), and 2,4,6-trinitrophenol (picric acid, Kishida Chemical Co., Ltd.) were dissolved in ultrapure water to final concentrations of 0.3%, 2.9%, 2%, and 0.1%, respectively, and Zamboni fixative was prepared.

[0260] (Measurement of c-Fos positive cell count)

[0261] After observing SPK 14 days after administration of the base eye drops or a 0.3 w / v% compound (1) suspension eye drops (22 days after surgery), general anesthesia by isoflurane inhalation was administered. After euthanasia by bloodletting with physiological saline solution, the medulla oblongata was extracted by perfusing with Zamboni fixative. The extracted medulla oblongata was thinly sliced ​​and stained by immunohistochemical staining using an anti-c-Fos antibody (product name: Rabbit Anti-Human c-Fos Polyclonal Antibody, sc-52, manufactured by Santa Cruz Biotechnology, Inc.). The specimen was observed under a fluorescence microscope, and the number of cells with strong staining intensity among the cells stained by the anti-c-Fos antibody within the Vi / Vc region was counted.

[0262] (result)

[0263] Figure 1 shows the effect on SPK, and Table 3 shows the effect on the number of c-Fos positive cells in the Vi / Vc region of the medulla oblongata. The 0.3 w / v% compound (1) suspension eye drops significantly reduced the SPK score 7 days after administration (15 days after surgery) compared to the base eye drops, and the effect continued 14 days after administration (22 days after surgery). Thus, it was shown that compound (1) improves objective symptoms.

[0264] In addition, the 0.3 w / v% suspension of compound (1) reduced the number of c-Fos positive cells in the Vi / Vc region of the medulla oblongata compared to the base eye drops. Thus, it was shown that compound (1) inhibits the Vi / Vc region.

[0265]

[0266] (Test Example 2 Dose-responsiveness of compound (1) with respect to the number of blinks under dry conditions in a scopolamine-induced rat dry-eye model)

[0267] (Used animals)

[0268] Male SD rats (weighing 253.1g to 273.0g at the time of arrival) purchased from Nihon Charles River were used. From the time of arrival until the day of rearing under low humidity conditions, the animals were reared in a rearing room set to a room temperature of 23℃±3℃, humidity of 55%RH±10%RH, and 12-hour lighting (08:00 on, 20:00 off). The animals were fed solid feed (product name: Labo MR Stock, manufactured by Nihon Nosan Kogyo) by a continuous feeding method, and were allowed to freely consume tap water that had passed through an ultrafiltration device via a water bottle. This experiment was conducted with the approval of the Animal Experiment Ethics Committee based on the Animal Welfare and Management Act (Act No. 105 of October 1, 1973; last amended: Act No. 46 of May 30, 2014), etc.

[0269] (Test substance)

[0270] Compound (1) was used as a test substance. Similar to Test Example 1, compound (1) was suspended in a buffer solution to prepare suspension eye drops with concentrations of compound (1) of 0.1 w / v%, 0.3 w / v%, and 1.0 w / v%. Additionally, as a control group, base eye drops containing only a base that does not contain compound (1) were also prepared.

[0271] (Test Method)

[0272] (Construction of a scopolamine-induced rat dry eye model)

[0273] A scopolamine-induced rat dry eye model was prepared in the same manner as in Test Example 1.

[0274] (Low humidity environment)

[0275] About 2.5 hours after installing the osmotic pressure pump, dry air supplied from an air compressor was sent into the experimental chamber (SJ-1500N, Natsume Seisakusho) to create a low humidity environment (20%RH or less).

[0276] (administration)

[0277] 0.5 hours before measuring the number of blinks, 5 μL of the base eye drops or a suspension of 0.1 w / v%, 0.3 w / v%, or 1.0 w / v% compound (1) was administered as a single eye drop to the right eye using a micropipette.

[0278] (Measurement of blink count)

[0279] After the 8th day following the commencement of rearing in a low-humidity environment, the rats were removed from the rearing cages and placed in a cage (behavioral measurement environment cage) with a metal mesh covering the entire surface to facilitate the measurement of blink counts. After acclimatizing for 0.5 hours under normal conditions, the behavioral measurement environment cages were transferred to an experimental chamber, and the number of blinks of the rats' right eyes was measured for 5 minutes under a low-humidity environment. Additionally, the experiment was conducted in four phases using the same animals with a withdrawal period of at least 2 days (crossover test).

[0280] (result)

[0281] The results are shown in Figure 2. Compound (1) reduced the number of blinks in the range from 0.1 w / v% to 1.0 w / v%, and a significant effect was observed at 0.3 w / v% and 1.0 w / v%. Thus, it was shown that compound (1) improves subjective symptoms over a wide concentration range.

[0282] (Test Example 3: Persistence of compound (1) with respect to the number of blinks in a dry environment in a scopolamine-induced rat dry eye model)

[0283] The duration of the improvement effect on subjective symptoms was examined using the same evaluation method as in Test Example 2. The number of blinks of the right eye was measured for 5 minutes in a low humidity environment after 0.5 hours after a single dose of the base eye drops or after 0.5, 4, or 8 hours after a single dose of the 1.0 w / v% compound (1) suspension eye drops.

[0284] The results are shown in Fig. 3. The number of blinks after 0.5, 4, and 8 hours after administering the 1.0 w / v% compound (1) suspension eye drops can be reduced compared to the number of blinks after 0.5 hours after administering the base eye drops, and in particular, the number of blinks was significantly reduced at 0.5 and 4 hours. Thus, it was shown that compound (1) maintains the effect of improving subjective symptoms for a long time.

[0285] (Test Example 4 Long-term administration test in a scopolamine-induced rat dry eye model)

[0286] Using a scopolamine-induced rat dry eye model prepared in the same manner as Test Example 2, a 1.0 w / v% compound (1) suspension eye drops was administered for a long period. Additionally, the model was treated in a low humidity environment (20% RH or less) only when measuring the number of blinks.

[0287] After one week had passed since the osmotic pressure pump was implanted, the 1.0 w / v% compound (1) suspension eye drops and base eye drops were administered repeatedly for 8 days. The 1.0 w / v% compound (1) suspension eye drops and base eye drops were administered 5 μL to the right eye four times a day using a micropipette.

[0288] On the 8th day after sample administration, the improvement effect of SPK (SPK score) was evaluated using the same method as in Test Example 1. In addition, the number of blinks of the right eye was measured for 5 minutes in a low-humidity environment 4 hours after the first administration on the 7th day (2 weeks after surgery) using the same method as in Test Example 2.

[0289] The effect on SPK is shown in Figure 4. The 1.0 w / v% compound (1) suspension eye drops significantly reduced the SPK score compared to the base eye drops.

[0290] Figure 5 shows the effect on the number of blinks in a low humidity environment. The 1.0 w / v% compound (1) suspension eye drops reduced the number of blinks compared to the base eye drops.

[0291] (Consideration)

[0292] From the results of Table 3 of Test Example 1 in this specification, it was shown that compound (1) has an effect of inhibiting the Vi / Vc region. In addition, from FIG. 1 of Test Example 1 and FIG. 2 and 3 of Test Examples 2 and 3, it was shown that compound (1) has an effect of improving objective symptoms and subjective symptoms. Therefore, it was shown that compound (1) has a dry eye treatment effect.

[0293] In addition, compound (1) is presumed to have an effect that inhibits the Vi / Vc region, although this is not certain, thereby improving the objective and subjective symptoms that are therapeutic effects of dry eye. That is, it is presumed that dry eye can be treated by inhibiting the Vi / Vc region.

[0294] (Test Example 5: Clinical Test Example)

[0295] (Measurement Items)

[0296] Key evaluation items

[0297] Regarding the safety and tolerability of compound (1)

[0298] · Number and severity of adverse events, including clinical test results, vital signs, and abnormal changes in physical and ophthalmic examinations · Pharmacokinetic (PK) profile C of compound (1) max , t max , AUC 0-last , AUC 0-∞ , t last , AUC %extrap , t 1 / 2 , MRT 0-last , MRT 0-∞ Measurement of , Vd / F, CL / F.

[0299] Regarding the effectiveness of compound (1)

[0300] · Difference between compound (1) and placebo in changes in dry eye symptoms (visual analog scale [VAS])

[0301] Secondary evaluation items

[0302] Regarding the effectiveness of compound (1)

[0303] · Changes in dry eye signs (CFS score (superior, inferior, uterine, nasal, total), conjunctival lisamine green staining score, lead wiper epithelial disturbance score, tear film breakup time (TBUT))

[0304] · Changes in dry eye symptoms (VAS, Ocular Surface Disease Index [OSDI (R) ], Dry Eye Survey 5 [DEQ-5] Score)

[0305] (Protocol)

[0306] (A) Single dose

[0307] Screen eligible subjects. Randomize subjects to receive a single dose of a placebo or a specific concentration of compound (1) eye drops.

[0308] Blood for PK measurement is collected at predetermined times before and after administration. The above measurement items are evaluated for the assessment of ocular and systemic safety after administration.

[0309] (B) Multiple administrations

[0310] Eligible subjects are screened. Subjects are randomized to receive either a placebo or eye drops of a specific concentration of the compound (1). Multiple administrations are performed over a specific period.

[0311] The above measurement items are evaluated for the assessment of ocular and systemic safety after administration.

[0312] (Test Example 6: Vi / Vc regulatory action)

[0313] A scopolamine-induced rat dry eye model is prepared as described in Test Example 1. For a total of 14 days, from 8 to 21 days after implantation of the osmotic pump, the base eye drops or eye drops containing the test compound are administered ophthalmologically. Ophthalmic administration is performed four times a day at intervals of at least 2 hours, with 5 μL administered to the right eye using a micropipette.

[0314] 14 days after administration of the base eye drops or eye drops containing the test compound (22 days after surgery), general anesthesia by isoflurane inhalation is administered, and after euthanasia by bloodletting with physiological saline, the medulla oblongata is extracted by perfusion with Zamboni fixative. After thinly slicing the extracted medulla oblongata, it is stained by immunohistochemical staining using an anti-c-Fos antibody (trade name: Rabbit Anti-Human c-Fos Polyclonal Antibody, sc-52, manufactured by Santa Cruz Biotechnology, Inc.). The specimen is observed under a fluorescence microscope, and the number of cells with high staining intensity among the cells stained by the anti-c-Fos antibody within the Vi / Vc region is counted.

[0315] The Vi / Vc region regulating function of the compound under test is confirmed in the same way as in Test Example 1.

[0316] (to give)

[0317] As described above, the present disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the present disclosure should be interpreted only by the claims. It is understood that patents, patent applications, and other documents cited in this specification are to be referenced to this specification as if their contents were specifically described in this specification. The present application claims priority to Japanese Patent Application No. 2019-184053 filed with the Japan Patent Office on October 4, 2019, and the contents thereof are to be referenced as if the entirety thereof constitutes the contents of the present application. Industrial applicability

[0318] The present disclosure is applicable in fields such as medical, pharmaceutical, healthcare, biology, and biochemistry.

Claims

Claim 1 A composition comprising 0.1 to 1.0 w / v% of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for treating dry eye by improving eye discomfort and corneal epithelial disorders. Claim 2 A composition according to claim 1, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide. Claim 3 A composition according to claim 1 or 2, wherein the dry eye syndrome is accompanied by subjective symptoms. Claim 4 In paragraph 3, the composition wherein the above dry eye syndrome is accompanied by eye discomfort accompanied by dryness. Claim 5 A composition according to claim 1 or 2, wherein the dry eye syndrome is accompanied by objective symptoms. Claim 6 A composition according to claim 1 or 2, wherein the dry eye syndrome involves subjective symptoms and objective symptoms. Claim 7 A composition, which is an eye drop, according to claim 1. Claim 8 A composition that is a suspension in paragraph 1. Claim 9 A composition according to claim 1, wherein the dry eye syndrome is a tear-reducing type dry eye syndrome. Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete

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