Ophthalmic composition for promoting tear fluid secretion

Abstract

To provide an ophthalmic composition capable of promoting tear fluid secretion.SOLUTION: The present invention relates to an ophthalmic composition for promoting tear fluid secretion, the composition comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition for promoting tear secretion. [Background technology]

[0002] Corneal and conjunctival epithelial disorders are caused by endogenous diseases such as dry eye, or exogenous diseases such as contact lens wear, and are characterized by symptoms such as lacrimation, foreign body sensation, eye pain, and congestion. As a therapeutic agent for corneal and conjunctival epithelial disorders, an eye drop containing sodium hyaluronate, which has a corneal epithelial growth promoting effect and a moisture retaining effect, has been marketed. In addition, it has been reported that diquafosol sodium, a therapeutic agent for dry eye, promoted tear secretion and improved corneal epithelial disorders in a rat dry eye model (e.g., Non-Patent Document 1).

[0003] On the other hand, Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in intracellular immune activation signal transduction, and drugs with Janus kinase inhibitory activity are expected to improve autoimmune diseases and allergic diseases by suppressing excessive activation of immune responses. Here, 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: delgocitinib) is known as one of the compounds that have an inhibitory effect on Janus kinase (for example, Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2017 / 006968 [Non-patent literature]

[0005] [Non-Patent Document 1] Diquas Ophthalmic Solution 3% Package Insert (Revised November 2017) Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a novel ophthalmic composition capable of promoting tear secretion. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems, and have unexpectedly found that 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile promotes tear secretion and improves corneal and conjunctival epithelial disorders. The present invention is based on this finding, and provides the following inventions.

[0008] [1] An ophthalmic composition for promoting tear secretion, comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof. [2] The ophthalmic composition described in [1], which is used to improve corneal and conjunctival epithelial disorders. [3] The ophthalmic composition described in [1], which is used to improve dry eye. [4] An ophthalmic composition for improving corneal and conjunctival epithelial disorders, comprising 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof. [5] The ophthalmic composition according to [2] or [4], wherein the corneal and conjunctival epithelial disorder is caused by dry eye. [6] The ophthalmic composition according to any one of [1] to [5], wherein the content of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof is 0.01% by mass to 1% by mass based on the total amount of the ophthalmic composition. [7] The ophthalmic composition according to any one of [1] to [6], which is an eye drop. [8] A method for promoting tear secretion, comprising administering to a subject 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof, or an ophthalmic composition containing either or both. [9] A method for improving corneal and conjunctival epithelial disorders, comprising administering to a subject 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof, or an ophthalmic composition containing either or both.

[10] The method according to [9], wherein the corneal and conjunctival epithelial disorder is caused by dry eye.

[11] Use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof for the manufacture of an ophthalmic composition for promoting tear secretion.

[12] Use of 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof for the manufacture of an ophthalmic composition for improving corneal and conjunctival epithelial disorders.

[13] The use described in

[12] , wherein the corneal and conjunctival epithelial disorder is caused by dry eye.

[14] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof for use in promoting tear secretion.

[15] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof for use in improving corneal and conjunctival epithelial disorders.

[16] The compound or salt thereof according to

[15] , wherein the corneal and conjunctival epithelial disorder is caused by dry eye. Effect of the Invention

[0009] According to the present invention, an ophthalmic composition capable of promoting tear secretion can be provided. [Brief description of the drawings]

[0010] [Figure 1] 1 is a graph showing the lacrimal secretion promoting effect by a single eye drop administration of delgocitinib to normal rabbits in Test Example 1. [Diagram 2] 1 is a graph showing the lacrimal secretion promoting effect by a single eye drop administration of delgocitinib in normal mice in Test Example 2. [Diagram 3] (A) is a graph showing the lacrimal secretion promoting effect by single instillation of delgocitinib in normal rats in Test Example 3. (B) is a graph showing the lacrimal secretion promoting effect by single instillation of delgocitinib in lacrimal gland-excised rats in Test Example 3. [Figure 4] 1 is a graph showing the tear volume increasing effect by repeated instillation of delgocitinib in lacrimal gland-excised rats in Test Example 4. [Diagram 5] 1 is a graph showing the effect of improving corneal and conjunctival epithelial damage by repeated instillation of delgocitinib in lacrimal gland-excised rats in Test Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Hereinafter, an embodiment of the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

[0012] The ophthalmic composition according to this embodiment contains 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof.

[0013] 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: delgocitinib) has the following formula: [ka] (Hereinafter, this compound is also referred to as "delgocitinib"). Delgocitinib or a salt thereof can be produced, for example, by the methods described in WO 2017 / 006968 and WO 2018 / 117151.

[0014] The salt of delgocitinib is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, etc.

[0015] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts, etc. Examples of salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.

[0016] Delgocitinib or a salt thereof has the effect of promoting the secretion of tears. Therefore, as one embodiment of the present invention, an ophthalmic composition for promoting tear secretion containing delgocitinib or a salt thereof is provided. In addition, promotion of tear secretion is considered to be a major factor in improving corneal and conjunctival epithelial disorders. Therefore, as one embodiment of the present invention, an ophthalmic composition for improving corneal and conjunctival epithelial disorders containing delgocitinib or a salt thereof is provided. It should be noted that there has been no report to date on the promotion of tear secretion by inhibition of Janus kinase.

[0017] The ophthalmic composition according to the present embodiment can be used for any of corneal and conjunctival epithelial disorders caused by endogenous diseases such as dry eye (xerophthalmia), Sjogren's syndrome, and Stevens-Johnson syndrome, or corneal and conjunctival epithelial disorders caused by exogenous diseases such as postoperative, drug-induced, traumatic, and contact lens wear. In particular, the ophthalmic composition according to the present embodiment contains delgocitinib or a salt thereof, which promotes tear secretion, and is therefore preferably used for improving corneal and conjunctival epithelial disorders caused by endogenous factors, and more preferably used for improving corneal and conjunctival epithelial disorders caused by dry eye. Dry eye causing corneal and conjunctival epithelial disorders may be dry eye caused by an autoimmune disease such as Sjogren's syndrome, or may be dry eye caused by factors other than autoimmune diseases.

[0018] In addition, the ophthalmic composition according to the present embodiment contains delgocitinib or a salt thereof, and therefore can be used to improve dry eye, which may be caused by an autoimmune disease such as Sjogren's syndrome, or may be caused by a factor other than an autoimmune disease.

[0019] The content of delgocitinib or a salt thereof in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set according to the type and content of other blended components, the formulation form, etc. As for the content of component (A), from the viewpoint of more significantly exhibiting the effects of the present invention, for example, based on the total amount of the ophthalmic composition according to this embodiment, the total content of delgocitinib or a salt thereof may be 0.001% by mass to 10% by mass, 0.001% by mass to 5% by mass, 0.003% by mass to 3% by mass, 0.005% by mass to 1% by mass, 0.01% by mass to 0.5% by mass, 0.015% by mass to 0.4% by mass, 0.02% by mass to 0.3% by mass, or 0.03% by mass to 0.3% by mass.

[0020] The ophthalmic composition of this embodiment may contain various additives in appropriate amounts, selected appropriately in accordance with the formulation form in a conventional manner, and one or more types may be used in combination, as long as the effects of the present invention are not impaired.

[0021] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical) or physiologically acceptable range.

[0022] The ophthalmic composition according to the present embodiment can be prepared, for example, by adding and mixing delgocitinib or a salt thereof, and other components as necessary, to a desired content. Specifically, for example, the above components are dissolved or suspended in purified water, and sterilized by filtration sterilization or the like.

[0023] The ophthalmic composition according to the present embodiment can be in various dosage forms depending on the purpose, for example, a liquid, a gel, a semi-solid (ointment, etc.), etc. Among these, a liquid is preferred, and an aqueous liquid is more preferred.

[0024] The ophthalmic composition according to this embodiment can be used, for example, as eye drops (also called eye drops or eye drops. Eye drops include artificial tears and eye drops that can be applied while wearing contact lenses).

[0025] When the ophthalmic composition according to this embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and cause few side effects.

[0026] As one embodiment of the present invention, a method for promoting tear secretion is provided by administering delgocitinib or a salt thereof, or an ophthalmic composition containing them to a subject. Also, as one embodiment of the present invention, a method for improving corneal and conjunctival epithelial disorders is provided by administering delgocitinib or a salt thereof, or an ophthalmic composition containing them to a subject.

[0027] As one embodiment of the present invention, there is provided a use of delgocitinib or a salt thereof for the manufacture of an ophthalmic composition for promoting tear secretion. Also, as one embodiment of the present invention, there is provided a use of delgocitinib or a salt thereof for the manufacture of an ophthalmic composition for improving corneal and conjunctival epithelial disorders.

[0028] As one embodiment of the present invention, delgocitinib or a salt thereof is provided for use in promoting tear secretion. Also, as one embodiment of the present invention, delgocitinib or a salt thereof is provided for use in improving corneal and conjunctival epithelial disorders. EXAMPLES

[0029] The present invention will be specifically described below based on test examples, but the present invention is not limited thereto. In the following test examples, unless otherwise specified, the unit of content "%" means "w / v%" and is synonymous with "g / 100 mL".

[0030] [Test Example 1: Lacrimal secretion promoting effect by single eye drop administration of delgocitinib in normal rabbits] The tear secretion-promoting effect of delgocitinib was evaluated in normal rabbits. Delgocitinib was dissolved and stirred in PBS (Kohjin Bio Co., Ltd.) to prepare a 0.05% delgocitinib solution. After placing a male Japanese white rabbit (Oriental Yeast Co., Ltd.) in a holding tube, PBS or 0.05% delgocitinib solution was instilled at a dose of 50 μL / eye. After 15 minutes, Schirmer's test paper was inserted into the conjunctival sac on the outer corner of the eye. After 1 minute, the test paper was removed and the length of the wet part of the test paper was measured, which was taken as the tear volume. The results are shown in Figure 1.

[0031] As shown in Figure 1, tear volume was significantly increased in the delgocitinib solution group compared to the PBS group (Student's t test).

[0032] [Test Example 2: Tear secretion promoting effect by single eye drop administration of delgocitinib in normal mice] The tear secretion-promoting effect of delgocitinib was evaluated using normal mice. Delgocitinib was dissolved and stirred in PBS (Kohjin Bio Co., Ltd.) to prepare delgocitinib solutions of various concentrations (0.0125%, 0.05% and 0.2%). Female C57BL / 6J mice (Japan SLC Co., Ltd.) were restrained, and PBS or delgocitinib solutions of various concentrations were instilled at a dose of 3 μL / eye. After 15 minutes, a phenol red thread (Zone Quick, Ayumi Pharmaceutical Co., Ltd.) was inserted into the conjunctival sac on the outer corner of the eye. After 15 seconds, the phenol red thread was removed, and the length of the wet part of the phenol red thread was measured, and this measurement was taken as the tear volume. The results are shown in Figure 2.

[0033] As shown in FIG. 2, tear volume increased in each delgocitinib solution group compared to the PBS group, and a significant increase was confirmed especially in the 0.05% and 0.2% groups (Dunnett's test).

[0034] [Test Example 3: Lacrimal secretion promoting effect by single ocular administration of delgocitinib in normal rats and rats with lacrimal gland removed] The tear secretion-promoting effect of delgocitinib was evaluated using normal rats and rats with lacrimal gland removed. As a test substance, a 0.05% delgocitinib solution (active ingredient delgocitinib, additives sodium chloride, potassium chloride, sodium hydroxide, boric acid and chlorhexidine gluconate were mixed in purified water and dissolved and stirred) was prepared. As a control substance, pilocarpine hydrochloride (Tokyo Chemical Industry Co., Ltd.) was dissolved and stirred in saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory, Inc.) to prepare a 3% pilocarpine solution. Normal male Sprague-Dawley (SD) rats (Japan SLC Co., Ltd.) and SD rats that had had their main and accessory lacrimal glands removed one week earlier were instilled with saline, 3% Diquas eye drops (Santen Pharmaceutical Co., Ltd.), 3% pilocarpine solution, or 0.05% delgocitinib solution at a dose of 5 μL / eye. After 10 minutes, anesthesia was induced using Somnopentyl (Kyoritsu Seiyaku Co., Ltd.), and after another 5 minutes, Schirmer's test paper was inserted into the conjunctival sac on the outer corner of the eye. After 1 minute, the test paper was removed and the length of the wetted part of the test paper was measured, and this measurement was taken as the tear volume. The results are shown in Figure 3.

[0035] As shown in Figure 3, in normal rats, tear volume was significantly increased in the 3% Diquas ophthalmic solution group, 3% pilocarpine solution group, and 0.05% delgocitinib solution group compared to the saline group (Mann-Whitney U test). On the other hand, in lacrimal gland-excised rats, tear volume was significantly increased only in the 3% Diquas ophthalmic solution group and 0.05% delgocitinib solution group compared to the saline group (Mann-Whitney U test).

[0036] [Test Example 4: Increase in tear volume by repeated instillation of delgocitinib in lacrimal gland-excised rats] The tear volume-increasing effect of delgocitinib was evaluated using lacrimal gland-excised rats, which are used as a dry eye model. Delgocitinib was dissolved and stirred in PBS (Kohjin Bio Co., Ltd.) to prepare delgocitinib solutions of various concentrations (0.0125%, 0.05%, and 0.2%). Normal male Sprague-Dawley (SD) rats (Japan SLC Co., Ltd.) and SD rats that had had their main lacrimal glands removed for one week were repeatedly instilled with PBS or delgocitinib solutions of various concentrations at a dose of 5 μL / eye four times a day. Four weeks after the start of instillation, PBS or delgocitinib solutions of various concentrations were instilled at a dose of 5 μL / eye, and 10 minutes later, anesthesia was induced using Somnopentyl (Kyoritsu Seiyaku Co., Ltd.), and 5 minutes later, Schirmer's test paper was inserted into the conjunctival sac on the outer corner of the eye. After 1 minute, the test paper was removed and the length of the wet part of the test paper was measured, and this measurement was taken as the tear volume. The results are shown in Figure 4.

[0037] As shown in Figure 4, tear volume was significantly increased in each delgocitinib solution group compared to the PBS group (Steel test).

[0038] [Test Example 5: Improvement of corneal and conjunctival epithelial damage by repeated instillation of delgocitinib in lacrimal gland-excised rats] The effect of delgocitinib in improving corneal epithelial damage was evaluated using lacrimal gland-excised rats, which are used as a dry eye model. Fluorescein sodium salt (Sigma-Aldrich Japan) was dissolved in Otsuka saline injection (Otsuka Pharmaceutical Factory, Inc.) to prepare a 10 mg / mL fluorescein staining solution. Delgocitinib was dissolved and stirred in PBS (Kohjin Bio Co., Ltd.) to prepare delgocitinib solutions of various concentrations (0.0125%, 0.05%, and 0.2%). PBS or delgocitinib solutions of various concentrations were instilled into the eyes of male SD rats (Japan SLC Co., Ltd.) one week after removal of the main lacrimal gland, four times a day at a dose of 5 μL / eye. Four weeks after the start of instillation, 10 mg / mL fluorescein staining solution was instilled at a dose of 1 μL / eye. After anesthesia was induced with isoflurane inhalation anesthetic solution (Pfizer Inc.), photographs were taken with a fluorescence microscope (Leica Microsystems). The cornea in the photograph was divided into four sections, and the staining score of each section was scored from 0 to 5 points, and the sum of the scores of the four sections was taken as the corneal epithelial damage score of that eye. The results are shown in Figure 5.

[0039] As shown in Figure 5, the corneal epithelial damage score was significantly reduced in the delgocitinib solution groups at each concentration compared to the PBS group (Steel test).

Claims

[Claim 1] The invention described in the specification.

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